An efficient and chemoselective deprotection of tert-butyldimethylsilyl (TBDMS) ethers using tailor-made ionic liquid

Article abstract of DOI:10.1016/j.tetlet.2012.02.016

Phenolic tert-butyldimethylsilyl (TBDMS) ethers can be deprotected to yield phenols in excellent yield using tailor-made ionic liquid [dihexaEGim][OMs] (dihexaEGim = dihexaethylene glycolic imidazolium salt) as an organic catalyst with alkali-metal fluoride in tert-amyl alcohol. On the contrary, all TBDMS protecting groups can be cleaved cleanly from the bis-TBDMS ether using the same reaction in CH₃CN solvent instead of tert-alcohol at 100 °C. This [dihexaEGim][OMs]/tert-amyl alcohol media system allows the highly selective phenolic deprotection reaction of various bis-TBDMS ethers containing both phenolic and aliphatic TBDMS ethers to provide the corresponding phenols in high yield.

Full text of DOI:10.1016/j.tetlet.2012.02.016

Tetrahedron Letters 53 (2012) 2051–2053
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Tetrahedron Letters
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An efficient and chemoselective deprotection of tert-butyldimethylsilyl
(TBDMS) ethers using tailor-made ionic liquid
⇑
Vinod H. Jadhav, Sang Bong Lee, Hwan-Jeong Jeong, Seok Tae Lim, Myung-Hee Sohn, Dong Wook Kim
Department of Nuclear Medicine, Cyclotron Research Center, Research Institute of Clinical Medicine, Chonbuk National University Medical School, Jeonju,
Jeonbuk 561-712, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
Phenolic tert-butyldimethylsilyl (TBDMS) ethers can be deprotected to yield phenols in excellent yield
using tailor-made ionic liquid [dihexaEGim][OMs] (dihexaEGim = dihexaethylene glycolic imidazolium
salt) as an organic catalyst with alkali-metal fluoride in tert-amyl alcohol. On the contrary, all TBDMS pro-
tecting groups can be cleaved cleanly from the bis-TBDMS ether using the same reaction in CH3CN sol-
vent instead of tert-alcohol at 100 °C. This [dihexaEGim][OMs]/tert-amyl alcohol media system allows
the highly selective phenolic deprotection reaction of various bis-TBDMS ethers containing both phenolic
and aliphatic TBDMS ethers to provide the corresponding phenols in high yield.
Received 5 January 2012
Revised 1 February 2012
Accepted 3 February 2012
Available online 11 February 2012
Keywords:
Chemoselective deprotection
Desilylation
Ó 2012 Elsevier Ltd. All rights reserved.
tert-Butyldimethylsilyl group
Ionic liquid
tert-Alcohol
Fluoride
The selective removal of a protecting group is one of the most
important and widely used synthetic transformations for the mul-
tistep syntheses of complex targeting molecules.1 The tert-butyldi-
methylsilyl (TBDMS) group has occupied a privileged position in
organic synthesis chemistry as a protecting group for alcohols and
phenols because of the ease of protecting and deprotecting, its good
stability under various reaction conditions.2 Significant research in
silylation chemistry has resulted in the development of various
types of desilylation reactions. It is well-known that the deprotec-
tion reaction of TBDMS ethers to alcohols using tetrabutylammo-
nium fluoride (TBAF) in THF has been used commonly for the
removal of TBDMS. However, TBAF can lead to side reactions due
to its strong basicity, and restrict the wide application of this
reagent for this purpose.3 Thus, numerous alternative methods
such as (Lewis) acid/based media protocols,4,5 halide-source proto-
cols (in particular fluoride),6 and reductive protocols7 have been
developed for the deprotection of silyl ethers. Although there are
only a few reports about the selective deprotection reaction of phe-
nolic TBDMS ethers in the presence of aliphatic TBDMS ethers using
mild basic media protocols such as K2CO3/aqueous EtOH,8a Cs2CO3/
DMF-H2O,8b NaOH/Bu4NHSO4,8c some of these protocols have syn-
thetic limitations such as a long reaction time, a troublesome aque-
ous work-up, or a low efficiency. Therefore, the selective cleavage of
phenolic TBDMS ethers is still a challenging task.
Due to their unique chemical and physical properties, ionic
liquids have played a crucial role in the field of chemistry as an
eco-friendly alternative to replace volatile organic solvents.9 In
particular, imidazolium based ionic liquids as a phase-transfer type
promoter or catalyst show good performance in the nucleophilic
substitution reactions using alkali-metal salts.10 Recently, we
reported tailor-made ionic liquids—hexaethylene glycolic imidazo-
lium salts ([hexaEGmim][OMs] and [dihexaEGim][OMs]) as organ-
ic catalysts designed for nucleophilic fluorination with alkali-metal
fluorides (Fig. 1). These ionic liquids could generate a low basic
fluoride source (‘flexible’ fluoride11) efficiently from alkali-metal
fluoride in tert-alcohol medium.12 In this Letter, we introduce the
facile chemoselective cleavage of phenolic TBDMS ether in the
presence of alkyl TBDMS ether with alkali-metal fluoride, such as
KF and CsF, using tailor-made ionic liquid [hexaEGmim][OMs]
and [dihexaEGim][OMs] as catalysts.
O
N
N
5OH OMs-
[hexaEGmim][OMs]
O
O
HO
N
N
5OH OMs-
5
[dihexaEGim][OMs]
Figure 1. Hexaethylene glycolic imidazolium salts; [hexaEGmim][OMs] and
[dihexaEGim][OMs] (hexaEGmin = 1-hexaethylene glycolic 3-methylimidazolium
cation; dihexaEGim = 1,3-dihexaethylene glycolic imidazolium cation).
⇑
Corresponding author. Tel.: +82 63 250 2396; fax: +82 63 255 1172.
E-mail address: kimdw@chonbuk.ac.kr (D.W. Kim).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2012.02.016

2052
V. H. Jadhav et al. / Tetrahedron Letters 53 (2012) 2051–2053
Table 1
Desilylation of bis-TBDMS ether 1a
O
OTBDMS
O
OTBDMS
+
O
OH
0.5 equiv of
ionic liquid,
MF, solvent
OTBDMS
OH
OH
1
3
2
Entry
Ionic liquid (0.5 equiv)
MF
Time (h)
Temp (°C)
Solvent
Yieldb (%)
2
3
1
2
3
4
5
6
7
8
—
—
CsF
TBAF
—
CsF
CsF
CsF
CsF
KF
5
70
25
25
70
70
70
100
70
t-Amyl alcohol
THF
CH2Cl2
t-Amyl alcohol
t-amyl alcohol
CH3CN
76c
—
—
93
97
71c
—
24c
96
10 (min)
5
1
BF3ꢀEt2O
95
[Hexaegmim][OMs]
[Dihexaegim][OMs]
[Dihexaegim][OMs]
[Dihexaegim][OMs]
[Dihexaegim][OMs]
6c
40 (min)
Trace
29c
98
1
1
2
CH3CN
t-Amyl alcohol
93
5c
a
b
c
All reactions were carried out on a 1.0 mmol reaction scale of bis-TBDMS ether 1 using 3 mmol of CsF in 4.0 mL of solvent at the mentioned reaction temperature.
Isolated yields.
Yields were determined by 1H NMR spectroscopy.
Table 2
Selective phenolic deprotection of various substrates with CsF using [dihexaEGim][OMs] in tert-amyl alcohola
Entry
Substrate
Product
Time (min)
40
Yieldb (%)
OTBDMS
OTBDMS
O
O
1
96
HO
TBDMSO
TBDMSO
TBDMSO
OTBDMS
OTBDMS
OTBDMS
OTBDMS
2
3
4
20
15
20
94
95
94
HO
HO
OMe
OMe
OTBDMS
OTBDMS
OTBDMS
OH
OTBDMS
OTBDMS
H
H
5
30
97
H
H
H
H
HO
HO
TBDMSO
TBDMSO
O
O
O
O
6
7
15
15
90
96
OTBDMS
CHO
OTBDMS
CHO
HO
TBDMSO
OMe
OMe
a
All reactions were carried out on a 1.0 mmol scale of substrate with 3.0 equiv of CsF and 0.5 equiv of [dihexaEGim][OMs] in 4.0 mL of t-amyl alcohol at 70 °C.
Isolated yields.
b
Table 1 illustrates the desilylation reactions of bis-TBDMS ether
showed a relatively good chemoselective cleavage of phenolic
TBDMS ether moiety in the bis-TBDMS ether 1, providing the phe-
nol compound 2 in a 76% yield with 24% of diol 3 (entry 1), com-
pared with the same deprotection reactions using conventional
methods such as TBAF/THF and BF3ꢀEt2O (entries 2 and 3, respec-
tively). Surprisingly, a comparison of entries 1 and 4 demonstrates
that the use of catalytic amount (0.5 equiv) of a tailor-made ionic
1 containing both phenolic and aliphatic TBDMS ethers as a model
compound under various reaction conditions. Initially, considering
the previous results of the highly efficient tert-alcohol media
system in fluorination using alkali-metal fluoride, we attempted
to perform the desilylation of bis-TBDMS ether 1 with CsF in tert-
amyl alcohol solvent, and this CsF/tert-alcohol media system

V. H. Jadhav et al. / Tetrahedron Letters 53 (2012) 2051–2053
2053
liquid [hexaEGmim][OMs] could increase both the reaction rate
Supplementary data
and the chemoselectivity significantly in this deprotection reac-
tion, affording the phenol product 2 in a 93% yield with only 6%
of the diol 3. Moreover, the deprotection reaction using [dihexaE-
Gim][OMs] containing two hydroxyl components could remove
only the TBDMS group of the phenolic position in the bis-TBDMS
ether 1 within 40 min, providing phenol 2 in nearly quantitative
yield (97%, entry 5).13 However, the same reaction in CH3CN sol-
vent instead of tert-alcohol showed a relatively low chemoselectiv-
ity and afforded phenol 2 in a 71% yield together with diol 3 in a
29% yield (entry 6). In addition, at 100 °C, only the diol compound
3 could be obtained nearly quantitatively (entry 7). These results
suggest that the tailor-made ionic liquid [hexaEGmim][OMs] and
[dihexaEGim][OMs] can generate the activated fluoride from alka-
li-metal fluoride such as CsF efficiently by phase-transfer effect,
thereby increasing the reaction rate, and also the protic atmo-
sphere from both tert-alcohol media and hydroxyl group of these
ionic liquids (in particular, two hydroxyl group of [dihexaE-
Gim][OMs]) can reduce the basicity of the activated fluoride, there-
by enhancing the chemoselectivity of the phenolic desilylation
reaction in the presence of aliphatic silyl ethers. Entry 8 shows
that, when using KF as the fluoride source, the selective phenolic
desilylation reaction also proceeded smoothly, affording phenol 2
in good yield.
Table 2 shows the selective phenolic desilylation of various bis-
TBDMS ethers with CsF using 0.5 equiv of [dihexaEGim][OMs] cat-
alyst in tert-amyl alcohol. This protocol allowed the selective
deprotection of the phenolic TBDMS ether in the presence of vari-
ous sec-alkyl or benzylic TBDMS ethers to proceed nearby quanti-
tatively in a series of bis-TBDMS ether substrates (entries 1–4). In
entry 5, the monosilylated estradiol14 was obtained in a 97% yield
by this selective phenolic desilylation reaction. Entry 6 shows that
the aryl-TBDMS ether component of Kojic acid15 in the presence of
alkyl TBDMS ether could be cleaved by this deprotection method to
generate mono-silylated Kojic acid in a 90% yield. Finally, a TBDMS
group attached on the vanillin was successfully removed without
the loss of aldehyde functionality (96%, entry 7).
Supplementary data (experimental procedures and character-
ization data of all compounds) associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.2012.02.016.
References and notes
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In summary, we have developed an efficient method for the
selective deprotection of TBDMS-protected phenols in the presence
of TBDMS-protected alkyl alcohols with alkali-metal fluoride using
tailor-made ionic liquids ([dihexaEGim][OMs]) in tert-alcohol. This
[dihexaEGim][OMs]/tert-alcohol media system can enhance the
reaction rate as well as the selectivity of the phenolic deprotection
reaction using CsF significantly. Moreover, this protocol was very
useful to synthesize various mono-silylated compounds.
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13. Typical Procedure of selective deprotection of phenolic TBDMS-ether (Entry 5 in
Table 1): CsF (456 mg, 3 mmol) was added to the mixture of tert-butyl(3-(40-
(tert-butyldimethylsilyloxy)biphenyl-4-yloxy)propoxy)dimethylsilane
(1)
(473 mg, 1.0 mmol), [dihexaEGmim][OMs] (346 mg, 0.5 mmol) and t-amyl
alcohol (4 L) in reaction vial. The reaction mixture was stirred over 40 in at
70 °C. We determined the reaction time by checking TLC. The reaction mixture
was filtered and washed with diethyl ether. The filtrate was evaporated under
reduced pressure. Flash column chromatography (5% EtOAc/hexanes) of the
Acknowledgments
filtrate
afforded
347 g
(0.97 mol,
97%)
of
40-(3-tert-
This work was supported by the Nuclear Research & Develop-
ment Program of the National Research Foundation of Korea
(NRF) Grant funded by the Korean government (MEST) (Grant
code: 2011-0006322 and 2011-0030952), the Conversing Research
Center Program through the MEST (Grant code: 2011K000705) and
research funds of Chonbuk National University in 2011.
butyldimethylsilyloxy)propoxy)biphenyl-4-ol (2).
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Milstein, D.; Degani, H.; Sussman, J. L. J. Med. Chem. 2011, 10, 3575–3580; (b)
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