Deprotection of silyl ethers using ZnBr2 and H2O in CH2Cl2

Article abstract of DOI:10.1016/S0040-4039(02)01680-5

TES- and TBS-protected alcohols undergo deprotection upon treatment with excess ZnBr₂ and water in CH₂Cl₂ at 44-50°C. TIPS-protected alcohols also undergo deprotection but at slower rates. TBDPS-protected alcohols and silyl-protected phenols are unreactive under these conditions, allowing for selective deprotection of differentially-protected bis-silyl ethers.

Full text of DOI:10.1016/S0040-4039(02)01680-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 7151–7153
Deprotection of silyl ethers using ZnBr and H O in CH Cl
2
2
2
2
R. David Crouch,* Joanna M. Polizzi, Rebecca A. Cleiman, Jihae Yi and Candice A. Romany
Department of Chemistry, Dickinson College, Box 1773, Carlisle, PA 17013, USA
Received 10 July 2002; revised 11 August 2002; accepted 12 August 2002
Abstract—TES- and TBS-protected alcohols undergo deprotection upon treatment with excess ZnBr and water in CH Cl at
2
2
2
4
4–50°C. TIPS-protected alcohols also undergo deprotection but at slower rates. TBDPS-protected alcohols and silyl-protected
phenols are unreactive under these conditions, allowing for selective deprotection of differentially-protected bis-silyl ethers.
2002 Elsevier Science Ltd. All rights reserved.
©
Protection/deprotection sequences continue to be cru-
most require the use of CH CN. We have developed a
3
14
cially important in natural product synthesis and in the
method that employs ZnBr2 and water in CH Cl to
2 2
1–3
preparation of other complex organic molecules. Silyl
protecting groups are of particular value when interme-
diate compounds contain hydroxyl groups and the
development of new methods for their attachment and
removal remains an active area of research. Although
protic acids and fluoride sources continue to be widely
used to deprotect silyl ethers, a number of Lewis acids
have been shown to be effective in promoting desilyla-
remove some silyl groups from protected primary and
secondary alcohols and wish to share our results.
A recent communication described the use of excess
ZnBr in CH Cl to deprotect t-butyl esters and t-butyl
2
2
2
15
ethers under especially mild conditions. Earlier work
in our laboratory showed that ZnCl /H O in CH Cl
effected the desilylation of TES-protected alcohols.
2
2
2
2
6
1
1
–3
tion of protected alcohols. Examples from the recent
Unfortunately, those results were unreliable. Based on
4
5
6
literature include: BF , BCl3, PdCl (CH CN) ,
Wu’s results, we thought ZnBr might be more depend-
3
9
2
3
2
2
7
8
BiBr , Sc(OTf) , InCl , cerium(III) chloride heptahy-
able than ZnCl in removing TES groups and set out to
3
3
3
11
2
1
0
12
drate/NaI,
Zn(BF4)2
and Ce(OTf)4.
Although
investigate the possible utility of this system. The results
of our preliminary studies are summarized in Table 1.
many of these reagents provide the added advantage of
1
3
promoting selective desilylation of bis-silyl ethers,
4,5
some have not been systematically studied. Others
Reactions were initially performed using 5.0 equiv. of
8,10,12
require the use of relatively expensive reagents
and
ZnBr and no water was added, in accord with Wu’s
2
a
Table 1. Deprotection of TES-protected 3-phenyl-1-propanol
Entry
ZnBr2 (equiv.)
H O (equiv.)
Solvent
CH Cl
Temperature (°C)
Reaction time (h)
Yield (%)
2
1
2
3
4
5
6
7
5.0
5.0
5.0
5.0
5.0
5.0
5.0
0
0
0
0
5.0
5.0
5.0
25
25
43
43
25
45–50
86
3
77
76
84
85
82
87
70
2
2
2
2
2
2
2
CH Cl
Overnight
3
6
3
3
2.5
2
CH Cl
2
CH Cl
2
CH Cl
2
CH Cl
2
ClCH CH Cl
2
2
a
Products were isolated via column chromatography and found to be spectrally identical to authentic 3-phenyl-1-propanol.
*
0
Corresponding author.
040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01680-5

7
152
R. D. Crouch et al. / Tetrahedron Letters 43 (2002) 7151–7153
1
4
work. In general, reactions in reagent grade CH Cl2
underwent deprotection but longer reaction times were
required than for less sterically hindered silyl groups.
Attempts to deprotect silyl-protected phenols failed
(Table 2). In every instance, silyl ether was the only
product recovered. This result was not entirely surpris-
ing given the relative resistance of silyl-protected phe-
2
produced desilylated product in a narrow range of
yields. Marginal improvement was observed when 5.0
equiv. of water was added and when the reaction was
heated. The use of reagent grade solvent without drying
and adding water has previously been advantageous in
12
17
silyl deprotection reactions. Decreasing the amount of
nols to mildly acidic hydrolysis.
ZnBr and/or water failed to improve product yield.
2
Similarly, attempts to use 1,2-dichloroethane as solvent
and allow an increase in the reaction temperature failed
to improve yields. The optimized conditions were 5.0
It is noteworthy that TBDPS-protected alcohols were
largely unreacted after 24 h, pointing to the potential
use of this method in selectively deprotecting bis-silyl
ethers. This possibility was tested using bis-silyl ethers 1
which were subjected to our reaction conditions and
equiv. of ZnBr and 5.0 equiv. of water in CH Cl at
2
2
2
45–50°C for 3 h.
9
produced selectively deprotected alcohols 2 in good
A typical procedure follows: To a stirring solution of 1
equiv. of silyl ether in reagent grade CH Cl (approxi-
yields. Selective desilylation of TES- or TBS-protected
alcohols in the presence of TIPS-protected alcohols is
less likely since a significant amount of the TIPS group
was removed in 3 h.
2
2
mately 4 mL of solvent/mmol of substrate) was added
.0 equiv. of anhydrous ZnBr followed by 5.0 equiv. of
5
2
water. A water condenser was affixed and the heteroge-
neous mixture then stirred at 45–50°C for 3 h when
TLC showed the reaction to be complete. The flask was
cooled to room temperature and CH Cl was added for
2
2
volume. The contents of the flask were transferred to a
separatory funnel, the flask being rinsed with additional
CH Cl . The organic layer was then washed twice with
2
2
water and twice with saturated aqueous NaHCO . The
3
organic layer was dried with MgSO , filtered and con-
centrated in vacuo. Purification of the crude product
mixture was achieved using column chromatography.
4
The stability of silyl-protected phenols to these condi-
tions prompted us to investigate whether or not our
method might also serve as a useful means for the
selective deprotection of alkyl silyl ethers in the pres-
16
To our surprise, other silyl protecting groups were
also removed under these reaction conditions. These
results are summarized in Table 2. TBS-protected pri-
mary alcohols as well as TES- and TBS-protected sec-
ondary alcohols underwent deprotection cleanly.
TIPS-protected primary and secondary alcohols also
8,9,13,17–25
ence of aryl silyl ethers.
were prepared and subjected to our deprotection proto-
col, yielding selectively deprotected alcohols 4. No
evidence of deprotection of the aryl silyl ether was
Thus, bis-silyl ethers 3
2
6
27,28
observed in either case.
a
Table 2. Deprotection of silyl ethers

R. D. Crouch et al. / Tetrahedron Letters 43 (2002) 7151–7153
7153
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tion Grant that provided student-faculty summer
research grants. Additional support from Dickinson
College through a sabbatical research grant and Dana
Internship is gratefully acknowledged.
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6. H NMR data for: (a) 3a (CDCl , 300 MHz) l 0.15 (s,
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