A practical protocol for the highly E-selective formation of aryl-substituted silylketene acetals

Article abstract of DOI:10.1021/ol101580y

The E/Z-selectivity in the formation of silylketene acetals derived from phenylacetate esters, mediated by LiHMDS, has been studied by in situ NMR techniques. The formation is seen to be highly E-selective with use of the newly developed protocol. Isolated aryl-substituted silylketene acetals are now attainable with high levels of E-geometrical purity in excellent yield.

Full text of DOI:10.1021/ol101580y

ORGANIC
LETTERS
2010
Vol. 12, No. 16
3712-3715
A Practical Protocol for the Highly
E-Selective Formation of
Aryl-Substituted Silylketene Acetals
Wesley R. R. Harker,† Emma L. Carswell,‡ and David R. Carbery*,†
Department of Chemistry, UniVersity of Bath, Bath, BA2 7AY, United Kingdom, and
MSD, Newhouse, Motherwell, ML1 5SH, United Kingdom
d.carbery@bath.ac.uk
Received July 8, 2010
ABSTRACT
The E/Z-selectivity in the formation of silylketene acetals derived from phenylacetate esters, mediated by LiHMDS, has been studied by in situ
NMR techniques. The formation is seen to be highly E-selective with use of the newly developed protocol. Isolated aryl-substituted silylketene
acetals are now attainable with high levels of E-geometrical purity in excellent yield.
Silylketene acetals are versatile and reactive nucleophiles
which find widespread use in organic synthesis,1 and in
particular, C-C bond forming contexts such as aldol2 and
Ireland-Claisen [3,3]-sigmatropic rearrangement reactions.3
In many situations the diastereoselectivity and/or enantiose-
lectivity of the studied transformation is dependent upon the
E/Z ratio of the silylketene acetal.4 Therefore, controlling
the E/Z ratio during the formation of the silylketene acetal
unit can be crucial for a successful and stereoselective
reaction.
As aromatic functionality is ubiquitous in organic chem-
istry, the controlled formation of silylketene acetals bearing
aromatic substituents and their subsequent transformations
can be regarded as an important issue. However, in the
majority of instances, aryl-substituted silylketene acetals are
typically formed and used with moderate levels of E/Z purity.
A number of recent transformations with phenylacetate
derived silylketene acetals have done so with levels of E/Z
purity between 2:1 and 4:1.5-7 Studies have concluded that,
although the E-enolate from phenylacetate esters forms
kinetically, unsuitable and impractical E/Z mixtures are
ultimately isolated.8,9 The inability to prepare aryl-substituted
† University of Bath.
‡ MSD.
(1) For selected recent synthetic usage of silylketene acetals, see: (a)
Nishiyama, Y.; Kaiba, K.; Umeda, R. Tetrahedron Lett. 2010, 51, 793. (b)
Le Engers, J.; Pagenkopf, B. L. Eur. J. Org. Chem. 2009, 6109. (c) Shiina,
I.; Iizumi, T.; Yamai, Y.; Kawakita, Y.; Yokoyama, K.; Yamada, Y.
Synthesis 2009, 2915. (d) Kise, N.; Isemoto, S.; Sakurai, T. Org. Lett. 2009,
11, 4902. (e) Denmark, S. E.; Eklov, B. M.; Yao, P. J.; Eastgate, M. D.
J. Am. Chem. Soc. 2009, 131, 11770. (f) Alaimo, P. J.; O’Brien, R.; Johnson,
A. W.; Slauson, S. R.; O’Brien, J. M.; Tyson, E. L.; Marshall, A.-L.;
Ottinger, C. E.; Chacon, J. G.; Wallace, L.; Paulino, C.; Connell, Y. S.
Org. Lett. 2008, 10, 5111. (g) Alden-Danforth, E.; Scerba, M. T.; Lectka,
T. Org. Lett. 2008, 10, 4951. (h) Zikou, L. C.; Igglessi-Markopoulou, O.
Synthesis 2008, 1861. (i) Denmark, S. E.; Chung, W. J. Org. Chem. 2008,
73, 4582. (j) Cho, D. W.; Lee, H.-Y.; Oh, S. W.; Choi, J. H.; Park, H. J.;
Mariano, P. S.; Yoon, U. C. J. Org. Chem. 2008, 73, 9. (k) Reisman, S. E.;
Doyle, A. G.; Jacobsen, E. N. J. Am. Chem. Soc. 2008, 130, 7198. (l) Notte,
G. T.; Leighton, J. L. J. Am. Chem. Soc. 2008, 130, 6676. (m) Denmark,
S. E.; Chung, W.-J. Angew. Chem., Int. Ed. 2008, 47, 1890. (n) Song, J. J.;
Tan, Z.; Reeves, J. T.; Fandrick, D. R.; Yee, N. K.; Senanayake, C. H.
Org. Lett. 2008, 10, 877. (o) Cho, S. W.; Romo, D. Org. Lett. 2007, 9,
1537.
(3) For recent reviews concerning the Ireland-Claisen rearrangement,
see: (a) Castro, A. M. Chem. ReV. 2004, 104, 2939. (b) Chai, Y. H.; Hong,
S. P.; Lindsay, H. A.; McFarland, C.; McIntosh, M. C. Tetrahedron 2002,
58, 2905. (c) McFarland, C. M.; McIntosh, M. C. The Claisen Rearrange-
ment; Hiersemann, M. N., Nubbemeyer, U. , Eds.; Wiley-VCH Verlag
GmbH & Co. KGaA: Weinheim, Germany, 2007; p117
.
(4) For a specific discussion regarding the relevance of E/Z silylketene
acetal geometry to diastereoselection in the Ireland-Claisen [3,3]-sigma-
tropic rearrangement, see: Ireland, R. E.; Wipf, P.; Armstrong, J. D. J. Org.
(2) For an overview, see: Modern Aldol Reactions; Mahrwald, R., Ed.;
Wiley-VCH Verlag GmbH & Co. KGaA: Weinheim, Germany, 2004.
Chem. 1991, 56, 650
.
10.1021/ol101580y  2010 American Chemical Society
Published on Web 07/29/2010

silylketene acetals in high geometrical purity suggests a
significant gap in the synthetic repertoire, which would
benefit from the devlopment of a new protocol to answer
this issue.
°C and finally at 25 °C.13 However, these initial experiments
were complicated by the overlap of the isopropyl methine
signal with the minor Z-silylketene acetal signals, leading
to an inability to detect E/Z silylketene acetal ratios. To
overcome this, H1-isopropyl phenylacetate 3a was instead
examined (Scheme 2).
2
Our own experience with silylketene acetals in an
Ireland-Claisen rearrangement context10,11 has prompted us
to re-examine this issue of E/Z control during the formation
of silylketene acetals derived from phenylacetates. We were
keen to closely model the expected silylketene acetal
formation from enamide-phenylacetate 1 as this rearrange-
ment had been observed to proceed with particularly high
diastereoselectivity (Scheme 1).
Scheme 2. Silylketene Acetal Formation of Phenylacetate 3a
Scheme 1. Ireland-Claisen Rearrangement of an Enamide
The data obtained from this initial experiment were
informative with only a single E-silylketene acetal isomer
observed at -95 °C. However, on warming to -50 °C and
to 25 °C a change in E/Z purity was observed (E/Z ) 61:1
and 30:1, Figure 1).
The time dependence of starting material consumption and
E/Z ratio has been followed at the intermediate temperature
of -50 °C (Figures 2 and 3). This monitoring clearly
demonstrates an initial fast yet partial consumption (ca. 30%)
of ester 3a, which was unexpected at the loading level of
LiHMDS used (1.7 equiv, Figure 2). After 3 h the reaction
mixture is warmed to 25 °C (final data point) with an ensuing
jump in the consumption of 3a.
Accordingly, isopropyl phenylacetate was initially chosen
as a model substrate, mirroring the secondary ester motif
seen in 1. An internal quench was utilized with the addition
of an isopropyl phenylacetate solution to a mixture of
Me3SiCl and LiHMDS in a dry NMR tube at -95 °C under
a stream of N2. The NMR tube was then rapidly transferred
to the precooled spectrometer prior to NMR experimentation.
2
A similar scenario is observed when monitoring the E/Z
ratio of the forming silylketene acetal (Figure 3). Initially
high levels of E/Z control are observed. A plateau in the
level of silylketene acetal E/Z geometry is observed while
the conversion remains low. However, on warming to room
temperature a striking worsening of the observed silylketene
acetal E/Z ratio is seen to occur (final data point, Figure 3).
The observation presented in Figure 1, i.e. high levels
of E/Z control, requires consideration in the context of
the previously reported studies concerning the formation
of phenylacetate derived silylketene acetals with poor E/Z
control. The conditions used by Fuji8a and Solladie´-
Cavallo8c involve the use of LDA (1.2 equiv) and an
external Me3SiCl quench (4 equiv) 30 min after initiation
of enolate formation at -78 °C. However, the most
interesting comparison is with the study of Corset,8b which
most closely mirrors the protocol presented in this
communication where both LiHMDS (1.2 equiv at -70
°C) and an internal Me3SiCl quench (6 equiv) are used.
However, an isolated E/Z ratio of 4:1 in the Corset study
contrasts markedly with the level of E/Z selectivity
Standard THF has been used without recourse to H8 THF,
for NMR spectroscopy, more closely mimicing the developed
synthetic conditions even though locking and shimming
operations at cryogenic temperatures become more chal-
lenging.12
We were delighted to observe the formation of the
expected silylketene acetal at -95 °C, on warming to -50
(5) (a) Su, S.; Porco, J. A. Org. Lett. 2007, 9, 4983. (b) Ollevier, T.;
Nadeau, E. Org. Biomol. Chem. 2007, 5, 3126. (c) Ollevier, T.; Nadeau, E.
Synlett 2006, 219. (d) Itoh, J.; Fuchibe, K.; Akiyama, T. Synthesis 2006,
4075. (e) Akiyama, T.; Matsuda, K.; Fuchibe, K. Synthesis 2005, 2606. (f)
Akiyama, T.; Itoh, J.; Fuchibe, K. Synlett 2002, 1269. (g) Akiyama, T.;
Takaya, J.; Kagoshima, H. AdV. Synth. Catal. 2002, 344, 338
.
(6) Mioskowski and co-workers have reported the preparation of three
para-substituted aryl substituted silylketene acetals with the p-methoxy
system reported as a 13:1 E/Z mixture; see: Heurtaux, B.; Lion, C.; Le
Gall, T.; Mioskowski, C. J. Org. Chem. 2005, 70, 1474
.
(7) The use of highly Z-enriched phenyl acetate derived silylketene
acetals in Rh(II)-catalyzed aminations has been described. However, the
method of silylketene acetal formation is not discussed, see :Tanaka, M.;
Kurosaki, Y.; Washio, T.; Anada, M.; Hashimoto, S. Tetrahedron Lett. 2007,
48, 8799
.
(8) (a) Tanaka, F.; Fuji, K. Tetrahedron Lett. 1992, 33, 7885. (b) Corset,
J.; Froment, F.; Lautie, M. F.; Ratovelomanana, N.; Seyden-Penne, J.;
Strzalko, T.; Roux-Schmitt, M. C. J. Am. Chem. Soc. 1993, 115, 1684. (c)
Solladie-Cavallo, A.; Csaky, A. G. J. Org. Chem. 1994, 59, 2585
.
(9) For a study of the sensitivity of enolization conditions in the aldol
reaction of phenylacetate esters, see: Pinheiro, S.; Lima, M. B.; Gonc¸alves,
C. B. S. S.; Pedraza, S. F.; de Farias, F. M. C. Tetrahedron Lett. 2000, 41,
(12) The use of a sealed tube insert to assist NMR locking was
considered. However, drying the sealed insert carefully becomes
impractical, leading to potential synthetic complications. Solvent sup-
pression techniques were not required as THF and silylketene acetal
signals were not coincident.
(13) The intermediate temperature of -50 °C was chosen as
quenching studies have shown that rearrangement of 1 proceeds smoothly
at -50 °C.
4033
(10) Ylioja, P. M.; Mosley, A. D.; Charlot, C. E.; Carbery, D. R.
Tetrahedron Lett. 2008, 49, 1111
.
.
(11) Tellam, J. P.; Kociok-Ko¨hn, G.; Carbery, D. R. Org. Lett. 2008,
10, 5199
.
Org. Lett., Vol. 12, No. 16, 2010
3713

1
Figure 1. Variable temperature H NMR study of silylketene acetal formation of phenylacetate 3a in THF. Line broadening due to poor
shimming at low temperature.
Table 1. Control Experiments
4 (E/Z)a
(-95 °C)
4 (E/Z)a
(-50 °C)
4 (E/Z)a
(25 °C)
entry
M
R (equiv)
1
Li
Li
Li
Li
Li
Li
Na
Li
Li
Me (1.7)
Me (1.7)
Me (6)
>100:1
71:1
61:1
42:1
>100:1
>100:1d
8:1
>100:1
8:1
10:1
30:1
16:1
64:1
56:1
5:1
33:1
6:1
4:1
2b
3
>100:1
>100:1
>100:1
>100:1
-
>100:1
>100:1
4:1
4c
5
6
7
8
Me (6)
Me (1.7)e
Me (1.1)
Me (6)
Figure 2. Time dependence of percent 3a present in the formation
of silylketene acetal 4a at -50 °C. Initial data point (t ) 0) observed
at -95 °C prior to warming to -50 °C. Final data point measured
at 25 °C.
iPr (6)
Et (6)
Me (6)
9
10
>100:1
4:1
22:1
4:1
f
-
a E/Z ratio measured by 1H NMR integration of appropriate silylketene
acetal signals. b Initiated at -78 °C. c Observed at -65 °C for 60 min.
d Observed at -25 °C. e External quench: Me3SiCl added to reaction mixture
30 min after initiation of enolate generation. f LDA used as base.
These control experiments have been informative and clearly
point to temperature control and enolate lifetime as key
parameters in accessing high E/Z purity. Accordingly, initiation
at higher temperatures (entry 2), the use of an external quench
(entry 5), and lower loadings of silyl chloride (entry 6) all lead
to diminished E/Z purity. In contrast higher loadings of
trimethylsilyl chloride lead to a more rapid silylation and
reduced E/Z interconversion (entries 3 and 4). Indeed, complete
silylation is now observed at -50 °C after approximately 20
min; in all other instances a similar pattern of subtrate
conversion is oberved to that originally displayed in Figure 2.
The nature of the amide base counterion is crucial with
NaHMDS leading to reduced E/Z control (entry 7). Bulkier silyl
chlorides also lead to lowered E/Z control (entries 8 and 9).
Finally, the necessity of a disilazide base is apparent when
compared with the poor E/Z control observed with LDA, in
agreement with the prior studies (entry 10).8
Figure 3. Time dependence of E/Z control in the formation of 4a
at -50 °C. Initial data point (t ) 0) observed at -95 °C prior to
warming to -50 °C. Final data point measured at 25 °C.
obtained with the presented protocol. In an attempt to
clarify these differences we have performed a number of
control experiments aimed at identifying the key features
controlling the high levels of E-silylketene acetal purity
seen in this protocol (Table 1).
In the instance of silylketene acetal 4a, we have observed
that an NMR sample in THF retained a significant excess of
3714
Org. Lett., Vol. 12, No. 16, 2010

the E-geometrical isomer after extended periods of time at
room temperature. Accordingly, after 48 h, the E/Z ratio was
observed as 10:1. This ratio remains significantly in excess
of the ratios described in the literature and points toward
this simple protocol for silylketene acetal formation being
valuable in organic synthesis. For this study to offer synthetic
utility we have looked to isolate these silylketene acetals with
high levels of E/Z purity. Excellent yields of isolated
silylketene acetals derived from phenylacetates are obtained
with good to excellent E/Z control (Table 2).
By employing an excess of silyl chloride, adding the
substrate slowly by syringe pump, and holding the reaction
before warming to room temperature, excellent E/Z ratios
i
of the Pr-silylketene acetal can be obtained (entry 3). The
sensitivity of E/Z control should also be noted, with higher
E/Z control obtained relative to the use of the Me ester 3b
t
(entry 4) or Bu ester 3c (entry 5).
In conclusion, E/Z control during the formation of phe-
nylacetate derived silylketene acetals is reported and is
observed to be highly E-selective for the first time with this
reported protocol, in contrast to current literature understand-
ing. The precise level of E-purity and the rate of E/Z
isomerization is not only dependent on the nature of the ester
alkoxy moiety, but in fact is highly influenced by initiation
temperatures and the rate of silylation. We are currently
examining the nature and rate of enolate interconversion
relative to silylation and will report in due course.
Table 2. Isolation of Phenylacetate-Derived Silylketene Acetals
Acknowledgment. We gratefully thank EPSRC, Univer-
sity of Bath, and MSD for studentship funding (W.R.R.H.).
The EPSRC Mass Spectrometry Service, University of
Swansea, is thanked for mass spectral analysis. We would
like to offer thanks to Dr. John Lowe (Bath), Dr. Samantha
Rutherford, and Mr. Ross Lennen (MSD) for assistance with
performing NMR experiments and NMR data manipulation.
entry
ester
methoda
R
(E/Z)b
yieldc
1
2
3
4
5
3a
3a
3a
3b
3c
A
B
C
C
C
CDMe2
CDMe2
CDMe2
Me
68:1
17:1
>100:1
67:1
81
88
82
80
76
C(Me)3
25:1
a Methods: (A) ester added to base via syringe pump and Me3SiCl (1.7
equiv) before warming to room temperature; (B) ester added to base by
hand and Me3SiCl (1.7 equiv) before warming to room temperature; and
(C) ester added to base via syringe pump and Me3SiCl (6 equiv), holding
at -95 °C for 30 min before warming to room temperature. b E/Z ratio
measured by 1H NMR integration of appropriate silylketene acetal signals.
c Isolated yield.
Supporting Information Available: Experimental pro-
cedures, compound characterization data, and NMR spectra.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL101580Y
Org. Lett., Vol. 12, No. 16, 2010
3715