A convenient method for the synthesis of α-silylacetic acids

Article abstract of DOI:10.1016/j.tetlet.2008.03.050

A method is described for the preparation of α-silylacetic acids of the type R₃SiCH₂CO₂H by treating trimethylsilyl acetate with LDA followed by quenching with chlorosilanes.

Full text of DOI:10.1016/j.tetlet.2008.03.050

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 3101–3103
A convenient method for the synthesis of a-silylacetic acids
Alex V. Shtelman, James Y. Becker *
Department of Chemistry, Ben-Gurion University of the Negev, Beer Sheva 84105, Israel
Received 6 January 2008; revised 27 February 2008; accepted 10 March 2008
Available online 14 March 2008
Abstract
A method is described for the preparation of a-silylacetic acids of the type R3SiCH2CO2H by treating trimethylsilyl acetate with LDA
followed by quenching with chlorosilanes.
Ó 2008 Elsevier Ltd. All rights reserved.
a-Trialkylsilylacetic acids are important intermediates in
organic synthesis. They undergo thermal and base-cata-
lyzed rearrangements to isomeric acyloxysilanes1 and their
dianions provide highly efficient routes to a,b-unsaturated
acids and butyrolactones.2 Also, they are used widely for
various biological purposes, such as preparing labelled
diethyl malonate3 and synthesizing a,b-unsaturated thiol
esters4 and a-silyl thioesters.5,6 Nevertheless, a more exten-
sive use of such versatile compounds has been hampered by
the low yields, lack of selectivity and relatively high cost.
Sommer et al.7 were the first to report the synthesis of a-
silylacetic acids by the carbonation of Grignard reagents
derived from the appropriate chlorides. However, this
method was too costly and resulted in low yields. Follow-
ing that work, a more detailed and improved procedure
was published much later by Weguny and Schafer8 Emde
and Simchen9 prepared trimethylsilylacetic acid by using
trimethylsilyl trifluoromethanesulfonate as the silylating
reagent, but the yield of the product was also poor. Ains-
worth and Kuo10 reported that ClSiMe3 reacts with the
dianion of acetic acid to give equal amounts of O- and
C-silyl derivatives. It is also claimed11 that if the enolate
is formed in a mixture of ether and THF and refluxed for
24 h prior to quenching with trimethylchlorosilane, the a-
silyl ester is obtained in 70% yield. Apparently, it turned
out that the latter quoted yield is not always reproducible,
and is highly sensitive to the experimental conditions.12
Moreover, when Hudrlik et al.13 applied the same exper-
imental conditions but used different silylating agents,
O ? C migration of the trimethylsilyl group was detected.
The observation that C-silylation of esters of acetic acid
is quite sensitive to the bulkiness of the silyl group or ‘soft-
ness’ of the electrophilic silicon moiety is known.14 For
example, Larson and coworkers reported15,16 the a-silyl-
ation of esters and lactones and found that the yields of
the C-silylation products depended on the nature of the
silyl group.
Based on the above data, it seems that to date and to the
best of our knowledge, there is no general method for the
preparation of a-silylacetic acids in a reproducible way that
delivers good yields. Herein we report a useful and general
method for the synthesis of a-silylacetic acids using
common and commercially available starting materials.
Following the procedure described in Ref.15, initially we
attempted to prepare a-diphenylmethylsilyl acetic acid
from the corresponding ethyl and tert-butyl esters. How-
ever, in our hands, hydrolyzing ethyl and tert-butyl-a-
diphenylmethylsilyl esters under both mild basic17 and
acidic18 conditions always resulted in the desilylation of
the desired products. Attempts to hydrolyze tert-butyl-a-
diphenylmethylsilyl esters under neutral conditions19 led
to the same result. Finally, we adopted the experimental
conditions described by Ainsworth and Kuo10 showing
that trimethylsilyl esters of carboxylic acids can readily
hydrolyze in the presence of ammonium chloride.
*
Corresponding author. Tel.: +972 8 6461197; fax: +972 8 6472943.
E-mail address: becker@bgu.ac.il (J. Y. Becker).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.03.050

3102
A. V. Shtelman, J. Y. Becker / Tetrahedron Letters 49 (2008) 3101–3103
In the present work we used silyl esters (instead of alkyl
OSiMe3
OLi
H
H
R3SiCl
R3SiCl
O
-silylated
esters) as precursors and examined the C-silylation of
trimethylsilyl acetate (CH3CO2SiMe3) with a variety of
silylating agents to afford good yields of the corresponding
C-silylated products (Table 1, entries 1–6).20
C
C
Product
A
LiN(iPr)2
-78 ºC
MeCO2SiMe3
We found that the yield of the C-silylated product
increases when the lithium enolate salt is allowed to stand
at À78 °C for 2 h prior to quenching with the alkylchlorosi-
lane. However, if the enolate salt is immediately quenched
at À78 °C, the yield of the C-silylated product is reduced
significantly. We also found that after adding a chlorosi-
lane, continuous cooling of the reaction mixture at
À78 °C for an additional 2 h was necessary to produce a
higher yield of the C-silylated product. We assume that
the rate of silylation at carbon is slow at this low tempera-
ture, and therefore, a rapid heating to room temperature
shifts the equilibrium towards O-silylation, resulting in a
decrease in the yield of the C-silylated product.
OSiMe3
OLi
H
C
-silylated
C
C
Product
H
B aggregate
Scheme 1. Equilibrium between the two O-lithiated structures.
SiR3
1) LiN(iPr)2 /- 78 ºC / 2h
RCH2CO2SiMe3
RCHCO2H
2) ClSiR3 /-78 ºC / 2h
3) H+
Scheme 2. a-Silylation of trimethylsilyl esters.
There is no general method to assign the structures of
lithium enolates in solutions, except for isolated cases.
However, mechanistic studies of enolate alkylations have
afforded diverse hypotheses. The reaction could proceed
via dimer-21 or tetramer-based22 intermediates. Recently,
it has been shown that the C-alkylation of b-amino esters
proceeds via hexameric enolates, which exist as such both
in the solid state and in THF solution.23
Based on the above observations, the existence of a
C-lithiated ester enolate has been ruled out. Therefore, it
is likely that O- versus C-silylation depends on the equilib-
rium between the two OLi structures, monomeric ‘A’ and
aggregated ‘B’, as depicted in Scheme 1. Recent work24
has proven that hexameric enolate (OLi structure B) under-
goes C-alkylation directly without deaggregation. Conse-
quently, it is conceivable that the 2 h reaction time before
quenching (described above) is required to obtain an
aggregation state allowing efficient C-silylation at low
temperature.
trimethylsilyl esters of other carboxylic derivatives of the
type RCH2CO2SiMe3 (R = Cl, Ph), which can stabilize a
carbanion at the a position (entries 7–8, Table 1, and
Scheme 2), aiming towards higher yields of the desired C-
silylated products. The a-silylation of these esters was
examined with diphenylmethylchlorosilane which was pre-
ferred over trimethylchlorosilane due to it being a ‘softer’
electrophile and therefore, more reactive towards the
carbon terminus of the ambient nucleophile. Consequently,
C-silylation is favoured with diphenylmethylchlorosilane,
whereas O-silylation is favored with trimethylsilylchlorosi-
lane.15 Surprisingly, the yield of the product with
ClCH2CO2SiMe3 decreased (entry 7) compared to those
obtained with CH3CO2SiMe3 (entries 1–6), while that with
PhCH2CO2SiMe3 was almost nil. These results indicate
that the inductive effect plays a minor role compared with
steric effects. Therefore, the yield of the C-silylated product
is dictated mostly by the bulkiness of the group attached to
the carbon at the a position, that is, it increases in the order
H > Cl > Ph.
After the successful preparation of a-silyl acetic acids
from trimethylsilylacetate we attempted the reaction with
In conclusion, the present study describes the experi-
mental conditions under which C-silylation is preferred
over O-silylation of lithiated trimethylsilyl esters. Appar-
ently, the outcome is very sensitive to the experimental
reaction conditions, substitution pattern at the a position
of the silylated esters and the nature of the silylated
chlorosilane reagent.
Table 1
Yields of a-silylcarboxylic acids of the type (R3Si)CH(R)CO2H
Entry
R
R3
Yield of product (%)
1 (1)
2 (2)
3 (3)
4 (4)
5 (5)
6 (6)
7 (7)
8
H
H
H
H
H
H
Cl
Ph
Me3
n-Pr3
i-Pr3
Ph3
Me2(Ph)
Ph2(Me)
Ph2(Me)
Ph2(Me)
72a
77b
72b,c
70a
75a
Acknowledgement
78a
50b
This research was supported (in part) by The Israel
Science Foundation.
Trace
a
Yield of pure compound.
Yield is based on 1H NMR integration due to difficulties in purification
b
by column chromatography and separation from siloxanes (R3SiOSiR3)
impurities.
Supplementary data
c
This particular acid was obtained as its trimethylsilyl ester. So far,
Experimental procedures, characterization data and
attempts to hydrolyze it have failed. It undergoes decomposition (C–Si
desilylation) in 1 N HCl, stirring for 1 h, at 50 °C, or for 24 h at rt or in 2
N NaOH for 1 h at rt.
1
copies of H, 13C and 29Si NMR spectra of all the a-silyl-
acetic (and other) acids are presented. Supplementary data

A. V. Shtelman, J. Y. Becker / Tetrahedron Letters 49 (2008) 3101–3103
3103
stirring for 2 additional hours at À78 °C the reaction was warmed to
room temperature. A solution of saturated sodium chloride (30 ml)
was added and the reaction mixture was hydrolyzed with 1 N HCl to
pH 3. The aqueous layer was extracted with diethyl ether (30 ml  3)
and the combined organic extracts were washed with water, dried over
anhydrous MgSO4, filtered and concentrated. The residual crude
product was dissolved in 30 ml of THF, and 20 ml of saturated
ammonium chloride solution was added. The reaction mixture was
then stirred at room temperature for 1 h. Afterwards the aqueous
layer was extracted with diethyl ether (30 ml  3) and the combined
organic extracts were washed with water and dried over anhydrous
MgSO4, filtered and concentrated in vacuo. The residual product was
crystallized from hexane to give a-(trialkylsilyl) acetic acids in good
yields. Based on this method, two new a-silyl products have been
prepared: a-tri-n-propylsilylacetic acid (2) and a-triisopropylsilyl
trimethylsilylacetate (3). Spectral data of tri-n-propylsilylacetic acid
(2): 1H NMR (500 MHz, CDCl3) d 0.64–0.68 (m, 6H), 0.96 (t,
J = 17.5 Hz, 9H), 1.27–1.43 (m, 6H), 1.90 (s, 2H), 11.85 (br s, 1H);
13C NMR (125 MHz, CDCl3) d 15.1, 17.0, 18.3, 23.2, 180.7; 29Si
NMR (100 MHz, CDCl3) d 4.3; IR 1687 cmÀ1; MS (MALDI-TOF)
m/z calcd for C11H24O2Si: 216.40. Found 238.93 (MNa+), 260.90
(M2Na+). Spectral data of a-triisopropylsilyl trimethylsilylacetate (3):
1H NMR (500 MHz, CDCl3) d 0.15 (s, 9H), 1.06 (d, J = 7.5 Hz, 18H),
1.26–1.28 (m, 3H), 1.94 (s, 2H); 13C NMR (125 MHz, CDCl3) d À1.3,
12.0, 17.9, 29.0, 173.2; 29Si NMR (100 MHz, CDCl3) d 1.2, 18.7;
LCMS (ESI) m/z calcd for C14H32O2Si2: 288.6. Found 289.1 (MH+),
311.0 (MNa+).
associated with this article can be found, in the online
version, at doi:10.1016/j.tetlet.2008.03.050.
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