MIDA-Vinylsilanes: Selective Cross-Couplings and Applications to the Synthesis of Functionalized Stilbenes

Article abstract of DOI:10.1021/ol503065a

(Chemical Equation Presented). A rapid and stereodefined synthesis of MIDA-boryl vinylsilanes has been achieved through the hydrosilylation of an alkynylboronic ester. The E products which contain a silyl and boryl group can be selectively cross-coupled i

Full text of DOI:10.1021/ol503065a

Letter
pubs.acs.org/OrgLett
MIDA−Vinylsilanes: Selective Cross-Couplings and Applications to
the Synthesis of Functionalized Stilbenes
Mark G. McLaughlin, Catherine A. McAdam, and Matthew J. Cook*
School of Chemistry and Chemical Engineering, Queen’s University Belfast, Belfast BT9 5AG, Northern Ireland
S
* Supporting Information
ABSTRACT: A rapid and stereodefined synthesis of MIDA−boryl vinylsilanes has been achieved through the hydrosilylation of
an alkynylboronic ester. The E products which contain a silyl and boryl group can be selectively cross-coupled in a two-step
bidirectional sequence to provide a rapid and high-yielding synthesis of complex styrenes.
tilbenes and their derivatives have been known to have
Snumerous applications in both medicinal and material
chemistry.1 Stilbenoids such as resveratrol, piceatinnol, and
pterostilbene show a broad range of therapeutic activity against
cancer, hepatitis C, and diabetes alongside exhibiting anti-
inflammatory and cardioprotective properties.2 Additionally,
the photophysical properties of stilbenes have been extensively
studied,3 finding use in organic light emitting diodes
(OLED’s),4 optical brighteners, and photoresistors.5
can be unmasked through the use of aqueous K3PO4 slowly
releasing the corresponding boronic acid which then performs
the cross-coupling reaction (eq 1). This strategy has been used
to form polyenes, biaryl (and heterobiaryl) compounds, Z-
stilbenes, and 1,1-disubstituted alkenes.12
Because of the very specific and controlled hydrolysis
conditions required to unmask the active boronic acid, other
palladium-catalyzed reactions can be performed in the presence
of MIDA boronates. Indeed, Suzuki−Miyaura coupling
reactions using an exogenous boronic acid can be carried out
on vinyl and aryl halides containing an MIDA boronate.12
Following this initial Suzuki coupling, a second coupling
reaction can be performed using very specific hydrolysis
conditions (eq 2). This has been used for the synthesis of
The synthesis of stilbenes has traditionally been dominated
by the Wittig reaction and its derivatives;6,7 however, these rely
on easy access to the corresponding phosphonium salts and
aldehydes alongside compatibility with the basic conditions.
One solution is the use of palladium catalyzed cross-coupling
reactions such as the Heck,8 Suzuki−Miyaura,9 Stille,10 and
Hiyama couplings.11 Although more functional group tolerant
than the Wittig-type reactions, these can lose modularity due to
the intermediacy of styryl organometallic or halide species.
Even though there are numerous methods in use to prepare
stilbenes, the establishment of new routes to their synthesis in a
robust and selective manner remains highly desirable.
MIDA boronates, pioneered by Burke and co-workers, offer
synthetic chemists a reliable, bench-stable, functional handle
which can be used as in Suzuki cross-couplings.12 These act as
protected boronic acids which can be readily synthesized and
purified through column chromatography. They are tolerant of
many standard Suzuki−Miyaura coupling conditions and can be
polyenes natural products such as amphotericin B12a and
synechoxanthin.12j We envisaged that this approach could be
further augmented by the formation and use of vinyl groups
that contain both an MIDA boronate and a silane whereby
Received: October 20, 2014
Published: December 16, 2014
© 2014 American Chemical Society
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Letter
sequential Suzuki and Hiyama couplings could be performed to
form complex styrenes in a rapid and modular fashion (eq 3).
Boryl vinylsilanes have been previously reported and can be
synthesized through the hydroboration of a silylacetylene13 via
a lithium−tin exchange reaction of the corresponding silyl
vinylstannane, followed by trapping with a borate14 or by a
silylboration of an alkyne.15 Although effective, many of these
approaches rely on the use of highly air and moisture sensitive
boranes such as 9-BBN or Cy2B groups which cannot be
purified or stored and there are no reports of Hiyama couplings
with these moieties.16 Herein we report the development of
bidirectional strategy based on the hydrosilylation of alkynyl
MIDA boronic esters and subsequent selective cross-coupling
reactions.
We needed to develop a rapid and reliable method for the
formation of the requisite vinyl groups and we examined the
use of platinum catalyzed hydrosilylations. We have previously
reported the hydrosilylation of propargylic and allylic alcohols
using a PtCl2/XPhos system which provides the corresponding
silanes in excellent yields and selectivity.17 These conditions
were excellent for the hydrosilylation of readily available
ethynyl MIDA boronate ester 1,18 providing the desired vinyl
silane 2 in excellent yield. We chose to utilize the
benzyldimethylsilane as this would be optimal for the Hiyama
coupling using Trost-type conditions.19
first coupling was filtered through Celite and subjected to the
next set of coupling conditions, following a solvent swap.
Gratifyingly we found that this approach led to higher yields of
4a with a 94% overall yield being obtained from 2.20 Employing
either route, the product was formed as a single regioisomer
with complete transfer of alkene geometry from the hydro-
silylation step.
With these conditions in hand, we began examining the
scope of the reaction and found that this protocol was very
robust (Scheme 2). Both electron-rich and electron-deficient
substrates performed well in both the Suzuki and Hiyama
couplings, and heterocycles could be incorporated. Ortho
substituents were also tolerated alongside free phenols, indoles,
and electrophilic pyridines. In all cases, excellent yields were
obtained over the two steps to provide highly substituted
styrenes. Complete selectivity was obtained with no sym-
Scheme 2. Substrate Scope
With the MIDA−vinylsilane in hand, we turned our attention
to the sequential cross-coupling reaction sequence (Scheme 1).
Scheme 1. Sequential Suzuki−Hiyama Cross-Couplings
a
Filtered through pad of Celite, concentrated, and used directly for the
b
second coupling reaction. Isolated yield over two steps.
The challenge was in identifying conditions that would allow
for the facile hydrolysis of the MIDA boronate ensuring the
silane remained intact. We subjected 2 to conditions previously
reported by Burke and co-workers and were delighted to
observe that the Suzuki product was produced in 85% yield.12
The vinylsilane 3 was then subjected to Hiyama coupling
conditions11 resulting stilbene product 4a in 91% yield. As both
reactions were very efficient and high yielding, we performed a
“telescoped” version whereby the reaction mixture from the
a
5 mol % Pd(OAc)2, 10 mol % SPhos, 1.2 equiv of R1X (X = I, Br),
b
7.5 equiv of K3PO4; 1,4-dioxane/H2O, 60 °C, 12 h. 2.5 mol %
Pd2dba3, 1.2 equiv of R2I, 2 equiv of TBAF, THF, 25 °C, 12 h.
c
Filtered through pad of Celite, concentrated, and used directly for the
d
second coupling reaction. Isolated yields over entire coupling
sequence. Suzuki coupling performed using aryl iodide. Suzuki
coupling performed using aryl bromide.
e
f
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Letter
metrical products being observed and the geometric integrity of
the E alkene was maintained. We also examined the vinyl−vinyl
coupling variant as this can lead to erosion of alkene geometry.
Gratifyingly, we found that 1-iodohex-1-ene could be coupled
in the Hiyama step to provide a single geometric isomer of
diene 4k.
We also investigated the selective formation of unsym-
metrical trisubstituted stilbenes. First, we performed the
hydrosilylation of propynyl MIDA ester 5 which proceeded
in excellent yield and produced a single regio- and geometric
isomer of the methyl-substituted silane 6 (eq 5). The addition
functionality and provides products as a single regio and
geometric isomer. This is the first report of a bench stable silyl
vinylbornic ester which can be used in a bidirectional coupling
strategy. The applications of this method are currently being
explored in total synthesis.
ASSOCIATED CONTENT
* Supporting Information
■
S
Detailed experimental procedures, full characterization of all
compounds reported, and copies of NMR spectra (1H and
13C). This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: m.cook@qub.ac.uk.
Notes
appears to be directed by sterics with the large size of the
MIDA boronic ester dictating the formation of 6 as a single
isomer.21 With 6 in hand, we then performed the same Suzuki−
Hiyama protocol which was utilized in the unsymmetrical case
(Scheme 3). Once again, the reaction proceeded well and
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge Queen’s University Belfast, DEL
(studentship to M.G.M.) and Eli Lilly (CASE award to C.A.M.)
for support.
Scheme 3. Synthesis of Trisubstituted Olefins
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