A mild, efficient and selective deprotection of t-butyldimethylsilyl-protected phenols using cesium carbonate

Article abstract of DOI:10.1016/S0040-4039(03)00736-6

A mild and efficient method for the deprotection of aryl t-butyldimethysilyl (TBS) ethers is described. The protecting group TBS could be cleaved from aryl silyl ethers using cesium carbonate in DMF-H₂O at room temperature to give the corresponding phenols in excellent yields. The reaction conditions allowed selective deprotection of aryl TBS-protected phenols in the presence of TBS, phenyloxycarbonyl or tetrahydropyranyl-protected alcohols.

Full text of DOI:10.1016/S0040-4039(03)00736-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 3859–3861
A mild, efficient and selective deprotection of
t-butyldimethylsilyl-protected phenols using cesium carbonate
Zhi-Yong Jiang and Yan-Guang Wang*
Department of Chemistry, Zhejiang University, Hangzhou 310027, PR China
Received 20 December 2002; revised 24 February 2003; accepted 6 March 2003
Abstract—A mild and efficient method for the deprotection of aryl t-butyldimethysilyl (TBS) ethers is described. The protecting
group TBS could be cleaved from aryl silyl ethers using cesium carbonate in DMF–H O at room temperature to give the
2
corresponding phenols in excellent yields. The reaction conditions allowed selective deprotection of aryl TBS-protected phenols in
the presence of TBS, phenyloxycarbonyl or tetrahydropyranyl-protected alcohols. © 2003 Elsevier Science Ltd. All rights
reserved.
As synthetic targets have become increasingly complex,
protection/deprotection protocols using silyl groups
have been the most popular methods due to their easy
formation and removal, and their stability to a wide
Cs CO on aryl silyl ethers. We then found that p-
2 3
methylphenylsilyl ether could be cleaved using 0.5
equiv. Cs CO in DMF–H O (10:1, v/v) at room tem-
2
3
2
perature to give p-methylphenol (Scheme 1). We also
1
range of reagent and reaction conditions. Among silyl
tested other solvents such as THF–H O, dichloro-
2
ethers, those carrying the t-butyldimethylsilyl (TBS)
groups are the most popular for the latter’s easy instal-
lation and stability. The deprotection of TBS is usually
carried out with tetrabutylammonium fluoride
methane–H O, acetonitrile–H O, dioxane–H O, water,
2
2
2
and ethanol–H O. As shown in Table 1, the results
2
indicate that wet DMF is the most suitable solvent.
1
2
3
(
TBAF), aqueous acid and aqueous HF–CH CN.
We examined a variety of substrates including aryl TBS
3
15
Although a large number of deprotection methods are
available for discrimination between different trialkylsil-
ethers and alkyl TBS ethers. As shown in Table 2, all
aryl TBS ethers could be cleaved smoothly using 0.1–
0.5 equiv. Cs CO in wet DMF at room temperature
4
–12
yl groups,
relatively few methods have been devel-
2
3
oped for the selective removal of aryl TBS ethers in the
(Table 2, entries 1–11), while alkyl (Table 2, entries
14–17), benzyl and allyl TBS ethers gave very poor
deprotected products or did not react under the same
conditions. However, benzyl and allyl TBS ethers could
be cleaved at 100°C to afford the corresponding alco-
hols in high yields (Table 2, entries 12 and 13). We
observed that the deprotection of aryl TBS ethers was
facilitated if an electron-withdrawing group was present
on the aromatic ring (Table 2, entries 1–4). On the
other hand, the presence of an electron-donating group
on the aromatic ring impeded the desired transforma-
tion (Table 2, entries 10–11).
9,13
presence of alkyl TBS ethers.
Considering that both
alcoholic and phenolic hydroxyl groups are present in
many complex natural products such as vancomycin
and teicoplanian, the differential deprotection of alco-
holic and phenolic silyl ethers is of considerable inter-
1
3
est. In this context, we have developed a mild and
efficient methodology wherein aryl TBS ethers are
selectively deprotected in the presence of alkyl TBS
ethers by using cesium carbonate (Cs CO ), which is a
2
3
non-toxic and mild base.
Initially, we found that aryl trimethylsilyl (TMS) ethers
and aryl TBS ethers could couple with aryl halides to
give the corresponding biaryl ethers in excellent yields
by using cesium carbonate in DMF. This result
prompted us to investigate the deprotecting effects of
In order to establish the chemoselectivity of this
method, the aryl silyl ethers containing other sensitive
14
groups were allowed to cleave in DMF–H O (10:1, v/v)
2
*
Corresponding author. Tel.: +86-571-87951512; fax: +86-571-
7951512; e-mail: orgwyg@css.zju.edu.cn
8
Scheme 1.
0
040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00736-6

3
860
Z.-Y. Jiang, Y.-G. Wang / Tetrahedron Letters 44 (2003) 3859–3861
Table 1. Deprotection of TBS ethers in various solvents
Entry
Equiv. of Cs CO
Solvent
T (°C)
Reaction time (h)
Yield (%)
2
3
1
2
3
4
5
6
7
0.5
1.0
1.0
0.5
1.0
1.0
0.5
DMF–H O (10:1, v/v)
rt
2.5
24
24
24
24
24
24
97a
2
THF–H O (50:1, v/v)
rt/reflux
rt/reflux
rt/reflux
rt/reflux
rt/reflux
rt/reflux
No reaction
No reaction
Trace/61a
No reaction
No reaction
Trace
2
b
DCM–H O
2
CH CN–H O (10:1, v/v)
3
2
Dioxane–H O (10:1, v/v)
2
H O
2
EtOH–H O (10:1, v/v)
2
a
Isolated yield (average of two runs).
H O-saturated dichloromethane.
2
b
Table 2. Deprotection of aryl and alkyl TBS ethers to phenols and alcohols using Cs CO in DMF–H O (10:1, v/v)
2
3
2
Entry
Silyl ethers
Equiv. of Cs CO
T (°C)
Reaction time (h)
Yield (%)a
2
3
1
2
3
4
5
6
7
8
9
4-NO C H OTBS
0.1
0.1
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
1.0
1.0
1.0
1.0
1.0
1.0
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
100
100
100
100
100
100
0.5
1.0
1.0
2.5
2.5
2.5
2.5
3.0
3.0
3.0
3.0
1.0
3.0
12
99
99
99
95
98
97
96
95
92
88
88
95
89
37
23
2
6
4
4-ClC H OTBS
6
4
4-CHOC H OTBS
6
4
2-CHOC H OTBS
6
4
C H OTBS
6
5
4-MeC H OTBS
6
4
4-t-BuC H OTBS
6
4
2-MeC H OTBS
6
4
3-MeC H OTBS
6
4
10
11
12
13
14
15
16
17
3-NH C H OTBS
2
6
4
4-MeOC H OTBS
6
4
C H CH OTBS
6
5
2
C H CHꢀCHCH OTBS
6
5
2
ClCH CH OTBS
2
2
n-C H17OTBS
24
48
48
8
b
i-C H17OTBS
8
8
Cyclo-C H11OTBS
No reaction
6
a
Isolated yield (average of two runs).
Yield based on GC analysis.
b
in the presence of 0.5 equiv. of cesium carbonate at
be achieved with 1.0 equiv. of cesium carbonate at
100°C (Scheme 2).
1
5
room temperature. Our results are summarized in
Table 3. The aryl silyl ethers could be deprotected
cleanly to give the corresponding phenols in very high
yields, while TBS-protected alcohols (Table 3, entries 1
and 10), carboxylic esters (Table 3, entries 2–4, 7 and
7
It has been reported that K CO /EtOH and LiOH/
2
3
13
DMF could cleave aryl silyl ethers easily. Further-
9
), and a representative example each of a tetra-
hydropyranyl (THP)-protected alcohol (Table 3, entry
), sulfonate (Table 3, entry 6) as well as phenyloxycar-
Table 3. Selective deprotection of aryl TBS ethers
5
bonyl-protected alcohol (Table 3, entry 8) were
unscathed under these conditions.
It is important to seek a method to deprotect aryl TBS
ethers in the presence of alkyl TBS ethers, since this
selectivity is often required in the synthesis of complex
molecules in many laboratories. Although TBAF is
widely used for deprotection of silyl ethers, its use in
this particular transformation requires carefully con-
trolled reaction conditions. Recently, Ankala and co-
workers reported a selective deprotection of aryl TBS
ethers in the presence of alkyl TBS ethers, but an excess
of base (i.e. 3.0 equiv. of LiOH in DMF) must be used.
In our case, the bis-TBS ethers 1 and 4 were depro-
tected selectively to the corresponding phenols 2 and 5
using 0.5 equiv. of cesium carbonate at room tempera-
ture. Indeed, we found that complete desilylation can
R1
R2
Entry
Reaction
time (h)
Yield
(%)a
1
2
3
4
5
6
7
8
9
CH OTBS
CH CO CH
CO
COOC H
CH OTHP
CH OTs
CH O CPh
CH OCO CH Ph
H
H
H
H
H
H
H
H
2.5
2.5
1.0
1.0
2.5
2.5
2.0
2.0
2.0
3.0
98
96
96
95
90
93
91
91
92
95
2
2
2
3
CH
2
3
2
5
1
3
2
2
2
2
2
2
2
CHꢀCHCOOCH3
CHꢀCHCH OTBS
OMe
OMe
1
0
2
a
Isolated yield (average of two runs).

Z.-Y. Jiang, Y.-G. Wang / Tetrahedron Letters 44 (2003) 3859–3861
3861
Scheme 2.
more, a study of the stability of alkyl and aryl silyl
ethers under acidic and basic conditions by Davies et
al. revealed that while acidic conditions facilitate cleav-
age of alkyl silyl ethers, basic conditions favor cleavage
1978, 56, 2725–2730; (c) Collington, E. W.; Finch, H.;
Smith, I. J. Tetrahedron Lett. 1985, 26, 681–684.
3. Newton, R. F.; Reynold, D. P.; Finch, N. A. W.; Kelly,
D. R.; Robert, S. M. Tetrahedron Lett. 1979, 20, 3981–
3982.
1
6
of aryl silyl ethers. Our investigation has shown that
Cs CO can serve as an appropriate base to perform the
2
3
4. Schmittling, E. A.; Sawyer, J. S. Tetrahedron Lett. 1991,
32, 7207–7210.
required selective deprotection.
5
. Wilson, N. S.; Keay, B. A. Tetrahedron Lett. 1996, 37,
53–156.
. Vaino, A. R.; Szarek, W. A. Chem. Commun. 1996,
351–2352.
7. Wilson, N. S.; Keay, B. A. Tetrahedron Lett. 1997, 38,
87–190.
In summary, we have developed a mild and efficient
method for the deprotection of aryl TBS ethers. The
protecting group TBS could be cleaved from aryl TBS
1
6
2
ethers using cesium carbonate in DMF–H O at room
2
temperature to give the corresponding phenols in high
yields. The reaction conditions allow selective deprotec-
tion of aryl TBS-protected phenols in the presence of
TBS, phenyloxycarbonyl or tetrahydropyranyl-pro-
tected alcohols. This method can be used for a wide
range of substrates.
1
8. Bartoli, G.; Bosco, M.; Marcantoni, E.; Sambri, L.;
Torregiani, E. Synlett 1998, 209–211.
9. Crouch, R. D.; Stieff, M.; Frie, J. L.; Cadwallader, A. B.;
Bevis, D. C. Tetrahedron Lett. 1999, 40, 3133–3136.
1
0. Matsuo, I.; Wada, M.; Ito, Y. Tetrahedron Lett. 2002, 43,
273–3275.
3
1
1. Bartoli, G.; Cupone, G.; Dalpozzo, R.; Nino, A. D.;
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Acknowledgements
1
1
1
1
2. Wang, M.; Li, C.; Yin, D.; Liang, X. T. Tetrahedron Lett.
This work was financially supported by the National
Natural Science Foundation of China (No. 20272051)
as well as the Teaching and Research Award Program
for Outstanding Young Teachers in Higher Education
Institutions of MOE, P.R.C. We also thank Dr. Ma
Chen and Mr. Li Jubiao and Mr. Zhao Jiankui for
their assistance in this work.
2
002, 43, 8727–8729.
3. Ankala, A. V.; Fenteany, G. Tetrahedron Lett. 2002, 43,
729–4732.
4
4. Zhao, J. K.; Wang, Y. G. Chinese Chem. Lett. 2003, in
press.
5. General procedure for deprotection of t-butyldimethylsilyl
ethers: A mixture of t-butyldimethylsilyl ether (1 mmol),
Cs CO (0.5 mmol) in DMF–H O (10:1, v/v, 1.1 mL) was
2
3
2
stirred at room temperature until the reaction was
finished as indicated by thin-layer chromatography
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