Ruthenium-catalyzed vinylsilane synthesis and cross-coupling as a selective approach to alkenes: benzyldimethylsilyl as a robust vinylmetal functionality.

Article abstract of DOI:10.1021/ol034463w

[reaction: see text] Ruthenium-catalyzed alkyne hydrosilylation or silyl-alkyne Alder ene reactions provide entry into benzyldimethylsilyl (BDMS)-substituted alkenes. The BDMS-vinylsilanes are further elaborated through mild palladium-catalyzed cross coup

Full text of DOI:10.1021/ol034463w

ORGANIC
LETTERS
2003
Vol. 5, No. 11
1895-1898
Ruthenium-Catalyzed Vinylsilane
Synthesis and Cross-Coupling as a
Selective Approach to Alkenes:
Benzyldimethylsilyl as a Robust
Vinylmetal Functionality
Barry M. Trost,* Michelle R. Machacek, and Zachary T. Ball
Department of Chemistry, Stanford UniVersity, Stanford, California 94305
bmtrost@stanford.edu
Received March 17, 2003
ABSTRACT
Ruthenium-catalyzed alkyne hydrosilylation or silyl-alkyne Alder ene reactions provide entry into benzyldimethylsilyl (BDMS)-substituted alkenes.
The BDMS-vinylsilanes are further elaborated through mild palladium-catalyzed cross coupling and show significant stability to intervening
synthetic operations, including silyl ether deprotection.
In the course of several recent studies into the synthesis of
variously substituted vinylsilane products by simple addition
reactions in the presence of a ruthenium catalyst,1,2 we are
investigating the synthetic elaboration of the vinylsilane
products. Palladium-catalyzed cross-coupling reactions of
vinylsilanes have been increasingly investigated in recent
years and are an important synthetic application of these
products.3-5 Typically, silanes with heteroatom substituents
are necessary for efficient reactivity,6 and hydrosilylation
with alkoxysilanes followed by cross-coupling can be an
efficient process.2,7 However, in the context of Alder ene
reactions,1 extension to alkoxy silanes proved to be prob-
lematic, as the alkoxy-alkynylsilane reagents are much less
stable than their alkoxy-vinylsilane counterparts and are
subject to hydrolysis and/or decomposition even under the
mild Lewis acid conditions of the ruthenium catalyst.
In addition to these challenges specific to our investiga-
tions, alkoxy-vinylsilanes in general suffer from a number
of drawbacks. The sterically undemanding silanes that give
the best results in cross-coupling reactions are sensitive to
acidic or basic hydrolysis. This problem becomes much
worse when molecules contain neighboring functionality such
as hydroxyl groups, since the vinylsilane then cyclizes to
give an even less stable silacycle, necessitating the use of
hydroxyl protecting groups. Finally, such alkoxy-vinylsilanes
are generally incompatible with silicon-based protecting
groups, and in our view the incompatibility with silicon-
based protecting groups represents a substantial obstacle to
the use of silicon-based cross-coupling reactions in synthesis.4
(1) Trost, B. M.; Machacek, M. R. Angew. Chem., Int. Ed. 2002, 41,
4693-4697. Trost, B. M.; Machacek, M.; Schnaderbeck, M. J. Org. Lett.
2000, 2, 1761-1764.
(2) Trost, B. M.; Ball, Z. T. J. Am. Chem. Soc. 2001, 123, 12726-12727.
(3) (a) Denmark, S. E.; Pan, W. J. Organomet. Chem. 2002, 653, 98-
104. (b) Denmark, S. E.; Sweis, R. F. Org. Lett. 2002, 4, 3771-3774. (c)
Denmark, S. E.; Pan, W. T. Org. Lett. 2001, 3, 61-64. (d) Hirabayashi,
K.; Kawashima, J.; Nishihara, Y.; Mori, A.; Hiyama, T. Org. Lett. 1999, 1,
299-301.
(4) Denmark, S. E.; Sweis, R. F. J. Am. Chem. Soc. 2001, 123, 6439-
6440.
(5) Mowery, M.; DeShong, P. Org. Lett. 1999, 1, 2137-2140.
(6) Denmark, S. E.; Sweis, R. F. Acc. Chem. Res. 2002, 35, 835-846.
Denmark, S. E.; Sweis, R. F. Chem. Pharm. Bull. 2002, 50, 1531-1541.
(7) Denmark, S. E.; Wehrli, D. Org. Lett. 2000, 2, 565-568. Denmark,
S. E.; Wang, Z. G. Org. Lett. 2001, 3, 1073-1076.
10.1021/ol034463w CCC: $25.00 © 2003 American Chemical Society
Published on Web 05/07/2003

Table 2. Alder Ene Reactions of Benzyldimethylsilyl-alkynesa
Figure 1.
We set out to find a more stable, all-carbon-substituted silicon
group that would still function in cross-coupling. Although
some groups have utilized all-carbon silicon species in cross-
coupling reactions,8 the previously reported methods have
not been demonstrated to possess the desired attributes
described above.9 Phenyldimethylsilyl is an extremely stable
cross-coupling precursor but requires harsh activation
conditions.8c,d Thiophenyl9 and pyridyl8e groups provide
efficient coupling; however, their stability has not been well
demonstrated. Also, thiophenyl and pyridyl groups are
themselves reactive moieties that might interfere with
intervening chemistry. Efforts with the benzyldimethylsilyl
(BDMS) group in oxidation chemistry led us to consider the
use of this group for cross coupling.10 The BDMS group is
surprisingly stable to acid and buffered fluoride conditions,
as well as to strong base. However, it undergoes debenzy-
lation virtually instantaneously at 0 °C with TBAF in THF
as the first step in the oxidation of such species, presumably
to an Si-X intermediate,8b which then is oxidized by the
addition of peroxide. The ease of this transformation under
conditions identical to those commonly employed in cross-
coupling reactions led us to postulate that debenzylation in
the presence of an appropriate coupling partner, followed
by the addition of a palladium catalyst, would lead to cross-
coupled products in a simple operation.
a All reactions employed 1.0 equiv of alkyne and 5.0 equiv of alkene in
acetone (0.2 M) at room temperature and were complete within 4 h. b Yields
in parentheses represent yield based on recovered starting alkyne.
defined di- or trisubstituted olefins (Table 1).11 Whereas the
more reactive and labile alkoxy or strained cycloalkyl silanes
are not compatible with the alkene-alkyne coupling reaction,
the benzyldimethyl silyl group cleanly affords the 1,4-diene
products in good yields. Importantly, the BDMS group is
stable to chromatography and does not undergo silacycle
formation with the pendant free hydroxyl (Table 1, entry
3).
With access to the benzyldimethylvinylsilanes in hand, we
turned to the cross-coupling reaction. Treatment of 1,1-
disubstituted vinylsilanes and the desired electrophilic partner
with TBAF at 0 °C, followed by addition of 2.5% Pd2dba3‚
CHCl3 and stirring at ambient temperature, affords the 1,1-
disubstituted products.12 The mild reaction conditions lead
Initially, we investigated the ruthenium-catalyzed synthesis
of various benzyldimethylvinylsilanes through hydrosilylation
(Table 1) and alkyne-alkene coupling reactions (Table 2).
Both pathways produce highly functionalized, geometrically
Table 1. Alkyne Hydrosilylation with Benzyldimethylsilanea
(8) (a) Denmark, S.; Choi, J. J. Am. Chem. Soc. 1999, 121, 5821-5822.
(b) Denmark, S.; Wehrli, D.; Choi, J. Org. Lett. 2000, 2, 2491-2494. (c)
Anderson, J.; Anguille, S.; Bailey, R. Chem. Commun. 2002, 2018-2019.
(d) Fleming, I.; Henning, R.; Parker, D. C.; Plaut, H. E.; Sanderson, P. E.
J. J. Chem. Soc., Perkin Trans. 1 1995, 317. (e) Itami, K.; Nokami, T.;
Ishimura, Y.; Mitsudo, K.; Kamei, T.; Yoshida, J.-I. J. Am. Chem. Soc.
2001, 123, 11577-11585.
(9) During the course of this work, it was reported that alkenyldimethyl-
(2-thienyl)silanes offer significant acid and base stability and also function
in cross-coupling reactions: Hosoi, K.; Nozaki, K.; Hiyama, T. Chem. Lett.
2002, 138-139.
(10) Miura, K.; Hondo, T.; Takahashi, T.; Hosomi, A. Tetrahedron Lett.
2000, 41, 2129-2132.
(11) Note that the BDMS does slow the rate of the alkene-alkyne
coupling reaction in comparison to the TMS group. This lowers the turnover
number for very complex coupling partners.
(12) General Procedure for Cross Coupling. A solution of vinyl
benzyldimethylsilane (1 equiv) and aryl or vinyl halide (1.5 equiv) in THF
(0.3 M) under Ar was cooled to 0 °C. Tetrabuylammonium fluoride (2.2
equiv, 1 M in THF) was added dropwise, and the resulting solution was
stirred for 10 min. Solid Pd2dba3‚CHCl3 (2.5 0.025 equiv) was added, and
the reaction was allowed to warm to room temperature. Reactions were
generally complete within 4 h, whereupon the dark solution was flushed
through a plug of silica with ether, concentrated in vacuo, and purified via
silica chromatography.
a All reactions employed 1.0 equiv of alkyne and 1.2 equiv of BDMS-H
in acetone (x M) at room temperature and were complete within 20 min.
b Isolated as a 14:1 regioisomeric mixture.
1896
Org. Lett., Vol. 5, No. 11, 2003

to a general process that is tolerant of many functional
groups, including esters and free alcohols. A variety of
electrophilic partners (Table 3) can be successfully employed,
Table 4. Palladium-Catalyzed Cross-Coupling of Trisubstituted
Vinylsilanesa
Table 3. Palladium-Catalyzed Cross-Coupling of
1,1-Disubstituted Vinylsilanesa
a All reactions employed 1.0 equiv of vinyl BDMS and 1.5 equiv of
R-X in THF (0.3 M) at 0 °C. TBAF (2.2 equiv) was added, and the mixture
was stirred for 10 min followed by addition of 2.5% Pd2dba3‚CHCl3. The
mixture was then stirred at room temperature. Reactions were complete
within ca. 4 h. b Isolated as a 14:1 regioisomeric mixture from the
hydrosilylation step. c Reaction was performed at 50 °C.
including sterically hindered ortho-iodotoluene and hetero-
aromatics such as 3-iodopyridine. Furthermore, under the
same conditions, trans-iodoacrylate is coupled to afford a
synthetically useful 1,4-diene.
a All reactions employed 1.0 equiv of vinyl BDMS and 1.5 equiv of
R-X in THF (0.3 M) at 0 °C. TBAF (2.2 equiv) was added, and the mixture
was stirred for 10 min followed by addition of 2.5% Pd2dba3‚CHCl3. The
mixture was then stirred at room temperature. Reactions were complete
within ca. 4h. b Isolated as a 14:1 mixture of olefin regioisomers from the
hydrosilylation step. c Reaction performed at 50 °C.
Sterically encumbered vinylmetal species have consistently
been difficult coupling partners in classic cross-coupling
reactions such as the Stille reaction.13 Generally, these
substrates require extra additives, heat, and long reaction
times. However, the cross coupling of sterically hindered
trisubstituted benzyldimethylsilanes proceeds well under the
aformentioned conditions (Table 4).3a,c Sterically hindered
electrophiles (ortho-iodotoluene) still afford products in good
yield. Electron-rich aryl iodides (3-iodoanisole) also couple
in moderate yields. More striking is the coupling of activated
aryl bromides at room temperature in good yields. This mild
protocol performs better than those previously reported that
require higher temperatures and more forcing reaction
conditions.5
methodologies that are incompatible with such protecting
groups. Unfortunately, most activated vinyl silanes used for
cross-coupling are not stable to the mild protocols for
removal of silyl ether protecting groups. However, the BDMS
group is stable to many conditions typically employed to
remove silyl ethers. For example, an alcohol protected with
the robust TBDPS group (eq 2) can be cleanly liberated in
the presence of buffered fluoride, i.e., TBAF and AcOH, in
aqueous DMF without affecting the vinyl BDMS. To our
knowledge, this is the first demonstration of a silicon cross-
coupling precursor stable to silyl ether deprotection. Fur-
thermore, treatment of vinyl BDMS with mild acid or strong
base (3 M NaOH/MeOH) returns the vinyl silane unscathed.
We believe that the results presented here offer more
The ubiquity of silicon-based hydroxyl protecting groups
in synthesis puts serious constraints on cross-coupling
(13) (a) Han, X.; Stoltz, B. M.; Corey, E. J. J. Am. Chem. Soc. 1999,
121, 7600-7605. (b) For a general review of cross coupling: Stang, P. J.
Metal Catalyzed Cross Coupling Reactions; Diederich, F., Ed.; Wiley-
VCH: New York, 1998.
Org. Lett., Vol. 5, No. 11, 2003
1897

of silyl ethers,14 likely removes a silyl ether during the
TBAF-mediated cross-coupling of the BDMS-substituted
olefin.
Acknowledgment. We thank the National Science Foun-
dation and the National Institutes of Health for their generous
support of our programs. Z.T.B. is a Stanford Graduate
Fellow. Mass Spectra were provided by the Mass Spectrom-
etry Regional Center of the University of California-San
Francisco supported by the NIH division of Research
Resources.
Figure 2.
flexibility in timing the installation of a vinylmetal species,
allowing it now to be done at an early stage in chemical
synthesis. It is also possible to carry such groups through a
wide variety of intervening chemistry rather than being
required to install vinylmetal groups immediately prior to
their use. The stability of the BDMS group to silyl ether
deprotection is an important step toward an orthogonal
silicon-based cross-coupling method, though it is important
to note that the alternative, cross-coupling in the presence
Supporting Information Available: Experimental pro-
cedures as well as characterization data for all vinylsilanes
and coupling products. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL034463W
(14) Fluoride-free coupling of silyl groups bearing an Si-OH have been
shown to be compatible with silyl ethers. See ref 4.
1898
Org. Lett., Vol. 5, No. 11, 2003