Selective cleavage of phenolic tert-butyldimethylsilyl ethers using simple organic nitrogen bases

Article abstract of DOI:10.1016/j.cclet.2009.11.049

Simple organic nitrogen bases, such as Et₃N, pyridine, DBU, etc., were found to be convenient and useful reagents for deprotection of TBDMS groups on acidic hydroxyl groups. The efficiency of these bases has an apparent order: 1° amine > 2° amine > 3° amine and aliphatic base > aromatic base. In aqueous DMSO and at room temperature, phenolic TBDMS ethers were removed selectively in the presence of alcoholic TBDMS ethers. And catalytic base can make these reactions complete. This method is high-yielding, fast, clean, safe and cost-effective.

Full text of DOI:10.1016/j.cclet.2009.11.049

Available online at www.sciencedirect.com
Chinese Chemical Letters 21 (2010) 273–276
www.elsevier.com/locate/cclet
Selective cleavage of phenolic tert-butyldimethylsilyl ethers
using simple organic nitrogen bases
a
a,
b
a
Jian Rong Zhu , Ji Jun Xue , Wen Ze Li , Xue Song Chen , Ying Li
a,*
*
a
The State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, China
b
Zhejiang Jiuzhou Pharmaceutical Co. Ltd., 99 Waisha Rd., Jiaojiang Taizhou City, Zhejiang 318000, China
Received 15 June 2009
Abstract
Simple organic nitrogen bases, such as Et
3
N, pyridine, DBU, etc., were found to be convenient and useful reagents for
deprotection of TBDMS groups on acidic hydroxyl groups. The efficiency of these bases has an apparent order: 18 amine > 28
amine > 38 amine and aliphatic base > aromatic base. In aqueous DMSO and at room temperature, phenolic TBDMS ethers were
removed selectively in the presence of alcoholic TBDMS ethers. And catalytic base can make these reactions complete. This
method is high-yielding, fast, clean, safe and cost-effective.
#
2009 Ji Jun Xue. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: Selective cleavage; Phenolic tert-butyldimethylsilyl ethers; Organic nitrogen bases
Silyl groups are widely used to protect phenolic hydroxy groups in the synthesis of biologically potent compounds
and drugs. Many methods have been developed to remove silyl-protecting groups. Generally, fluoride compounds [1],
inorganic bases [2] and inorganic acids [3] are used to cleave tert-butyldimethylsilyl (TBDMS) ethers.
Tetrabutylammonium fluoride (TBAF) [3] is the most typical desilylating reagent, but it has no selectivity and
has possible side-reactions caused by the nucleophilicity of fluoride ion [4]. Inorganic bases [2] often remove acetyl
groups together with TBDMS. And inorganic acidic [3] conditions favor cleaving aliphatic silyl ethers. Oxidation
conditions [5] can also remove TBDMS from hydroxyl groups. Potassium peroxymonosulfate sulfate (OXONE) [5b]
preferred removing alcoholic TBDMS to phenolic TBDMS. Herein a series of simple organic bases were described for
selective deprotection of TBDMS on acidic hydroxyl groups under mild conditions.
Generally, TBDMS ether is stable to organic nitrogen bases, such as Et N, MeNH , 1,4-diazabicyclo[2.2.2] octane
3
2
(
TBDMS ether was desilylated very quickly and completely by Et N at room temperature, in the same way as inorganic
DABCO), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), etc. [6]. Surprisingly, in aqueous DMSO [7], 4-actylphenyl
3
reagents (MeCO K, Na MoO , etc.) did.
4
2
2
To investigate this reaction in detail, different solvent systems (Table 1) and bases were examined (Table 2). In
homogenous aqueous organic solvent systems, all of the reactions resulted in very high yields in appropriate reaction
time. Their reaction rates have such a sequence: in the presence of water, DMSO > DMF > CH CN > THF > EtOH.
3
*
Corresponding author.
E-mail addresses: xuejj@lzu.edu.cn (J.J. Xue), liying@lzu.edu.cn (Y. Li).
1001-8417/$ – see front matter # 2009 Ji Jun Xue. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
doi:10.1016/j.cclet.2009.11.049

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J.R. Zhu et al. / Chinese Chemical Letters 21 (2010) 273–276
Table 1
Desilylating reaction of 1a with Et
3
N (2.0 equiv.) in various solvents systems.
.
Entry
1
2
3
4
5
6
Solvent (v/v)
a
Time
b
Yield (%)
DMSO/H
2 h
2
O (5:1)
DMSO/H
2.5 min
97
2
O (10:1)
DMF/H
40 min
96
2
O (10:1)
CH
2 h
95
3
CN/H
2
O (10:1)
THF/H
6 h
2
O (10:1)
EtOH/H
2
O (10:1)
24 h
95
97
96
a
TLC monitored the substrate disappeared.
Isolated yield.
b
Table 2
Desilylating reaction of 1a with different organic nitrogen bases.
Entry
1
2
3
4
5
6
7
8
9
10
a
Bases
MeNH
2
MeNH
8 min
93
2
(0.1 equiv.) Me
2
N
Piperidine Me
3
N
Et
2
NPh Ph
3
N
Imidazole DBU
DBU (0.05 equiv.)
96
b
Time
Yield
<1 min
96
<1 min 1 h
96 95
10 min 24 h
96 95
48 h
96
5 h
96
<1 min 20 min
97
c
a
The amount of base is 2 equivalents unless noted.
TLC monitored the substrate disappeared.
Isolated yield.
b
c
Elsewise, the reaction rate is also related to the ratio of organic solvent and H O (entries 1 and 2, Table 1).
2
Furthermore, either in anhydrous DMSO or in H O, no reaction happened.
2
Different organic bases were tried in DMSO/H O (10:1, v/v) at room temperature. All of them gave excellent yields
2
in appropriate time (Table 2), including aliphatic amine and aromatic amine, primary amine, secondary amine and
tertiary amine, mono nitrogen base and dinitrogen base. Aliphatic amines (entries 1 and 3, Table 2) took less than an
hour to remove TBDMS completely while aromatic amines (entries 6–8) mostly needed several hours, even longer
time, to do the same. An apparent order of the reaction rate was found: primary amine (entry 1, Table 2) > secondary
amine (entry 3, Table 2) > tertiary amine (entry 5, Table 2) and alkyl-substituted nitrogen base (entries 1, 3 and 5,
Table 2) > aryl-substituted nitrogen base (entries 6 and 7, Table 2), which corresponded to their basicity sequence,
except piperidine (entry 4, Table 2). Piperidine is a stronger base than Me NH (entry 3, Table 2), but with less activity.
2
Furthermore, bulkier base is responsible for a slower reaction rate since the lone electron pair on nitrogen atom is
difficult to be attached to the target. When the lone electron pair of nitrogen atom was conjugated, the basicity of
nitrogen compound will decrease and it will be less efficient for the deprotection reaction, which explained the activity
order of these amines: Me N > imidazole > Et NPh > Ph N.
3
2
3
In aqueous DMSO, even catalytic amount of these bases could push the reaction forward and complete. The
reaction time is in inverse to the amount of base (Table 2). For example, 2 equivalents of MeNH took less than 1 min
2
to remove the TBDMS, and 0.1 equivalent of MeNH needs 8 min. 2 equivalents of DBU took less than 1 min to
2
consume the substrate (entry 9, Table 2), but 0.05 equivalents of it took 20 min (entry 10, Table 2).
We then investigated the substrate scope. Using DBU as the base, this method was successfully applied to a variety
of phenolic TBDMS ethers. The desilylation of 1b–1h in DMSO/H O (10:1, v/v) afforded the corresponding phenols
2
in virtually quantitative and isolated yields (entries 1–5, Table 3). Notably, phenolic TBDMS in compound 1f was
removed but the benzyl TBDMS ether of 1f survived (entry 5, Table 3). And this method did not work with compound
1
g (entry 6, Table 3). This method has good selectivity between phenolic TBDMS ethers and alcoholic TBDMS ethers.
Further, it should be noted that the desilylating reactions of TBDMS ethers 1a–1b and 1e (entry 9 in Table 2, entries 1
and 4 in Table 3) bearing electron-withdrawing groups on the aromatic ring were very fast in comparison with the
desilylating reactions of TBDMS ethers 1d and 1f (entries 3 and 5, Table 3). Phenolic TBDMS ethers bearing electron-
withdrawing groups were deprotected more easily than those bearing electron-donating groups. In compound 1e (entry

J.R. Zhu et al. / Chinese Chemical Letters 21 (2010) 273–276
275
Table 3
Chemoselective removal of various phenolic protecting groups by using DBU (2.0 equiv.) in DMSO/H
2
O (10:1, v/v) at room temperature [8].
a
b
Entry
1
Substrate
Product
Reaction time
5 min
Yield (%)
91
2
1 min
97
3
4
24 h
92
96
10 min
5
2 h
97
6
7
–
No reaction
40 h
90
a
TLC monitored the substrate disappeared.
Isolated yield.
b
4
), the carboxylic TBDMS ether was also cleaved. This method is also suitable for the cleavage of carboxylic TBDMS
esters. And aliphatic TBDMS ether can insist this reaction (entry 6, Table 3).
We also demonstrated the removal of Ac from phenolic hydroxyl groups using this method (entry 7, Table 3), which
was obviously slower than the removal of TBDMS. Thus, this method also has selectivity between Ac and TBDMS on
acidic hydroxyl groups.
In conclusion, we have developed a convenient and efficient method for the removal of TBDMS protection on
acidic hydroxyl groups, which can serve as a useful complement to the existing methodologies and find applications in
organic synthesis.
Acknowledgments
We are grateful to Dr. Qiang Gao (Shanghai Haoyuan Express Chemical Company Ltd. Of China) for his donation
of actin and their helpful advice and discussions. Project No. 20672050 supported by the National Natural Science
Foundation of China.
References
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(b) P.J. Kocienski, Protecting Groups, George Thieme Verlag, New York, 1994.

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J.R. Zhu et al. / Chinese Chemical Letters 21 (2010) 273–276
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[
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(
(
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[
[
[
6] K. Oyama, T. Kondo reported a method for removing TBDMS protection groups using 1, 1, 3, 3-tetramethylguanine, see K. Oyama, T. Kondo,
Org. Lett. 5 (2003) 209.
7] G. Maiti and S. C. Roy, have found that DMSO/H2O can remove TBDMS. However, it needs high temperature and has the same effect on
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8] Typical procedure for the deprotection: a solution of TBDMS ether (0.5 mmol) in a combination of H
treated with base (1 mmol) at room temperature until TLC indicates that no starting material remains. The reaction was quenched by adding
saturated aqueous NH Cl solution (5 mL), the mixture was extracted with Et
O (3 Â 20 mL) and the combined organic layers were washed with
O and brine. After drying (Na SO ) and solvent removal under reduced pressure vacuum, the crude product was purified on a silica gel column
eluting with petroleum ether/acetate to afford the corresponding phenol.
2
O and DMSO (1:10, v/v, 1 mL) was
4
2
H
2
2
4