Mild deprotection of 2-(trimethylsilyl)ethyl esters

Article abstract of DOI:10.1016/S0040-4039(01)01859-7

A method for the deprotection of 2-(trimethylsilyl)ethyl (TMSE) esters is described. Treatment of carboxylic esters with NaH in DMF cleanly produces the deprotected acid after extractive work-up. This method can be applied to sterically-hindered substrates as well as esters containing fluoride-labile functionality. A tandem alkylation/ester deprotection procedure is also presented.

Full text of DOI:10.1016/S0040-4039(01)01859-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 8593–8595
Mild deprotection of 2-(trimethylsilyl)ethyl esters
Michael H. Serrano-Wu,* Alicia Regueiro-Ren, Denis R. St. Laurent, Tina M. Carroll and
Balu N. Balasubramanian
Bristol-Myers Squibb Pharmaceutical Research Institute, 5 Research Parkway, Wallingford, CT 06492, USA
Received 18 September 2001; revised 2 October 2001; accepted 3 October 2001
Abstract—A method for the deprotection of 2-(trimethylsilyl)ethyl (TMSE) esters is described. Treatment of carboxylic esters with
NaH in DMF cleanly produces the deprotected acid after extractive work-up. This method can be applied to sterically-hindered
substrates as well as esters containing fluoride-labile functionality. A tandem alkylation/ester deprotection procedure is also
presented. © 2001 Published by Elsevier Science Ltd.
The 2-(trimethylsilyl)ethyl (TMSE) ester functionality
enjoys widespread use as a protecting group in organic
synthesis, largely due to its chemical stability to the
hydrolytic, oxidative, or reductive methods that are
commonly used to cleave other ester protecting
scaffold was treated with excess NaH (1.5 equiv.) and
electrophile (2.0 equiv.) in DMF, we were surprised to
discover that in addition to the desired oxime ether, a
side-product was generated where both the oxime and
carboxylic acid incorporated the same alkyl side-chain
1
groups. In fact, the only reported methods to remove
(
Scheme 1). We reasoned that this bis-alkylated product
TMSE groups from carboxylic acids involve tetra-
butylammonium fluoride (TBAF) or other fluoride
source, whereby the fluoride anion attacks silicon and
expels the carboxylate in addition to 1 equiv. of ethyl-
ene. However, deprotection methods relying on fluoride
preclude the use of silicon-based protecting groups
elsewhere in the molecule, and can also present
difficulties when the ester contains base-sensitive func-
tionality. Herein we report a novel method for the
deprotection of 2-(trimethylsilyl)ethyl esters that
addresses these synthetic limitations.
must arise from the in-situ deprotection of the TMSE
ester and subsequent alkylation by excess electrophile.
Control experiments identified that the combination of
NaH in DMF was sufficient to cleanly deprotect TMSE
2
esters in quantitative yields. In a typical procedure, the
TMSE ester is simply dissolved in DMF and treated
with 1.0 equiv. of NaH (60% dispersion in mineral oil)
and stirred at ambient temperature overnight. A screen
of other polar aprotic solvents (THF and CH CN)
3
identified DMF as the preferred solvent in terms of
3
reaction rate and product purity. Extractive work-up
During the course of our drug discovery efforts, we
required the parallel synthesis of carboxylic acid-con-
taining oxime ethers that could display a diverse range
of functionality appended to the oxime oxygen. We
chose the TMSE ester protecting group to allow for the
incorporation of unsaturated substituents, and we envi-
sioned that these side-chains could be introduced via
alkylation of the oxime. When our TMSE ester/oxime
affords the carboxylic acid in sufficiently pure form,
with the only contaminant being mineral oil from the
NaH which can be easily removed by trituration with
hexanes.
Table 1 summarizes the range of aromatic and aliphatic
substrates that were deprotected using this protocol.
OH
O
O
1
.5 equiv NaH
N
N
N
O
2.0 equiv BuBr
+
DMF
OTMSE
OTMSE
O
O
O
Scheme 1.
*
Corresponding author. Tel.: (203) 677-7019; fax: (203) 677-7702; e-mail: michael.serrano-wu@bms.com
0
040-4039/01/$ - see front matter © 2001 Published by Elsevier Science Ltd.
PII: S0040-4039(01)01859-7

8
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M. H. Serrano-Wu et al. / Tetrahedron Letters 42 (2001) 8593–8595
Table 1. Deprotection of TMSE esters using NaH/DMF
O
1-2 equiv NaH
DMF, rt
O
TMS
R
O
R
OH
2a-g
3a-g
Ester
Product
Yield (%)b
O
O
O
TMS
OH
8
3
2
2a
O
3a
3b
O
TMS
O
OH
9
2b
O
OH
O
O
TMS
87
2
c
3c
3d
O
O
TMS
O
OH
82
TIPSO
SEMO
TIPSO
SEMO
2d
O
O
TMS
O
OH
8
2
8
2
ea
O
3e
3f
OH
O
TMS
8
O
O
2
f
O
TMS
OH
O
86
HO
AcO
2
ga
3g
a
b
2
equiv. of NaH required.
Isolated yield.
Deprotection of the hindered esters 2b and 2c at ambi-
ent temperature exemplify the synthetic utility of this
methodology, as elevated temperatures or prolonged
reaction times are required for saponification of even
For substrates which contain a nucleophilic center, this
deprotection method can be combined with an in-situ
alkylation event to effect a two-step, one-pot transforma-
tion. Namely, when hydroxy ester 4 is treated with excess
(3.0 equiv.) NaH and 1.0 equiv. of allyl bromide in DMF
overnight, 4-allyloxybenzoic acid (5) is isolated in 95%
yield (Scheme 2). This tandem alkylation/deprotection
4
the methyl ester of 2b. Importantly, this protocol also
allows the selective deprotection of TMSE esters with-
out affecting fluoride-sensitive groups such as tri-iso-
propylsilyl (TIPS, ester 2d) and 2-(trimethylsilyl)-
5
ethoxymethyl (SEM, 2e) ethers. We also investigated
3
equiv NaH
HO
O
the compatibility of acetate esters with our deprotection
methodology (ester 2g), and we were surprised to
discover that with 1 equiv. of NaH, the acetate ester
was selectively cleaved; an additional equivalent of
base then cleanly produced the hydroxy naphthoic
acid 3g.
1 equiv allyl bromide
OTMSE
OH
DMF, rt
95%
O
O
4
5
Scheme 2.

M. H. Serrano-Wu et al. / Tetrahedron Letters 42 (2001) 8593–8595
8595
strategy should be applicable to other bifunctional
Acknowledgements
molecules containing nucleophilic heteroatoms or possi-
bly stabilized carbanions. Moreover, the recent demon-
stration of the 2-trimethylsilyl ethyl group as a versatile
linker for solid phase synthesis suggests an interesting
application of our novel deprotection methodology to
The authors would like to thank Professor Jim
Leighton (Columbia University) for helpful discussions.
6
immobilized ester substrates.
References
Several mechanistic possibilities may be proposed for
the deprotection of TMSE esters by NaH in DMF. We
favor a mechanism whereby NaH reacts with adventi-
tious moisture in the solvent, and that NaOH is in fact
1
. Greene, T. W.; Wuts, P. G. M. Protective Groups in
Organic Synthesis; John Wiley & Sons: New York, 1999;
pp. 399–400.
7
2. General experimental procedure: To a solution of the
TMSE ester (1.0 mmol) in 4 mL DMF (Aldrich) was
added NaH (40 mg, 1.0 mmol of a 60% dispersion in
mineral oil) in one portion as a solid. The heterogeneous
mixture was stirred overnight at room temperature. Upon
disappearance of starting material, the reaction was parti-
tioned between 1 N HCl and ether. The organic layer was
washed with water and brine, and then dried over MgSO4
prior to filtration and evaporation. The crude product
was purified by trituration with hexanes or flash chro-
matography.
the active species. In fact, a number of bases (KO-t-
Bu, KOTMS, KOEt) were identified as competent
8
hydroxide precursors. ‘Anhydrous’ hydroxide is
known to cleave simple (i.e. methyl and ethyl) esters by
attack at the carbonyl and subsequent acylꢀoxygen
9
,10
bond fissure,
and certainly this mechanism may
operate in the hydrolysis of unhindered esters such as
a. With sterically-demanding substrates, however, a
2
different reaction pathway involving hydroxide attack
at silicon may prevail. Subjecting ethyl mesitoate to the
standard reaction conditions affords no hydrolysis
product, whereas the corresponding TMSE ester 2b
undergoes clean deprotection at room temperature.
Moreover, an aliquot from the deprotection reaction of
3
. After 24 h at room temperature, the reaction of 2a in
THF proceeded to 31% conversion; in CH CN, 50%
3
conversion. Both reactions were contaminated with
unidentified by-products.
. Bender, M. L.; Dewey, R. S. J. Am. Chem. Soc. 1956, 78,
2
a revealed the generation of hexamethyldisiloxane
4
5
(
detected by GC/MS), which provides additional evi-
317–319.
dence for anhydrous hydroxide attacking silicon in a
similar fashion to fluoride. The observed stability of a
SEM ether to the reaction conditions (ester 2e) suggests
that the collapse of the putative silicate intermediate is
facilitated by expulsion of a good carboxylate leaving
group for the ester, while no such leaving group is
available for the SEM ether.
. The corresponding TES ether of 2d was quantitatively
deprotected under the reaction conditions to afford 4-
hydroxymethyl benzoic acid. Meanwhile, the TBS ether
of 2d gave a mixture of mono- and bis-deprotected
material.
6. Wang, B.; Chen, L.; Kim, K. Tetrahedron Lett. 2001, 42,
1463–1466.
7
. When the reaction is performed in the presence of 4 A
molecular sieves, the reaction proceeds to only 18% con-
version after 24 h.
,
In summary, we have discovered a novel method for
the deprotection of TMSE esters that offers an attrac-
tive alternative to existing methodology. In addition to
greater functional group tolerance, this mild method
generates volatile by-products that are easily removed
to afford analytically pure material. The incorporation
of this protocol into a tandem alkylation/deprotection
strategy contributes to the potential increased utility of
the TMSE ester protecting group in organic synthesis.
8. However, when aqueous 1 N NaOH was used with DMF
as solvent, incomplete conversion (53%) of 2a was
observed after 48 h.
9. Roberts, W.; Whiting, M. C. J. Chem. Soc. 1965, 1290–
1293.
10. Gassman, P. G.; Schenk, W. N. J. Org. Chem. 1977, 42,
918–920.