A mild and chemoselective method for the deprotection of tert-butyldimethylsilyl (TBDMS) ethers using iron(III) tosylate as a catalyst

Article abstract of DOI:10.1016/j.tetlet.2009.12.076

The most common method for the deprotection of TBDMS ethers utilizes stoichiometric amounts of tetrabutylammonium fluoride, n-Bu₄N⁺F^- (TBAF), which is highly corrosive and toxic. We have developed a mild and chemoselective method for the deprotection of TBDMS, TES, and TIPS ethers using iron(III) tosylate as a catalyst. Phenolic TBDMS ethers, TBDPS ethers and the BOC group are not affected under these conditions. Iron(III) tosylate is an inexpensive, commercially available, and non-corrosive reagent.

Full text of DOI:10.1016/j.tetlet.2009.12.076

Tetrahedron Letters 51 (2010) 1056–1058
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A mild and chemoselective method for the deprotection of
tert-butyldimethylsilyl (TBDMS) ethers using iron(III) tosylate as a catalyst
*
Jason M. Bothwell, Veronica V. Angeles, James P. Carolan, Margaret E. Olson, Ram S. Mohan
Laboratory for Environmentally Friendly Organic Synthesis, Department of Chemistry, Bloomington, IL 61701, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
The most common method for the deprotection of TBDMS ethers utilizes stoichiometric amounts of tet-
rabutylammonium fluoride, n-Bu4N+FÀ (TBAF), which is highly corrosive and toxic. We have developed a
mild and chemoselective method for the deprotection of TBDMS, TES, and TIPS ethers using iron(III) tos-
ylate as a catalyst. Phenolic TBDMS ethers, TBDPS ethers and the BOC group are not affected under these
conditions. Iron(III) tosylate is an inexpensive, commercially available, and non-corrosive reagent.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 24 November 2009
Revised 14 December 2009
Accepted 14 December 2009
Available online 21 December 2009
The tert-butyldimethylsilyl (TBDMS) protecting group, intro-
duced by Corey and coworkers,1 is one of the most common silyl-
protecting groups for alcohols and phenols. The TBDMS group owes
its popularity to several facts such as ease of introduction, stabilityto
a variety of reagents, and ease of selective deprotection. The most
common methods for the deprotection of the TBDMS group utilize
reagents containing fluoride ion with n-Bu4N+FÀ often being the re-
agent of choice.1 However, n-Bu4N+FÀ is very basic, a property that
can lead to side reactions with base-sensitive substrates.2 In addi-
tion, n-Bu4N+FÀ is extremely corrosive to the mucosa and the upper
respiratorytract3, a problemcompoundedbythefactthatn-Bu4N+FÀ
is required in stoichiometric amounts. Several alternative methods
have also been developed for the deprotection of TBDMS ethers.
These include Selectfluor (10.0 mol %),4 LiOAc (20.0 mol %),5 pyridi-
nium tribromide (PyÁBr3) (5.0–100.0 mol %),6 ZrCl4 (20.0 mol %),7
in developing environmentally friendly synthetic methodology
prompted us to investigate a mild and highly catalytic method for
the deprotection of TBDMS ethers utilizing inexpensive commer-
cially available reagents. Herein, we wish to report that iron(III) tos-
ylate28 is an efficient, inexpensive, easy to handle available catalyst
for the deprotection of TBDMS, TES, and TIPS ethers. Iron(III) tosylate
is commercially available as the hexahydrate and was used as such.
The experimental procedure is very simple and consists of stirring
thesilyl etherinmethanolas thecatalystis added. Theproductisiso-
lated by the removal of methanol and filtration of the residue
through a short silica column, thus avoiding an aqueous waste
stream. Products can also be isolated using an aqueous work up fol-
lowed by purification through silica gel chromatography.
The results of this study are summarized in Table 1. The best re-
sults were obtained with a catalyst loading of 2.0 mol % in metha-
nol as the solvent at room temperature. As can be seen from Table
1, a wide range of silyl ethers underwent smooth deprotection to
yield the corresponding alcohol. Although deprotection was
observed in ethanol as well as in THF/H2O (80/20, v/v), the reac-
tions in these solvents were somewhat sluggish and often did
not go to completion. While detailed mechanistic studies were
not carried out, a few points merit comment. In the synthesis of
the lactone fragment of lankacidin antibiotics, the use of p-TsOH
(10.0 mol %) has been reported for the deprotection of a TBDMS
tris(4-bromophenyl)aminium
hexachloroantimonate
(TBPA+
ÁSbCl6À) (5.0–10.0 mol %),8 sulfated SnO2 (1.0% by weight),9 silica
supported NaHSO4,10 TiCl4–Lewis base complexes (1.2 equiv),11 sul-
fonic acid-functionalized nanoporous silica,12 phosphomolybdic
acid,13 NiCl2 in 1,2-ethanediol (20.0 mol %),14 N-iodosuccinimide
(5.0 mol %),15 BiOClO4 (50.0–200.0 mol %),16 SbCl5 (10.0 mol %),17
ZnBr2 (5.0 equiv),18 Ce(OTf)4 (10.0 mol %),19 ceric ammonium ni-
trate
(10.0 mol %),20
tetrabutylammonium
tribromide
(10.0 mol %),21 TMSOTf (2.0 equiv),22 Zn(BF4)2 (4.0 equiv),23 and
DMSO–H2O (excess DMSO).24 Methods for the deprotection of
TBDMS ethers under acidic conditions have also been developed.
These include aqueous HF,25 CF3COOH/H2O (9:1),26 and CH3COOH
in aqueousTHF (13:7:3).27 As can be seen from these examples, most
of these reagents are not highly catalytic. Many of these reagents are
quite corrosive (N-iodosuccinimide, ZrCl4, ZnBr2, and SbCl5) and dif-
ficult to handle, while some must be synthesized in lab (sulfated
SnO2, phosphomolybidic acid on silica gel). Our continued interest
ether.29
A solution of iron(III) tosylate in CH3OH is acidic
(pH ꢀ 3) and hence not surprisingly, we were successfully able to
cleave the TBDMS ether of phenethyl alcohol using 6.0 mol %
p-TsOH. The same deprotection was unsuccessful when carried
out using 2.0 mol % Fe(OTs)3 and a proton scavenger, proton
spongeÒ
(7.0 mol %),
[1,8-(dimethylamino)naphthalene].30
Although these observations suggest that the true catalyst is p-
TsOH, the use of Fe(OTs)3 is preferable to p-TsOH because the latter
compound is much more toxic and its handling poses a greater
health hazard.31 The use of protic acids such as HCl or H2SO4 is less
desirable due to their corrosive nature. In addition, it is much more
* Corresponding author. Tel.: +1 309 556 3829; fax: +1 309 556 3864.
E-mail address: rmohan@iwu.edu (R.S. Mohan).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.12.076

J. M. Bothwell et al. / Tetrahedron Letters 51 (2010) 1056–1058
1057
Table 1
Deprotection of TBDMS Ethers using Fe(OTs)3Á6H2O as a catalyst
Fe(OTs)3.6H2O (2.0 mol%)
CH3OH, rt
ROSitBuMe2
ROH
Entry
Substratea
Product
Tb
Yieldc (%)
OSitBuMe2
OH
Ph
p-NO2C6H4CH2OH
1
2
3
1 h 45 min
4 h 30 min
1 h 45 min
77
77
79
Ph
p-NO2C6H4CH2OSitBuMe2
OSitBuMe2
OH
OSitBuMe2
OH
4
2 h 15 min
86
OSitBuMe2
OSitBuMe2
Ph
OH
5
6
2 h 50 min
1 h
82
82
Ph
OH
OSitBuMe2
OSitBuMe2
OH
7
8
2 h 30 min
3 h
81
73
OH
OSitBuMe2
OH
9
5 h
72
84
Ph
Ph
OSitBuMe2
O
OH
10d
27 h 35 min
O
O
O
OSitBuMe2
Boc
OH
Boc
11
2 h
79
N
N
H
H
OSitBuMe2
OH
OSitBuMe2
OH
12
2 h
91
84
OSitBuMe2
t
OSiMe2 Bu
13d
26 h
tBuMe2SiO
HO
HO
t
14
Me2 BuSiO
OSitBuPh2
OSitBuPh2
1 h 40 min
2 h 50 min
80
72
OSiiPr3
OH
15d
Ph
Ph
Ph
16
2 h 15 min
67
OH
OSiEt3
OSiEt3
OH
17
18e
20 min
80
86
Ph
p-Me2tBuSiOC6H4CH(OMe)2
p-Me2tBuSiOC6H4CHO
2 h 15 min
a
b
c
All silyl ethers were prepared from the corresponding alcohol or phenol using the literature methods.1b,35
Reaction progress was followed by gas chromatography or TLC, and reactions were worked up when <1% starting material remained.
Refers to the yield of isolated and purified product. All products are commercially available compounds and were characterized by 1H & 13C NMR, and GC analysis.
Reaction was heated at reflux.
d
e
The starting material was synthesized by the protection of p-hydroxybenzaldehyde as the TBDMS ether followed by acetalization following a literature procedure.36
difficult to control the pH of the solution with small amounts of
protic acid.
considerable attention in the literature.32 Under our reaction con-
ditions, at room temperature a phenolic TBDMS ether was unaf-
fected while an alkyl TBDMS group was cleaved (entry 12). Both
phenolic and alkyl TBDMS groups were cleaved under reflux condi-
tions (entry 13). The selective cleavage of a 2° TBDMS ether in the
presence of a 1° TBDPS (tert-butyldiphenylsilyl) ether using pyrid-
inium p-toluenesulfonate (30.0 mol %) in ethanol has been
described in the literature.33 A mixture of water and lithium chlo-
ride (50 equiv) in DMF at 90 °C (an environmentally unfriendly sol-
vent) has also been used to cleave a TBDMS group in the presence
of a TBDPS group.34 Under our reaction conditions, we were able to
The selective deprotection of functional groups is especially
desirable during the course of a total synthesis. A variety of chemo-
selective deprotections could be achieved under the reaction con-
ditions. Alkenes and alkynes remained unaffected (entries 4–8). A
TBDMS ether could be cleaved in the presence of a lactone (entry
10) and a Boc group (entry 11). The stability of the Boc group under
TBDMS deblocking conditions suggests potential useful application
to solid phase peptide synthesis. The selective cleavage of an alkyl
TBDMS ether in the presence of a phenolic TBDMS has received

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J. M. Bothwell et al. / Tetrahedron Letters 51 (2010) 1056–1058
cleave a 1° TBDMS ether in the presence of a 1° TBDPS ether (entry
14). As can be seen by comparing the literature examples, iron(III)
tosylate is much more efficient in effecting such chemoselective
deprotections. Although the deprotection of triisopropylsilyl ether
(entry 15) was slow at room temperature, heating the reaction
mixture at reflux resulted in complete deprotection. At room tem-
perature, an acetal group could be cleaved in the presence of a phe-
nolic TBDMS ether (entry 18).
In conclusion, a mild, chemoselective, and highly catalytic
method for the deprotection of tert-butyldimethylsilyl (TBDMS)
ethers using iron(III) tosylate has been developed. The resistance
of TBDPS and BOC groups to the reaction conditions should prove
especially useful in the course of total synthesis.
Representative procedure for the deprotection of TBDMS ethers.
Method A: A solution of (S)-tert-butyl 1-(tert-butyldimethylsilyl-
oxy)-3-phenylpropan-2-ylcarbamate (entry 11) (0.50 g, 1.4 mmol)
in CH3OH (5.0 mL) was stirred at room temperature as
Fe(OTs)3Á6H2O (0.0185 g, 0.0274 mmol, 2.0 mol %) was added. Reac-
tion progress was followed by TLC. At 2 h, the reaction was taken up
in EtOAc (20 mL), washed with aqueous saturated NaHCO3 (10 mL)
and aqueous saturated NaCl (10 mL), dried (Na2SO4) and concen-
trated on the rotary evaporator to yield 0.370 g of a white solid.
The crude product was purified by flash chromatography on 20 g
of silica gel (EtOAc/heptane, 40/60 v/v). Forty fractions (4 mL) were
collected and fractions 23–38 were concentrated to yield 0.27 g
(79%) of (S)-tert-butyl 1-hydroxy-3-phenylpropan-2-ylcarbamate
product as a white solid.13 1H NMR: d 1.40 (s, 9H), 2.05 (s, 1H),
2.81–2.84 (d, 2H, J = 7.2 Hz), 3.51–3.68 (m, 2H), 3.85 (s, 1H), 4.73
(s, 1H), 7.18–7.32 (m, 5H). 13C (10 peaks) d 28.28, 37.48, 53.75,
63.92, 79.68, 126.39, 128.44, 129.26, 137.86, 156.13.
Method B: A solution of tert-butyl(2-tert-butyldimethylsilyl-
oxy)benzyloxy)dimethylsilane (entry 12) (0.50 g, 1.4 mmol) in
CH3OH (5.0 mL) was stirred at room temperature as Fe(OTs)3Á6H2O
(0.0192 g, 0.0284 mmol, 2.0 mol %) was added. Reaction progress
was followed by GC and TLC. At 1 h 55 min, CH3OH was removed
ontherotaryevaporator.Theresidue(0.3705 g)waspurifiedbyflash
chromatography on 25 g of silica gel (EtOAc/heptane, 20/80 v/v).
Twenty four fractions (8 mL) were collected and fractions 7–22 were
combined and concentrated to yield 0.3084 g (91%) of (2-(tert-butyl-
dimethylsilyloxy)phenyl)methanol as a colorless liquid.13 The prod-
uct was determined by GC and NMR to be >99% pure. 1H NMR: d 0.26
(s, 6H), 1.02(s, 9H), 2.37 (s, 1H), 4.65 (s, 2H), 6.80–6.83(dd, J = 8.2 Hz,
1.0 Hz, 1H), 6.92–6.97 (td, 1H), 7.14–7.20 (td, J = 7.4 Hz, 2.0 Hz, 1H),
7.29–7.32 (dd, 1H). 13C (10 peaks) d À4.3, 18.1, 25.7, 61.7, 118.3,
121.3, 128.5, 128.7, 131.4, 153.3.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.12.076.
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Acknowledgment
36. Leonard, N. M.; Oswald, M. C.; Freiberg, D. A.; Nattier, B. A.; Smith, R. C.; Mohan,
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We gratefully acknowledge funding from the National Science
Foundation (RUI Grant # 0650682).