A R T I C L E S
Denmark et al.
In this and the following paper in this issue, the results of
mechanistic studies of two organosilicon coupling reactions are
presented through spectroscopic and kinetic analysis. The
tetrabutylammonium fluoride (TBAF)-promoted cross-coupling
reactions of silanes is described in this paper. The investigation
commenced with spectroscopic studies to identify key reaction
intermediates. This study was followed by a detailed kinetic
analysis to deduce the overall rate equation and help explain
the role of the reaction intermediates implicated in the spec-
troscopic studies. In the following paper, a fluoride-free cross-
coupling reaction of unsaturated silanolates is analyzed through
a comprehensive kinetic study. The selection of kinetic experi-
ments allowed for both the elucidation of the rate equation and
insight into the intermediates involved.
boranes proceeds with retention of configuration. Studies by
Soderquist employing 11B and 31P NMR spectroscopy as well
as kinetic analysis suggest that transmetalation proceeds through
a four-centered, µ2-hydroxyl complex between the borane and
palladium. This proposal is similar to the SE2 (cyclic) trans-
metalation mechanism implicated for certain organotin cross-
coupling reactions (Figure 2).
The aforementioned reports notwithstanding, there remains
a dearth of experimentally supported mechanistic knowledge
for many palladium-catalyzed, carbon-carbon bond forming
reactions.11 The advent of the organosilicon cross-coupling
reaction as a widely applicable and synthetically viable method
has, over the last 15 years, proceeded without a comprehensive
mechanistic study.12 Consequently, many questions about the
mechanistic differences from and similarities to other coupling
reactions remain unanswered.
Background
The modest pace at which this reaction developed relative to
organoboron and organotin cross-coupling reactions arises from
the long-held notion that a carbon-silicon bond is not suf-
ficiently polarized to participate as an effective donor. Hiyama
successfully addressed this problem by the use of a nucleophilic
fluoride source which he interpreted as the in situ generation
of a reactive pentacoordinate siliconate. Such siliconates are
believed to be sufficiently polarized to transfer the attached
organic group to an organopalladium(II) halide.13,14 This
discovery stimulated active investigation with many types of
fluoride donors as effective silicon cross-coupling reaction
promoters. Still, there are no investigations on record that
prove or disprove the existence of such siliconates in these
reactions.
Modulating the steric and electronic properties of ligands on
palladium has long been recognized as the method of choice to
enhance reactivity for certain organopalladium intermediates.
Nowhere has this been more clearly demonstrated than in the
newly developed ligands for mild Suzuki cross-coupling re-
actions with chloride electrophiles, substrates traditionally
considered to react at prohibitively low rates.15 Such ligands
are believed to accelerate both oxidative addition and trans-
metalation steps of the palladium catalytic cycle.
The impact of transition-metal-catalyzed cross-coupling reac-
tions on synthetic organic chemistry over the last quarter century
cannot be overstated. Synthetically useful variants such as the
Stille-Migita-Kosugi reaction have been probed in great
detail.4 Early on, Stille conducted mechanistic studies on the
cross-coupling reaction of organotin compounds with acyl
chlorides and proposed an SE2 mechanism for transmetalation.
Shortly thereafter, Farina provided a crucial kinetic analysis of
palladium ligand effects on organotin cross-coupling reactions.6
This study introduced a class of more effective ligands [Ph3As
and (2-furyl)3P] that allowed for milder and more efficient
reactions. Application of electrochemical techniques to inves-
tigate the function of palladium in the catalytic cycle has been
demonstrated through the elegant and insightful work of
Amatore and Jutand.7 Their findings have significantly elabo-
rated the simple “textbook” mechanism of the cross-coupling
process by identifying important roles of anionic palladium
intermediates in each step of the catalytic cycle. More recently,
Espinet and co-workers have employed kinetic analysis to
support an associative model for the key transmetalation step
in organotin cross-coupling reaction and have studied the nature
of this model [SE2 (cyclic) vs SE2 (open)] as well (Figure 2).8
The complexity of even the simplest mechanistic picture
(Figure 1) poses many questions that can be answered through
spectroscopic and kinetic analysis as well as elucidation of the
turnover-limiting step. For example, if fluoride activation of an
organosilane is turnover-limiting, then a more efficient activator
(9) Woerpel, K. A.; Ridgeway, B. H. J. Org. Chem. 1998, 63, 458.
(10) Matos, K.; Soderquist, J. A. J. Org. Chem. 1998, 63, 461.
(11) The mechanism of palladium-catalyzed aminations has also been the focus
of several in-depth mechanistic investigations. See: (a) Singh, U. K.;
Strieter, E. R.; Blackmond, D. G.; Buchwald, S. L. J. Am. Chem. Soc.
2002, 124, 14104. (b) Alcazar-Roman, L. M.; Hartwig, J. F.; Reingold, A.
L.; Liable-Sands, L. M.; Guzei, I. A. J. Am. Chem. Soc. 2000, 122, 4618.
(12) Hiyama has interpreted regiochemical and stereochemical outcomes of
palladium-catalyzed coupling of benzyl- and allyltrifluorosilanes as a result
of SE2- and SE′-type transmetalations that can be influenced by solvent,
catalyst ligands, and temperature. See: (a) Hatanaka, Y.; Hiyama, T. J.
Am. Chem. Soc. 1990, 112, 7793. (b) Hatanaka, Y.; Goda, K.; Hiyama, T.
Tetrahedron Lett. 1994, 35, 6511. Ohmura, H.; Matsuhashi, H.; Tanaka,
M.; Kuroboshi, M.; Hiyama, T.; Hatanaka, Y.; Goda, G. J. Organomet.
Chem. 1995, 499, 167.
(13) Isolable pentacoordinate fluorosilicates were demonstrated to undergo cross-
coupling reactions prior to this breakthrough. Yoshida, J.; Tamao, K.;
Yamamoto, H.; Kakui, T.; Uchida, T.; Kumada, M. Organometallics 1982,
1, 542.
(14) (a) Hatanaka, Y.; Hiyama, T. J. Org. Chem. 1988, 53, 918. (b) Hatanaka,
Y.; Hiyama, T. J. Org. Chem. 1989, 54, 270.
Figure 2. Proposed mechanism of transmetalation steps of specific Stille
and Suzuki cross-coupling reactions.
Despite its emergence as a powerful and general method for
carbon-carbon bond formation, the Suzuki-Miyaura cross-
coupling reaction of organoboron compounds is, mechanisti-
cally, a much less extensively studied system.5 Surprisingly,
insight into the reaction pathway is based mostly on speculation
and a few detailed reports. The most thorough mechanistic
investigations have focused on the stereochemical course of the
reaction of saturated alkylboron compounds. Both Woerpel9 and
Soderquist10 have reported that the transmetalation of alkyl-
(6) Farina, V.; Krishnan, B. J. Am. Chem. Soc. 1991, 113, 9585.
(7) (a) Amatore, C.; Jutand, A. J. Organomet. Chem. 1999, 576, 254. (b)
Amatore, C.; Jutand, A. Acc. Chem. Res. 2000, 33, 314.
(8) Casado, A. L.; Espinet, P. J. Am. Chem. Soc. 1998, 120, 8978. (b) Casado,
A. L.; Espinet, P.; Gallego, A. M. J. Am. Chem. Soc. 2000, 122, 11771.
(15) For a review on advances in palladium-catalyzed coupling reaction to aryl
chlorides, see: Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed. 2002, 41,
4176.
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4866 J. AM. CHEM. SOC. VOL. 126, NO. 15, 2004