Intramolecular [1,4]- S - To O -Silyl migration: A useful strategy for synthesizing z -silyl enol ethers with diverse thioether linkages

Article abstract of DOI:10.1021/ol403709g

An intramolecular [1,4]-S- to O-silyl migration has been used to form silyl enol ethers with Z-configurational control. The silyl migration also creates a new anion center at sulfur, which can subsequently react with electrophiles to generate Z-silyl enol ethers with diverse thioether linkages. The synthetic utility of this pathway was demonstrated by modifying the Z-silyl enol ethers with aldehydes via a Mukaiyama aldol reaction or Prins cyclization to generate functionalized organosulfur compounds.

Full text of DOI:10.1021/ol403709g

Letter
pubs.acs.org/OrgLett
Intramolecular [1,4]‑S- to O‑Silyl Migration: A Useful Strategy for
Synthesizing Z‑Silyl Enol Ethers with Diverse Thioether Linkages
Changzhen Sun,†,‡ Yuebao Zhang,†,‡ Peihong Xiao,† Hongze Li,† Xianwei Sun,† and Zhenlei Song*,†,‡
†Key‡Laboratory of Drug-Targeting of Education Ministry and Department of Medicinal Chemistry, West China School of Pharmacy,
and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, P. R. China
S
* Supporting Information
ABSTRACT: An intramolecular [1,4]-S- to O-silyl migration has been used to form silyl enol ethers with Z-configurational
control. The silyl migration also creates a new anion center at sulfur, which can subsequently react with electrophiles to generate
Z-silyl enol ethers with diverse thioether linkages. The synthetic utility of this pathway was demonstrated by modifying the Z-silyl
enol ethers with aldehydes via a Mukaiyama aldol reaction or Prins cyclization to generate functionalized organosulfur
compounds.
ilyl enol ethers1 are important synthons in a broad array of
synthetic transformations. The double-bond configuration
organic chemistry,4 the corresponding migration from a sulfur
to an oxygen has rarely been studied.5,6 This transformation
should be thermodynamically favorable because the Si−O bond
is stronger than the Si−S bond (ca. 110 vs 70 kcal/mol).7
Intrigued by the potential ease of this silyl migration,8 we
envisioned using it to form silyl enol ethers with configurational
control. In our proposed process (Scheme 1, bottom),
deprotonation of the α-silylthio ketone 1 would generate a
mixture of enolates E-2 and Z-2. It should be possible to shift
the product equilibrium permanently toward Z-2 if only the Z-
enolate could undergo intramolecular [1,4]-S- to O-silyl
migration rapidly and irreversibly to thiometallo Z-silyl enol
ether 3. The sulfur would act not only as a carrier for the silyl
migration but also as an anion center in 3 for the subsequent
formation of a C−S bond with electrophiles. In this way, a
thioether linkage9 could be introduced into 3 to provide Z-silyl
enol ether 4. Here, we report detailed studies of this reaction
pathway.
S
is a key determinant of the stereochemical outcomes of
reactions in which they participate, making the preparation of
geometrically defined silyl enol ethers a longstanding goal of
organic synthesis.2 Traditionally silyl enol ethers are synthe-
sized by α-deprotonation of carbonyl compounds, followed by
intermolecular silylation of the resulting enolate. Extensive
studies have shown that deprotonating acyclic ketones under
kinetic conditions favors formation of E-enolate, while
deprotonating the ketone under thermodynamic conditions
favors the Z-enolate (Scheme 1, top). However, this configura-
Scheme 1. Intermolecular Silylation of Enolate To Form E-
and Z-Silyl Enol Ether (Top). Intramolecular [1,4]-S- to O-
Silyl Migration Leads to Z-Silyl Enol Ether (Bottom)
The model scaffold α-silylthio ketone 1a was prepared in
92% yield by substituting α-bromo acetophenone with
commercially available HSSi(i-Pr)3. The reaction was initially
performed in THF using LiHMDS as the base and 1.2 equiv of
HMPA as additive (Table 1, entry 1). After deprotonation at
−78 °C for 2.0 h, the reaction was warmed to 0 °C to promote
S- to O-silyl migration and subsequent S-allylation with
allylbromide. The Z-silyl enol ether 4a was obtained in 41%
yield as a single isomer. The low efficiency is probably because
the relatively strong Li+ counterion retards both silyl migration
and S-allylation. Indeed, using the weaker counterions Na+ or
K+ led to higher yields of 74% and 52%, respectively (entries 2
and 3).10 The fact that we observed no O-allylation implies that
tional control is sometimes inefficient and unreliable, high-
lighting the need for intermolecular reactions that provide
better stereochemical control.
A potentially better alternative might be via an intramolecular
pathway through silyl migration.3 Surprisingly, although
intramolecular anionic silyl migration between a carbon and
an oxygen atom is a well-established, valuable process in
Received: December 21, 2013
Published: January 28, 2014
© 2014 American Chemical Society
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Table 1. Screening of Reaction Conditions
Table 2. Scope of Electrophiles
c
entry
1
base
solvent
HMPA (equiv)
yield (%)
LiHMDS
NaHMDS
KHMDS
NaHMDS
NaHMDS
THF
THF
THF
THF
Et2O
1.2
1.2
1.2
41
74
52
71
65
a
2
3
4
5
1.2
a
Reaction conditions: 0.15 mmol of 1a, 0.18 mmol of HMPA, and
0.20 mmol of NaHMDS (1.0 M in THF) in 2.0 mL of THF at −78
°C, 2.0 h, warmed to 0 °C, 0.5 h; then 0.13 mmol of allylbromide at 0
b
°C, 2.0 h. The Z-configuration was assigned by NOE experiments on
c
4a. Ratios were determined by 1H NMR spectroscopy. Isolated yields
after purification by silica gel column chromatography.
the S- to O-silyl migration is irreversible. The reaction
proceeded readily with NaHMDS in the absence of HMPA,
though a longer allylation time was required to achieve a final
yield of 71% (entry 4). Et2O was also a less effective solvent
than THF, giving 4a in 65% yield (entry 5).
Next, the scope of electrophiles was tested using 1a and a
range of alkyl halides (Table 2, entries 1−3), benzyl bromide
(entry 4), and propargyl bromide (entry 5). These reactions
gave Z-silyl enol ethers 4a−f tethered with diverse thioether
linkages. Monosubstituted and geminal disubstituted epoxides
also proved to be suitable electrophiles. The ring-opening
occurred regioselectively at the less substituted carbon to afford
4g−l in good yields (entries 6−11). Neither intra- nor
intermolecular O- to O-silyl migration was observed after
epoxide opening.
The multicomponent reaction was compatible with α-
silylthio ketones 1b−f that contained an alkyl group (Table
3, entry 1), an electron-rich or -deficient phenyl group (entries
2 and 3), or a heterocyclic moiety (entries 4 and 5). The
temperature for epoxide opening had to be increased to 60 °C
to ensure a good yield, except for the reaction in entry 3.
Although ketone 1b possessed two α-methylenes on each side
of the carbonyl group, deprotonation occurred regioselectively
at the thio-substituted methylene, even though this position is
more sterically hindered. This selectivity may be because the H
on the thio-substituted methylene is more acidic.
A control experiment was performed using an equimolar
mixture of 1a and acetophenone 5 under optimal conditions
(Scheme 2). The reaction with epoxide led to Z-silyl enol ether
4i in 68% yield. The original 5 was recovered in 98% yield, and
no intermolecular silylation product 6 was detected. These
results indicate that under our reaction conditions formation of
4i proceeds by intramolecular [1,4]-S- to O-silyl migration of
the corresponding Z-enolate. In contrast, β-thiosilyl propio-
phenone 7, which contains an additional methylene between
the carbonyl and thio groups, gave a complex reaction that did
not generate the expected thiometallo Z-silyl enol ether 8. The
failure to form 8 probably reflects the longer transfer distance
for [1,5]-S- to O-silyl migration, making it less favorable than
the analogous [1,4]-migration.8,11
a
b
Ratios were determined using 1H NMR spectroscopy. Isolated
yields after purification by silica gel column chromatography.
ketone 9a in 68% yield and with syn-stereochemical control.
Performing the reaction with branched or unbranched alkyl
aldehydes directly generated, respectively, α-thio β-hydroxy
ketones 9b in 50% yield or 9c in 93% yield.
In addition, we showed that Z-silyl enol ethers prepared from
epoxides subsequently underwent an S-tethered Prins cycliza-
tion with an aldehyde.13 This approach proceeded through a
chairlike transition state TS-11 to afford a wide range of
functionalized 1,4-oxathianes 11 in good yields and with 2,6-
cis/5,6-trans stereochemical control (Scheme 4). As some 1,4-
oxathianes selectively activate the ideal M3 receptor subtype,14
the synthetic approach we describe here may be useful for
generating new potential muscarinic receptor agonists.
In summary, intramolecular [1,4]-S- to O-silyl migration has
been utilized to form silyl enol ethers with Z-configurational
control. The silyl migration also creates a new anion center at
sulfur, which can subsequently react with electrophiles to
generate Z-silyl enol ethers with diverse thioether linkages. The
synthetic value of this approach was demonstrated by further
To demonstrate the synthetic utility of our approach, the
resulting Z-silyl enol ether 4b was used as a valuable synthon in
Mukaiyama aldol reactions12 with aldehydes (Scheme 3). The
reaction using benzaldehyde gave α-thio β-silylated hydroxy
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Table 3. Scope of α-Silylthio Ketone
Scheme 4. S-Tethered Prins Cyclization of 4i with
Aldehydes
a
a
b
1
Ratios were determined by H NMR spectroscopy. Isolated yields
c
after purification by silica gel column chromatography. Epoxide
a
Reaction conditions: 0.10 mmol of 4i, 0.20 mmol of aldehyde, and
opening was performed at 0 °C.
b
0.10 mmol of TMSOTf in 1.5 mL f Et2O, −78 to 0 °C. Isolated yields
after purification by silica gel column chromatography. The 2,6-cis/
5,6-trans-stereochemistry was assigned based on NOE experiments on
11a. Ratios were determined by H NMR spectroscopy.
c
Scheme 2. Control Experiment To Confirm the
Intramolecular [1,4]-S- to O-Silyl Migration and Attempts
To Achieve [1,5]-S- to O-Silyl Migration of 7
1
reacting the Z-silyl enol ethers with aldehydes via the
Mukaiyama aldol reaction or the Prins cyclization to provide
functionalized organosulfur compounds. Further applications of
this methodology are underway.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures and spectra data for products. This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
a
Scheme 3. Mukaiyama Aldol Reaction of 4b with Aldehydes
*E-mail: zhenleisong@scu.edu.cn.
Author Contributions
‡These authors contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for financial support from the NSFC
(21172150, 21321061, 21290180), the NBRPC (973 Program,
2010CB833200), the NCET (12SCU-NCET-12-03), and
Sichuan University 985 project.
a
Reaction conditions: 0.10 mmol of 4b, 0.20 mmol of aldehyde, and
b
0.10 mmol of Lewis acid in 1.5 mL of CH2Cl2 at −78 °C. BF3·OEt2
was used to generate 9a and 9b; TiCl4, to generate 9c. The syn-
c
stereochemistry was assigned based on NOE experiments on 10.
Ratios were determined by H NMR spectroscopy. Isolated yields
after purification by silica gel column chromatography.
d
1
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