Solvent-modulated chemoselective deprotections of trialkylsilyl esters and chemoselective esterifications

Article abstract of DOI:10.1016/j.tetlet.2005.07.049

A series of trialkylsilyl esters were deprotected or transesterificated into their corresponding carboxylic acids or methyl esters under a catalytic amount of CBr₄ in alcohol reaction system. This method enables to desilylate secondary sp³-carbon, sp²-carbon, sp-carbon and aryl tethered trialkylsilyl esters to carboxylic acids, whereas primary sp ³-carbon tethered trialkylsilyl esters were further converted into their methyl esters under CBr₄/MeOH reaction conditions. The highly chemoselective deprotections can be modulated and achieved by the introduced protecting trialkylsilyl groups and the used alcohols such as MeOH and EtOH under this photochemically-induced reaction conditions.

Full text of DOI:10.1016/j.tetlet.2005.07.049

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 6305–6309
Solvent-modulated chemoselective deprotections of
trialkylsilyl esters and chemoselective esterifications
Adam Shih-Yuan Lee* and Feng-Yih Su
Department of Chemistry, Tamkang University, Tamsui 251, Taiwan
Received 24 May 2005; revised 8 July 2005; accepted 11 July 2005
Abstract—A series of trialkylsilyl esters were deprotected or transesterificated into their corresponding carboxylic acids or methyl
esters under a catalytic amount of CBr4 in alcohol reaction system. This method enables to desilylate secondary sp3-carbon, sp2-
carbon, sp-carbon and aryl tethered trialkylsilyl esters to carboxylic acids, whereas primary sp3-carbon tethered trialkylsilyl esters
were further converted into their methyl esters under CBr4/MeOH reaction conditions. The highly chemoselective deprotections can
be modulated and achieved by the introduced protecting trialkylsilyl groups and the used alcohols such as MeOH and EtOH under
this photochemically-induced reaction conditions.
Ó 2005 Elsevier Ltd. All rights reserved.
Selective deprotections of trialkylsilyl ether and ester to
their corresponding alcohol and carboxylic acid is an
important tool and useful method in organic synthe-
sis.1–4 Although selective desilylating methods for tri-
alkylsilyl ethers5 have been extensively developed and
reported only a few selective deprotections for trialkyl-
silyl esters to carboxylic acids have been reported in
the literature.6–13
5% CBr4 / ROH
hv (TLC Lamp)
CO2SiiPr3
CO2H
R = MeOH
R = EtOH
R = EtOH
1 h
3.5 h
reflux, 3.5 h
51% + 44% Methyl Ester
94%
95%
Scheme 1.
temperature for 1 h by using a TLC lamp as light source
and a mixture of phenylacetic acid and methyl phenyl-
acetate was obtained as products. The deprotection of
triisopropylsilyl phenylacetate to phenylacetic acid was
obtained with 94% yield when the more steric hindered
EtOH was used instead of MeOH. The deprotection of
triisopropylsilyl phenylacetate to phenylacetic acid also
was achieved under CBr4/EtOH refluxing reaction con-
dition. The deprotection yield of trialkylsilyl ester under
3.5 h of photochemical reaction condition is consistent
with the reaction condition in which the irradiation time
was decreased to 0.5 h and then stirred at room temper-
ature for 3 h without irradiation. Thus, this mild photo-
chemically-induced desilylating method was introduced
as the typical reaction condition for investigation of tri-
alkylsilyl ester deprotection. Therefore, we investigated
the desilylating reactions for trialkylsilyl esters with sev-
eral trialkylsilyl groups such as tert-butyldimethylsilyl,
triisopropylsilyl and tert-butyldiphenylsilyl groups
under the photochemically-induced CBr4/MeOH reac-
tion conditions. Herewith, we wish to report a mild,
highly efficient and chemoselective deprotection and
Our previous studies showed that a highly chemoselec-
tive deprotection method for trialkylsilyl ethers14,15
and b-(trimethylsilyl)ethoxymethyl ethers16 and meth-
oxyethoxymethyl esters17 can be hydrolyzed by using a
catalytic amount of CBr4 in methanol or isopropanol
under thermal or ultrasonic reaction conditions. The
desilylation reaction for trialkylsilyl ester is easier and
faster than trialkylsilyl ether under acidic hydrolysis.
Thus, we believed and expected that the desilylation sys-
tem developed by us can be applied to the deprotection
of trialkylsilyl-protected carboxylic acids. We first,
investigated this desilylating reaction condition for trialk-
ylsilyl ester under a milder photochemical reaction
condition instead of a thermal reaction condition
(Scheme 1).
A reaction mixture of triisopropylsilyl phenylacetate
and CBr4 (0.05 equiv) in MeOH was irradiated at room
*
Corresponding author. Tel.: +886 2 2621 5656x2543; fax: +886 2
2622 3830; e-mail: adamlee@mail.tku.edu.tw
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.07.049

6306
A. S.-Y. Lee, F.-Y. Su / Tetrahedron Letters 46 (2005) 6305–6309
(secondary sp3-carbon, sp2-carbon, sp-carbon and aryl)
CBr4 / R2OH (5%/5 mL)
hv (30 min); stir at rt
R-CO2SiR1
R-CO2H or R-CO2Me
3
tethered trialkylsilyl esters were desilylated to their cor-
responding carboxylic acids. It should be noted that it
did not undergo further esterification19,20 when second-
ary sp3-carbon tethered trialkylsilyl ester was introduced
under the reaction conditions. The experimental results
showed that desilylation rate was determined by the
tethered configuration of trialkylsilyl ester and the steric
hindrance of protected trialkylsilyl group. The desilyl-
ation rate becomes much slower when the more steric
hindered trialkylsilyl groupsuch as tert-butyldiphenyl-
silyl groupwas introduced. It is difficult for tert-butyldi-
phenylsilyl benzoate to undergo desilylation reaction
even after a relatively prolonged reaction time (Table
1, entry 6). We also observed that desilylation rate of
sp2-carbon tethered trialkylsilyl esters was much faster
than secondary sp3-carbon, sp-carbon and aryl tethered
trialkylsilyl esters under the reaction conditions.
SiR13 = SitBuMe2, SiiPr3, SitBuPh2
R2OH = MeOH, EtOH
Scheme 2.
transesterification method for trialkylsilyl esters under
CBr4 in alcoholic reaction conditions18 (Scheme 2).
A series of trialkylsilyl esters were investigated under
CBr4/MeOH (5 mol%/5 mL) photoirradiation reaction
conditions and the results are shown in Table 1. The
results showed that only primary sp3-carbon tethered
trialkylsilyl esters (entries 1–3 and 5) were further trans-
formed to their corresponding methyl esters under this
typical reaction conditions whereas other configuration
Table 1. Desilylations of trialkylsilyl esters
Entry
1
Substrate
Product
R
Time (h)
Yielda (%)
Si-t-BuMe2
Si-i-Pr3
Si-t-BuPh2
3
8
9
92
89
81
( )6
( )6
CO2Me
CO2Σ
Si-t-BuMe2
Si-i-Pr3
Si-t-BuPh2
3
12
24
96
93
90
2
3
4
( )5
Br
CO2Me
Br
CO2
Σ
( )5
Si-t-BuMe2
Si-i-Pr3
Si-t-BuPh2
3.5
7
10.5
88
83
80
CO2Me
CO2
Σ
Si-t-BuMe2
Si-i-Pr3
Si-t-BuPh2
2.5
15
16
93
CO2H
CO2
Σ
75 (19)b
22 (60)b
Si-t-BuMe2
Si-i-Pr3
Si-t-BuPh2
2
5
11
96
86
84
CO2
Σ
CO2Me
5
6
7
8
9
Si-t-BuMe2
Si-i-Pr3
Si-t-BuPh2
9
26
48
89
81
NR (98)b
CO2H
CH3
CO2
CH3
Σ
Si-t-BuMe2
Si-i-Pr3
Si-t-BuPh2
5
30
48
93
90
54 (40)b
CO2
Σ
CO2H
Si-t-BuMe2
Si-i-Pr3
Si-t-BuPh2
1
2.5
5
98
92 (4)b
91 (7)b
CO2H
CO2
Σ
CO2H
CO2
Σ
Si-t-BuMe2
Si-i-Pr3
Si-t-BuPh2
5
30
48
92
89
61 (33)b
a The yields were determined after chromatographic purification.
b The recovery yield of the starting material after chromatographic purification.

A. S.-Y. Lee, F.-Y. Su / Tetrahedron Letters 46 (2005) 6305–6309
Table 2. Deprotections of primary sp3-C tethered trialkylsilyl estersa
6307
Entry
Substrate
Product
R
Time (h)
Yieldb (%)
Si-t-BuMe2
Si-i-Pr3
Si-t-BuPh2
1
4
12
97
73 (25)c
5 (91)c
( )6
1
( )6
CO2H
CO2
Σ
Si-t-BuMe2
Si-i-Pr3
Si-t-BuPh2
2
3.5
10
96
95
NR (97)c
CO2H
CO2
Σ
2
a The EtOH was used instead of MeOH for these deprotection reactions.
b The yields were determined after chromatographic purification.
c The recovery yield of the starting material after chromatographic purification.
Our experimental studies showed that primary sp3-
carbon tethered trialkylsilyl esters were hydrolyzed and
further converted to their corresponding methyl esters
under CBr4/MeOH reaction conditions. The transfor-
mations of carboxylic acids with alcohols into their
corresponding alkyl esters by using a catalytic amount
of CBr4 under thermal reaction conditions were previ-
ously reported by this laboratory.21,22 The further esteri-
fication process of primary sp3-carbon tethered
trialkylsilyl esters can be inhibited when EtOH was used
instead of MeOH. Thus, we further investigated several
primary sp3-carbon tethered trialkylsilyl esters under
CBr4/EtOH reaction conditions. All primary sp3-carbon
tethered trialkylsilyl esters were deprotected to carboxy-
lic acids and the results are shown in Table 2. The
desilylations of primary sp3-carbon tethered tert-
butyldimethylsilyl esters to carboxylic acids were
achieved with high yields under the reaction conditions.
The desilylation rate becomes much slower when the
more steric hindered tert-butyldiphenylsilyl group was
introduced. tert-Butyldiphenylsilyl phenylacetate was
resistant under CBr4/EtOH reaction condition (Table
2, entry 2).
tethered tert-butyldiphenylsilyl esters was less reactive
even when inert EtOH was used as solvent (Table 2).
This leads us to further investigate this highly chemo-
selective desilylating process among trialkylsilyl groups
for primary sp3-carbon tethered silyl esters. 1-tert-Butyl-
dimethylsilylcarboxyl-7-trialkylylsilylcarboxylheptane
was investigated under CBr4/EtOH reaction condition.
tert-Butyldimethylsilyl (TBDMS) groupof rpimary
sp3-carbon tethered silyl ester was deprotected selec-
tively whereas triisopropylsilyl (TIPS) and tert-butyl-
diphenylsilyl (TBDPS) groups were resistant under
the reaction conditions (Schemes 3 and 4).
Triisopropylsilyl benzoate undergoes desilylation reac-
tion much more slowly under CBr4/MeOH reaction
condition and tert-butyldiphenylsilyl benzoate is resis-
tant under the reaction condition (Table 1, entry 6).
The tert-butyldimethylsilyl (TBDMS), Triisopropylsilyl
(TIPS) and tert-butyldiphenylsilyl (TBDPS) groups pro-
tected silyl esters were investigated under the reaction
conditions and only TBDMS groupwas deprotected
selectively whereas TIPS and TBDPS groups were resis-
tant under the reaction conditions (Scheme 5).
The experimental results showed that the desilylating
rate becomes much slower when more bulky trialkylsilyl
Our studies showed that primary sp3-carbon tethered
trialkylsilyl esters were desilylated and further converted
to their corresponding methyl esters under CBr4/MeOH
reaction conditions. The results led us to investigate
further this highly chemoselective transesterification
groupis introduced (desilylation rate
t-BuMe2Si >
i-Pr3Si > t-BuPh2Si) or more steric hindered alcohol is
used (Table 1). The desilylation of primary sp3-carbon
CBr4 / EtOH (5%/5mL),
hv (30 min); stir at r.t.
( )5
( )5
tBuMe2SiO2C
CO2Σ
HO2C
CO2Σ
Σ = SiiPr3
2 h
1 h
96%
96%
Σ = SitBuPh2
Scheme 3.
O
CO2SitBuMe2
O
O
CO2H
CO2Σ
CBr4 / ROH (5%/5 mL),
hv (30 min); stir at r.t.
O
CO2Σ
Σ = SiiPr3
iPrOH
EtOH
24 h
4 h
89% + 6% S.M.
96%
Σ = SitBuPh2
Scheme 4.

6308
A. S.-Y. Lee, F.-Y. Su / Tetrahedron Letters 46 (2005) 6305–6309
ate (secondary sp3-carbon tethered) in CBr4/MeOH
CO2H
CO2SitBuMe2
(10%/10 mL) reaction condition (Scheme 7). The pri-
mary sp3-carbon tethered TBDMS ester underwent
transesterification into its methyl ester in 90% yield,
whereas the secondary sp3-carbon tethered TBDMS
ester was desilylated to its carboxylic acid with 91%
yield under the reaction condition.
CBr4 / ROH (5%/5 mL),
hv (30 min); stir at r.t.
ΣO2C
ΣO2C
Σ = SiiPr3
Σ = SitBuPh2 MeOH
EtOH
6 h
3 h
96%
97%
Scheme 5.
The experimental results showed that the further trans-
esterification reaction of tert-butyldimethylsilyl benzo-
ate is much slower than tert-butyldimethylsilyl
phenylacetate under CBr4/MeOH reaction condition
(Table 1, entries 5 and 6). Thus, a mixture of tert-butyl-
dimethylsilyl benzoate and tert-butyldimethylsilyl phen-
ylacetate was investigated under the reaction condition
and TBDMS phenylacetate was converted into its
methyl ester in 99% yield, whereas TBDMS benzoate
was desilylated to its acid with 90% yield and 8% of
TBDMS benzoate was recovered (Scheme 8).
process which distinguishes between primary sp3-carbon
tethered and secondary sp3-carbon tethered tert-butyl-
dimethylsilyl esters (Table 1, entries 5 and 7). A mixture
of tert-butyldimethylsilyl 2-phenylethanoate and tert-
butyldimethylsilyl 2-phenylpropanoate in CBr4/MeOH
(15 mol%/10 mL) was investigated under the reaction
conditions (Scheme 6). The primary sp3-carbon tethered
TBDMS ester was converted into its methyl ester in
99% yield, whereas the secondary sp3-carbon tethered
TBDMS ester was deprotected into carboxylic acid
(84%) and 12% of the corresponding methyl ester was
obtained under the reaction conditions.
Primary and secondary tethered tert-butyldiphenylsilyl
esters undergo desilylation or transesterification reac-
tions under CBr4/MeOH reaction condition much
slower than primary and secondary tethered tert-butyl-
dimethylsilyl esters (Tables 1 and 2). These results led
us to investigate the chemoselective transesterification
We also investigated the selectivity between tert-butyl-
dimethylsilyl cyclohexylpropanoate (primary sp3-carbon
tethered) and tert-butyldimethylsilyl cyclohexylmethano-
CO2SitBuMe2
CO2Me
99%
CBr4/MeOH (15%/10 mL)
hv (30 min); stirred 3 h at r.t.
+
CH3
CO2H
+
CH3
CO2SitBuMe2
84%
CH3
+
CO2Me
12%
Scheme 6.
CO2Me
CO2SitBuMe2
CBr4/MeOH (15%/10 mL)
90%
+
+
hv (30 min); stirred 3 h at r.t.
CO2H
CO2SitBuMe2
91%
Scheme 7.
CO2SitBuMe2
CO2Me
99%
CBr4/MeOH (15%/10 mL)
+
+
+
CO2H
hv (30 min); stirred 3 h at r.t.
CO2SitBuMe2
90%
CO2SitBuMe2
8%
Scheme 8.

A. S.-Y. Lee, F.-Y. Su / Tetrahedron Letters 46 (2005) 6305–6309
6309
CBr4 / MeOH (5%/5 mL),
( )5
tBuPh2SiO2C
CO2SitBuMe2
( )5
tBuPh2SiO2C
98%
CO2Me
hv (30 min); stir at r.t.
Scheme 9.
reactions between primary sp3-carbon tethered TBDPS
ester and primary sp3-carbon tethered TBDMS ester
under the reaction condition (Scheme 9). 1-tert-Butyl-
dimethylsilylcarboxyl-7-trialkylylsilylcarboxylheptane
was investigated and primary sp3-carbon tethered
TBDMS ester was selective transesterificated to its
methyl ester whereas TBDPS ester was resistant under
the reaction condition.
5. Crouch, R. D. Tetrahedron 2004, 60, 5833, and references
cited therein.
6. Nicolaou, K. C.; Ninkovic, F.; Sarabia, F.; Vourloumis,
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In conclusion, this reaction condition provides a simple
and highly chemoselective desilylation method for tri-
alkylsilyl esters. This method enables us to desilylate
secondary sp3-carbon, sp2-carbon, sp-carbon and aryl
tethered trialkylsilyl esters to their corresponding
carboxylic acids, whereas primary sp3-carbon tethered
trialkylsilyl esters were further converted into their
methyl esters under CBr4/MeOH reaction conditions.
The primary sp3-carbon tethered trialkylsilyl esters can
be deprotected to their corresponding carboxylic acids
under CBr4/EtOH reaction condition. The chemoselec-
tive deprotections and transesterifications among differ-
ent trialkylsilyl esters are manipulated by the bulkiness
of silyl groups and the used solvent.
17. Lee, A. S.-Y.; Hu, Y.-J.; Chu, S.-F. Tetrahedron 2001, 57,
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Acknowledgements
18. A solution of trialkylsilyl ester (1.0 mmol), CBr4
(0.05 mmol) and anhydrous CH3OH (5 mL) or EtOH in
a Pyrex culture tube is irradiated directly by a TLC lamp
at room temperature (UVltec Limited, 8 W, 254 nm) for
30 min and then stirred without irradiation at room
temperature. After the reaction was complete (analysis
by TLC), the organic solvent was removed directly under
reduced pressure. Further purification is achieved on a
flash chromatograph with ethyl acetate/hexane mixture as
the eluate.
We thank the National Science Council in Taiwan (NSC
92-2113-M-032-005) and Tamkang University for finan-
cial support.
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