Selective deprotection of either alkyl or aryl silyl ethers from aryl, alkyl bis-silyl ethers

Article abstract of DOI:10.1016/S0040-4039(02)00942-5

A pair of complementary methods was developed using CeCl₃·7H₂O/CH₃CN and LiOH/DMF to selectively deprotect alkyl and aryl silyl ethers, respectively, from the corresponding bis-silyl ethers in excellent yields.

Full text of DOI:10.1016/S0040-4039(02)00942-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 4729–4732
Selective deprotection of either alkyl or aryl silyl ethers from
aryl, alkyl bis-silyl ethers
Sudha V. Ankala and Gabriel Fenteany*
Department of Chemistry, University of Illinois at Chicago, 845 West Taylor Street, Chicago, IL 60607-7061, USA
Received 25 April 2002; revised 14 May 2002; accepted 15 May 2002
Abstract—A pair of complementary methods was developed using CeCl3·7H2O/CH3CN and LiOH/DMF to selectively deprotect
alkyl and aryl silyl ethers, respectively, from the corresponding bis-silyl ethers in excellent yields. © 2002 Elsevier Science Ltd. All
rights reserved.
The derivitization of alcohols as their tert-
butyldimethylsilyl (TBS) ethers has been recognized as
one of the most useful protection methods since its
introduction by Corey and Venkateswarlu in 1972
because of its easy installation and general stability to
basic and mildly acidic conditions.1 Although a large
number of deprotection methods are available for dis-
criminating between different trialkylsilyl groups,2,3 rel-
atively few methods have been developed for the
selective removal of alkyl TBS ethers in the presence of
aryl TBS ethers4 and vice versa.5 Considering that both
alcoholic and phenolic hydroxyl groups are present in
many complex natural products such as vancomycin,6
teicoplanin,7 pancreastatin8 and naturally occurring
amino acids,9 the differential deprotection of alcoholic
and phenolic silyl ethers is of considerable interest.
oratory equipment, others are limited in their use by the
nature of the substituents present on the aromatic ring.
In this context, we have developed an efficient method-
ology wherein alkyl silyl ethers are selectively depro-
tected in the presence of aryl silyl ethers by using
CeCl3·7H2O, which is an inexpensive, non-toxic, and
mild Lewis acid.10 Conversely, we have also developed
an alternative methodology for the selective deprotec-
tion of aryl silyl ethers in the presence of alkyl silyl
ethers using LiOH/DMF under mild conditions.
Investigation of reaction conditions for the selective
cleavage of alkyl silyl ethers using CeCl3·7H2O indi-
cated that 2.0 equiv. of cerium chloride in refluxing
acetonitrile (0.03 M)11 was optimal for the desired
deprotection, and the results are summarized in Table
1.† Efforts to make the reaction sub-stoichiometric in
cerium chloride resulted in retardation of progress of
the reaction. Substitution patterns and electronic prop-
erties of the aromatic ring have an effect on the rate of
selective deprotection of alkyl silyl ethers from bis-TBS
ethers (Table 1). We observed that the rate of deprotec-
tion of alkyl silyl ethers was accelerated if an electron-
donating group is present on the aromatic ring (entry 4,
Table 1). On the other hand, the presence of an elec-
tron-withdrawing group on the aromatic ring deceler-
ated the desired transformation (entries 5 and 6, Table
1). In addition, deprotection of the alkyl TBS group
from sterically hindered salicyl alcohol-derived bis-TBS
Available methods for the selective cleavage of alkyl
silyl ethers in the presence of aryl silyl ethers include the
use of BiBr3/wet CH3CN,4a TMSCl/H2O/CH3CN,4b I2/
MeOH4c and 40% aqueous HF/CH3CN.4d While each
of the above methods has merit, these deprotection
methods involve protic acids, which limits their use in
systems containing labile moieties. Similarly, selective
deprotection of phenolic TBS ethers has been achieved
by various research groups using KF/alumina,5a
NaOH/n-Bu4NHSO4,5b K2CO3/ethanol,5c K2CO3/kryp-
tofix/CH3CN,5d KF/alumina/ultrasound5e and TBAF/
THF.4d While some of these methods require high
temperatures, expensive reagents and non-standard lab-
Keywords: aryl, alkyl bis-silyl ethers; selective deprotection; alkanols;
phenols; tyrosine.
* Corresponding author. Tel.: 312-996-8542; fax: 312-996-0431;
e-mail: fenteany@uic.edu
† Addition of 1.0 equiv. of sodium iodide increased the solubility of
cerium salt in acetonitrile, but led to considerable amount of iodide
byproducts in the case of aromatic ring substituted with electron-
donating group. See also Table 1.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00942-5

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Table 1. Selective deprotections of aryl, alkyl bis-silyl ethers
ether (entry 3, Table 1) took longer than what is
required for its meta and para counterparts.
ethers, since we required this selectivity in the synthesis
of bioactive small molecules in our laboratory. To the
best of our knowledge, systematic studies of selective
deprotection of aryl silyl ethers in the presence of alkyl
silyl ethers have been reported only with TBAF/THF,4d
Concurrently, we sought a complementary method to
deprotect aryl TBS ethers in the presence of alkyl TBS

S. V. Ankala, G. Fenteany / Tetrahedron Letters 43 (2002) 4729–4732
4731
NaOH/n-Bu4NHSO4/1,4-dioxane5b and K2CO3/kryp-
tofix/CH3CN.5d Although TBAF is widely used for
deprotection of silyl ethers, its use in this particular
transformation requires careful control of reaction con-
ditions. In the case of K2CO3/kryptofix/CH3CN, 0.5
equiv. of kryptofix is needed for each equiv. of sub-
strate, thus limiting its utility in large scale synthesis.
Crouch et al. reported achieving selective deprotection
of aryl silyl ethers in the presence of alkyl silyl ethers
using 10 equiv. of NaOH and a phase transfer catalyst,
n-Bu4NHSO4. Furthermore, a study of the stability of
alkyl and aryl silyl ethers under acidic and basic condi-
tions by Davies et al. revealed that while acidic condi-
tions facilitate cleavage of alkyl silyl ethers, basic
conditions favor cleavage of aryl silyl ethers.12 In view
of these facts, we examined the ability of LiOH to act
as a base to perform the required selective deprotection
in DMF. We reasoned that DMF, being a polar aprotic
solvent, would generate an unencumbered hydroxide
ion, thus obviating the need to use a large excess of
base.
that this methodology is quite general and can be
readily applied to the synthesis of complex molecules.
General experimental procedure:
Method I: CeCl3·7H2O (0.5 mmol) was added to a
solution of bis-TBS ether (0.25 mmol) in acetonitrile
(7.5 mL) and the reaction mixture was refluxed until
completion of the reaction as indicated by thin-layer
chromatography (TLC). Then the reaction mixture was
cooled and partitioned between water and ethyl acetate.
The organic layer was washed with brine, dried
(Na2SO4) and evaporated under reduced pressure. The
residue was purified by flash chromatography over sil-
ica gel using ethyl acetate/hexane as eluent.
Method II: LiOH (0.75 mmol) was added to a stirred
solution of bis-TBS ether (0.25 mmol) in DMF (0.3
mL) and the reaction mixture was then stirred at room
temperature until completion, as indicated by TLC.
The reaction mixture was then diluted with ethyl ace-
tate, washed with water and brine, dried (Na2SO4) and
concentrated under reduced pressure. The phenol so
obtained was purified by flash chromatography over a
silica gel column using ethyl acetate/hexane as eluent.
The bis-TBS ether 1a was deprotected smoothly to
phenol 1c in 3 h using 3.0 equiv. of LiOH in DMF at
room temperature. Indeed, we found that complete
desilylation can be achieved with catalytic amounts of
LiOH (0.5 equiv.), but the reaction time increased
considerably. We also observed that deprotection of
phenolic TBS ethers is faster when electron-withdraw-
ing groups are present at the para position (entries 5
and 6, Table 1). In order to examine the stability of the
ester group functionality under the reaction conditions
required for phenolic TBS–ether deprotection, com-
pounds 9 and 10 were deprotected separately under the
optimized conditions. It was found that 9 afforded 11
in 86% yield, while 10 furnished 12 in 78% yield,
indicating that an ester group is well tolerated on both
the aromatic ring and the side chain.
Supplementary material
Spectral data for bis-TBS ether 6a: IR (film): 2989,
1
2930, 1341, 1110, 843, 777 cm−1. H NMR (400 MHz,
CDCl3): l 8.37(d, 1H, J=2.9 Hz), 8.03 (dd, 1H, J=8.8,
2.9 Hz), 6.79 (d, 1H, J=8.8 Hz), 4.74 (s, 2H), 1.01 (s,
9H), 0.96 (s, 9H), 0.28 (s, 6H), 0.13 (s, 6H). 13C NMR
(100 MHz, CDCl3): l 157.51, 141.99, 133.64, 123.51,
122.95, 117.32, 59.93, 25.82, 25.43, 18.32, 18.12.
HRMS: Calcd for C19H36NO4Si2 (M+H)+: 398.2183.
Found: 398.2187.
Spectral data for alkanol 6b: IR (film): 3282, 2929,
2858, 1512, 1255, 785 cm−1. 1H NMR (400 MHz,
CDCl3): l 8.30 (d, 1H, J=2.9 Hz), 8.07 (dd, 1H,
J=8.9, 2.9 Hz), 6.83 (d, 1H, J=8.9 Hz), 4.73 (s, 2H),
2.09 (br s, 1H), 1.01 (s, 9H), 0.30 (s, 6H). 13C NMR
(100 MHz, CDCl3): l 158.61, 141.71, 132.70, 124.37,
123.89, 117.74, 60.40, 25.47, 18.14. HRMS: calcd for
C13H22NO4Si (M+H)+: 284.4036. Found: 284.4039.
In summary, we describe a mild and efficient method
for the selective cleavage of alkyl silyl ethers from
systems containing both alkyl and aryl silyl ethers using
CeCl3·7H2O in acetonitrile. We report also that silyl-
protected phenols can be selectively deprotected in the
presence of silyl-protected alcohols using LiOH/DMF
under operationally simple conditions and mild temper-
atures. Furthermore, the above methods successfully
enable the selective deprotection of alkyl and aryl silyl
ethers from tyrosine derived bis-silyl ether, which shows
Spectral data for phenol 6c: IR (film): 3302, 2929, 1523,
1
1339, 1279, 833 cm−1. H NMR (400 MHz, CDCl3): l
9.08 (s, 1H), 8.10 (dd, 1H, J=8.9, 2.8 Hz), 7.91 (d, 1H,
J=2.8 Hz), 6.92 (d, 1H, J=8.9 Hz), 4.97 (s, 2H), 0.94
(s, 9H), 0.18 (s, 6H). 13C NMR (100 MHz, CDCl3): l
167.39, 140.47, 125.16, 123.99, 122.72, 117.07, 65.28,
25.51, 17.97. HRMS: Calcd for C13H22NO4Si (M+H)+:
284.4036. Found: 284.4031.
Spectral data for bis-TBS ether 8a: [h]2D5=−12.9 (c 1.27,
CHCl31). IR (film): 2929, 2359, 1708, 1508, 1256, 837
cm−1. H NMR (400 MHz, CDCl3): l 7.39–7.31 (m,
5H), 7.05 (d, 2H, J=8.1 Hz), 6.76 (d, 2H, J=8.1 Hz),
5.09 (s, 2H), 4.95 (br d, 1H), 3.91–3.82 (m, 1H), 3.52 (d,
2H, J=3.5 Hz), 2.79 (d, 2H, J=7.0 Hz), 0.99 (s, 9H),
0.92 (s, 9H), 0.19 (s, 6H), 0.04 (s, 6H). 13C NMR (100

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S. V. Ankala, G. Fenteany / Tetrahedron Letters 43 (2002) 4729–4732
References
MHz, CDCl3):
l 155.74, 154.04, 136.54, 132.55,
130.62, 130.21, 128.41, 127.95, 119.89, 66.46, 62.67,
53.51, 36.36, 25.79, 25.58, 18.14. HRMS: calcd for
C29H48NO4Si2 (M+H)+: 530.3122. Found: 530.3119.
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Spectral data for alkanol 8b: [h]2D5=−9.4 (c 1.0,
CHCl3). IR (film): 3321, 2928, 2359, 1696, 1509, 1255,
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839 cm−1. H NMR (400 MHz, CDCl3): l 7.37–7.30
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This work was supported by the University of Illinois
at Chicago (UIC), the UIC Campus Research Board
and the National Cancer Institute, NIH (CA095177
to G.F.).