γ-p-toluenesulfonyl-α,β-epoxysilane: A new and practical acrolein β-anion equivalent

Article abstract of DOI:10.1021/ol048160t

(Chemical Equation Presented) Reaction of γ-p-toluenesulfonyl- α,β-epoxysilane with alkyl halides and aldehydes followed by treatment with n-Bu₄NF affords α,β-unsaturated aldehydes via a Brook rearrangement-mediated tandem process under extremely mild conditions.

Full text of DOI:10.1021/ol048160t

ORGANIC
LETTERS
2004
Vol. 6, No. 26
4849-4851
γ
-p-Toluenesulfonyl-r,â-epoxysilane: A
New and Practical Acrolein
Equivalent
â-Anion
Michiko Sasaki and Kei Takeda*
Department of Synthetic Organic Chemistry, Graduate School of Medical Sciences,
Hiroshima UniVersity, 1-2-3 Kasumi, Minami-Ku, Hiroshima 734-8551, Japan
takedak@hiroshima-u.ac.jp
Received September 13, 2004
ABSTRACT
Reaction of
γ-p-toluenesulfonyl-r,â-epoxysilane with alkyl halides and aldehydes followed by treatment with n-Bu4NF affords r,â-unsaturated
aldehydes via a Brook rearrangement-mediated tandem process under extremely mild conditions.
R,â-Unsaturated aldehydes are important synthetic interme-
diates for a variety of chemical transformations and are also
found in many diverse classes of bioactive organic molecules.
Consequently, much effort has so far been devoted to the
development of synthetic methods for introducing or install-
ing this functionality. Among these, the most general and
commonly used methods include the Wittig-type homolo-
gation1 and the use of â-acyl vinyl anion equivalents.2 The
latter have been especially well studied ever since the first
report by Corey of a process in which 1,3-bis(methylthio)-
allyllithium was used as an acrolein â-anion equivalent.3
Most of these methods, however, require relatively harsh
reaction conditions to unmask the R,â-unsaturated aldehyde.
Herein, we report a new and practical acrolein â-anion
equivalent that is based on a Brook rearrangement-mediated
isomerization of epoxysilanes.
Recently, we observed that O-silyl cyanohydrins 1 of
â-silyl-R,â-epoxyaldehydes can function as â-siloxy allylic
carbanion equivalents via a tandem sequence (1 f 2) that
involves a base-promoted ring opening, Brook rearrange-
ment, and allylic alkylation (Scheme 1).4
Scheme 1. Tandem Base-Promoted Ring-Opening/Brook
Rearrangement/Allylic Alkylation of 1
This result led us to envision that metalated epoxysilane
3, with a leaving group at the γ-position, would react with
an electrophile to produce 4, which could be easily trans-
formed into the conjugated aldehyde 5 by desilylation with
concomitant elimination of the leaving group.
(1) (a) Nicolaou, K. C.; Ha¨rter, M. W.; Gunzner, J. L.; Nadin, A. Liebigs
Ann. Chem. 1997, 1283-1301. (b) Mann, S.; Carillon, S.; Breyne, O.;
Marquet, A. Chem.sEur. J. 2002, 8, 439-450.
(2) (a) Chinchilla, R.; Najera, C. Chem. ReV. 2000, 100, 1891-1928.
(b) Funk, R. L.; Bolton, G. L. J. Am. Chem. Soc. 1988, 110, 1290-1292.
(c) Pohmakotr, M.; Pisutjaroenpong, S. Tetrahedron Lett. 1985, 26, 3613-
3616. (d) Reich, H. J.; Clark, M. C.; Willis, W. W., Jr. J. Org. Chem. 1982,
47, 1618-1623. (e) Ogura, K.; Iihama, T.; Takahashi, K.; Iida, H.
Tetrahedron Lett. 1984, 25, 2671-2674. (f) Clinet, J.-C.; Linstrumelle, G.
Tetrahedron Lett. 1980, 21,3987-3990. (g) Cohen, T.; Bennett, D. A.; Mura,
A. J., Jr. J. Org. Chem. 1976, 41, 2506-2507. (h) Wada, M.; Nakamura,
H.; Taguchi, T.; Takei, H. Chem. Lett. 1977, 4, 345-348. (i) Kondo, K.;
Tunemoto, D. Tetrahedron Lett. 1975, 1007-1010. (j) Nakai, T.; Shiono,
H.; Okawara, M. Tetrahedron Lett. 1974, 3625-3628. (k) Leroux, Y.;
Mantione, R. Tetrahedron Lett. 1971, 591-592.
Scheme 2. Epoxysilanes 3 as an Acrolein â-Anion Equivalent
(3) Corey, E. J.; Erickson, B. W.; Noyori, R. J. Am. Chem, Soc. 1971,
93, 1724-1729.
10.1021/ol048160t CCC: $27.50
© 2004 American Chemical Society
Published on Web 11/23/2004

Table 1. One-Pot Synthesis of 91a,2b,8
Scheme 3. Preparation of 7 and Its Reaction with PhCH2Br
Followed by Demasking to 9
yield
(%)
RX
conditions
BrCH2Ph
1. -80 to -60 °C, 30 min
2. -80 to -70 °C, 15 min
1. -80 to -50 °C, 40 min
2. -80 to -70 °C, 20 min
1. -80 to -50 °C, 30 min
2. -80 to -70 °C, 15 min
85
84
82
68
74
ICH2(CH2)6CH3
BrCH2CHdCH(CH2)4CH3
We considered that the choice of the substituent Z would
be a key factor in controlling the success of the process.
Specific requirements for the group Z would be as follows.
It should have an ability to enhance the acidity of the
R-proton while giving a sufficiently reactive carbanion to
open the epoxide ring and lead to Brook-type rearrangement,
and thereafter serve as an effective leaving group for
subsequent â-elimination. We examined a variety of leaving
groups that fulfilled the above requirement, including pyridin-
2-sulfinyl, phenylsulfonyl, and p-toluenesulfonyl. Among
them, p-toluenesulfonyl derivative 7, which was prepared
from the known epoxy silane 65 readily derived from
propargyl alcohol, was found to provide the best result.6
When NaN(SiMe3)2 (NHMDS) was added to a cooled (-80
°C) solution of 7 and benzyl bromide, the reaction mixture
was allowed to warm to -60 °C over 30 min, and silyl enol
ether 8 was obtained in 93% yield. Conversion of 8 into the
conjugated aldehyde 9a7,2b was carried out by treatment with
n-Bu4NF in 86% yield. It should be noted that 7 does not
need chromatographic purification and possesses excellent
shelf stability at room temperature.
The effectiveness of the above process and the clean
reaction conditions prompted us to examine the entire
reaction in a one-pot process. When n-Bu4NF was added to
the reaction mixture at -80 °C after the initial alkylation
had been completed, 9a was obtained in much lower yields
(ca. 20-60%). However, this procedure did not always
provide consistent results. We attributed the lack of repro-
ducibility to a loss of homogeneity in the reaction due to
the increased viscosity of TBAF solution at lower temper-
atures. The use of diluted TBAF solution resulted in a slow
reaction and required an elevated temperature for completion,
which caused siginificant decomposition of the product even
ICH2CH2CH2CH2OSiMe2But 1. -80 to -40 °C, 45 min
2. -80 to -70 °C, 15 min
ICH2CH2CH2CO2Et
1. -80 °C, 5 min; then RX
-80 to -40 °C, 45 min
2. -80 to -70 °C, 20 min
at -70 °C. We suspected that the generation of nucleophilic
ammonium p-toluenesulfinate derivatives might be respon-
sible for the decomposition. To circumvent this side reaction,
we considered the addition of alcohols, expecting that the
enhanced solubility of TBAF would enable the reaction to
be accelerated and conducted at lower temperatures.
Accordingly, a THF solution of 7 and PhCH2Br was
treated with NHMDS at -80 °C and allowed to warm to
-60 °C. To this solution, recooled to -80 °C, was added
n-Bu4NF (1.0 equiv)/EtOH (3 equiv), and the solution was
allowed to warm to -70 °C. After the usual workup and
chromatographic purification, R,â-conjugated aldehyde 9a
was obtained in 85% yield (Table 1). The reaction of other
halides also proceeded well. It is noteworthy that the reaction
can tolerate functional groups such as siloxy and ester (entries
4 and 5). The reaction was also successful with an aldehyde
to give γ-hydroxy-R,â-unsaturated aldehydes 10 (Table 2).
Table 2. One-Pot Synthesis of 10
RCHO
yield (%)
(4) (a) Takeda, K.; Kawanishi, E.; Sasaki, M.; Takahashi, Y.; Yamaguchi,
K. Org. Lett. 2002, 4, 1511-1514. (b) Sasaki, M.; Kawanishi, E.; Nakai,
Y.; Matsumoto, T.; Yamaguchi, K.; Takeda, K. J. Org. Chem. 2003, 68,
9330-9339.
CH3(CH2)4CHO
(CH3)2CHCHO
(CH3)3CCHO
77a
71
80
(5) This compound was obtained with only one chromatographic
purification from propargyl alcohol by a six-step sequence; (1) protection
with ethoxy ethyl group, (2) n-BuLi/TBSCl, (3) p-TsOH/aq acetone, (4)
Red-Al reduction, (5) mCPBA, (6) MsCl/py and then NaI. See: Achma-
towicz, B.; Raubo, P.; Wicha, J. J. Chem. Soc., Perkin Trans. 1 1995, 17,
2193-2195.
(6) Treatment of pyridin-2-sulfinyl derivative with NHMDS in the
presence of benzyl bromide afforded a complex mixture. Although a similar
result was obtained with both phenylsulfonyl and p-toluenesulfonyl deriva-
tives, the latter is superior in terms of crystallizability.
a CH3COOH (1.0 equiv) was added in the desilylation.
In conclusion, we have demonstrated that γ-sulfonyl-R,â-
epoxysilane derivative 7 can serve as a practically useful
(8) Craig, D.; Etheridge, C. J.; Smith, A. M. Tetrahedron Lett. 1992,
33, 7445-7446.
(7) Rodney, F. A.; Pradeep, K. Tetrahedron Lett. 2003, 44, 1275-1278.
4850
Org. Lett., Vol. 6, No. 26, 2004

acrolein â-anion equivalent via a Brook rearrangement-
mediated tandem process.
roshima University, and the Natural Science Center for Basic
Research and Development (N-BARD), Hiroshima Univer-
sity, for the use of their facilities.
Acknowledgment. This research was partially supported
by the Ministry of Education, Science, Sports and Culture,
Japan, Grants-in-Aid for Scientific Research (B), No.
15390006, 2003, and Exploratory Research, No. 14657563,
2002, and the Naito Foundation. We thank the Research
Center for Molecular Medicine, Faculty of Medicine, Hi-
Supporting Information Available: Full experimental
details and characterization data for all new compounds
described in the text. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL048160T
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