ABSTRACT
Title of dissertation: HYPERCOORDINATE SILICON COMPOUNDS IN
ORGANIC SYNTHESIS: IMPROVED METHODS FOR
THE SYNTHESIS OF ARYL(TRIALKOXY)SILANE
DERIVATIVES; AND TRIMETHYLSILYL CYANIDE AS A
CYANIDE SOURCE FOR NUCLEOPHILIC
SUBSTITUTION
Amy Slover Manoso, Doctor of Philosophy, 2004
Dissertation directed by: Professor Philip DeShong
Department of Chemistry and Biochemistry
Palladium-catalyzed cross-coupling reactions are versatile methods for the
synthesis of carbon-carbon bonds.  The Stille and Suzuki cross-coupling protocols have
achieved prominence in the synthesis of pharmaceuticals and agrochemicals because of
the high yields, tolerance for functional groups, and excellent stereoselectivities.
However, there are features associated with each of these processes that limit the
generality: the Stille tin reagents and byproducts are toxic; and the Suzuki boron reagents
can be difficult to synthesize and purify.  Environmentally benign arylsilane derivatives
have emerged as powerful alternatives to conventional arylmetalloids for the Pd(0)-
catalyzed aryl-aryl coupling reaction with organohalides and organo(pseudo)halides
because they avoid the inherent limitations associated with traditional methodologies.  It
was previously reported that aryl(trialkoxy)silanes (also called siloxanes) are substrates
for fluoride-promoted, Pd(0)-catalyzed coupling reactions with allylic ester and aryl
derivatives providing cross-coupling products in high yields under mild conditions.
However, few detailed studies of the synthesis of these useful cross-coupling reagents
have been reported in the literature.
In chapter one of this thesis, two methods for the synthesis of aryl siloxanes are
studied and the optimal reaction conditions and the scope determined: (1) general reaction
conditions for the synthesis of aryl(trialkoxy)silanes from aryl Grignard and lithium
reagents and functional silanes have been developed; and (2) the scope of the
palladium-catalyzed silylation of aryl halides with triethoxysilane to generate
aryl(trialkoxy)silane derivatives has been expanded.  In tandem, these two methods
provide ready access to a wide range of aryl siloxane reagents for use in Pd(0)-mediated
cross-coupling reactions, including highly functionalized siloxane intermediates in the
synthesis of useful biologically active compounds.
In the first part of chapter one, the synthesis of aryl siloxanes from the
corresponding aryl organometallic reagent and tetraalkoxysilanes is described.  Although
examples in the literature have reported the use of a range of silicon electrophiles
(including SiCl4 and Cl?Si(OR)3), tetraalkyl orthosilicates (Si(OR)4) allow for the most
direct and convenient synthesis of arylsiloxanes, in that they are commercially available,
inexpensive, and air and moisture stable.  Using the reaction conditions developed herein,
o-, m- and p-substituted bromoarenes underwent equally efficient metallation and
silylation.  Mixed results were obtained with heteroaromatic substrates:
3-bromothiophene, 3-bromo-4-methoxypyridine, 5-bromoindole, and
N-methyl-5-bromoindole all underwent silylation in good yield, whereas a low yield of
siloxane was obtained from 2-bromofuran, and 2-bromopyridine failed to be silylated.
The synthesis of siloxanes via organo lithium and magnesium reagents is limited
by the formation of di- and triarylated silanes (Ar2Si(OR)2, and Ar3SiOR, respectively),
and dehalogenated (Ar-H) by-products.  Lower temperatures allowed for the formation of
predominantly monoaryl siloxanes, without requiring a large excess of the electrophile.
Optimal reaction conditions for the synthesis of siloxanes from aryl Grignard reagents
entailed addition of aryl magnesium reagents to 3 equiv of tetraethoxy- or
tetramethoxysilane at ?30 ?C in THF.  Aryl lithium species were silylated using 1.5 equiv
of tetraethoxy- or tetramethoxysilane at ?78 ?C in ether.  The proposed mechanism of
silylation involves formation of the anionic pentacoordinate monoaryl(tetraalkoxy)silicate
(ArSi(OR)4-), which unexpectedly is susceptible to nucleophilic attack by a second
equivalent of the aryl metalloid to form diaryl(dialkoxy)siloxane by-products.  The
reductive dehalogenation of the aryl halide starting material presumably occurs during the
metallation step, and is an inherent limitation of the use of organometallic reagents.
The second part of chapter one discusses an alternative to the preparation of
arylsilanes from organomagnesium or lithium intermediates: the silylation of aryl halide
derivatives by triethoxysilane (H?Si(OEt)3) in the presence of a Pd catalyst.  As initially
reported in the literature, the silylation reaction was limited to p-substituted, electron-rich
aryl iodide substrates.  As described in this thesis, a more general Pd(0)-catalyst/ligand
system has been developed which activates bromides and iodides: palladium (0)
dibenzylideneacetone (Pd(dba)2) is activated with 2-(di-tert-butylphosphino)biphenyl
(Buchwald's ligand) (1: 2 mole ratio of Pd : phosphine).  Electron-rich, para- and meta-
substituted aryl halides (including unprotected anilines and phenols) underwent silylation
to form the corresponding aryl(triethoxy)silane in fair to excellent yield; however, ortho-
substituted aryl halides failed to be silylated.  Aryl chlorides were inert under the reaction
conditions, and triflates were poor substrates for silylation, instead undergoing highly
efficient reductive deoxygenation.  The optimum silylation reagent is triethoxysilane;
hexamethoxydisilane failed to be activated under a range of conditions.  The major by-
product of this reaction is reductive dehalogenation of the aryl halide starting material.
Probable mechanisms for the silylation reaction and the reduction side-reaction are
presented and discussed.
The Pd-catalyzed silylation method is an excellent companion to the more
traditional organometallic approach to the formation of the Ar-Si bond.  Case in point,
ortho-substituted aryl siloxanes are readily synthesized from the Grignard or lithium
reagent.  Unlike the metallation approach, the Pd-catalyzed silylation technique can be
performed in the presence of a wide range of functional groups, including carbonyl-
containing electrophiles, and protic moieties such as phenols or primary amines.
In addition to the fluoride-promoted transfer of aryl moieties presented in chapter
one, silanes have also been shown to transfer nucleophiles such as azide and cyanide
anion.  Chapter two presents the development of a high yielding silicon-based method for
the preparation of alkyl nitriles, which serve as precursors to a variety of useful functional
groups.  Hypercoordinate cyanosilicate, prepared in situ by the reaction of
cyanotrimethylsilane (Me3SiCN) with tetrabutylammonium fluoride (TBAF), is an effective
source of nucleophilic cyanide.  Primary and secondary alkyl halides and sulfonates
underwent rapid and efficient cyanide displacement in the absence of phase transfer
catalysts with the silicate derivative; inversion of configuration was observed for optically
active alkyl halide substrates.  Tetrabutylammonium fluoride was the optimum activating
agent, and a full equivalent of fluoride ion was required for reaction completion.  A nearly
1 : 1 stoichiometry of substrate to cyanosilicate affected formation of alkyl nitriles in
acetonitrile or dioxane; in contrast, traditional methodologies typically employ a large
excess of reagents, toxic phase transfer catalysts or solvents such as DMSO, or heavy-
metal cyanide salts.  Relative to other cyanide sources, the hypercoordinate cyanosilicate
was much less basic, thereby mitigating the formation of elimination (alkene) by-products.
The Me3SiCN/TBAF system is significantly less reactive and less basic than
tetrabutylammonium cyanide (TBA-CN), therefore the mechanism of reaction most like
involves the in situ generation of a hypercoordinate cyanosilicate, rather than
disproportionation of Me3SiCN and TBAF to form TBA-CN in situ.
HYPERCOORDINATE SILICON COMPOUNDS IN ORGANIC SYNTHESIS:
IMPROVED METHODS FOR THE SYNTHESIS OF ARYL(TRIALKOXY)SILANE
DERIVATIVES; AND TRIMETHYLSILYL CYANIDE AS A
CYANIDE SOURCE FOR NUCLEOPHILIC SUBSTITUTION
by
Amy Slover Manoso
Dissertation submitted to the Faculty of the Graduate School of the
University of Maryland, College Park in partial fulfillment
of the requirements for the degree of
Doctor of Philosophy
2004
Advisory Committee:
Professor Philip DeShong, Chair/Advisor
Assistant Professor Lyle Isaacs
Professor Paul Mazzocchi
Professor Donald Nuss (Center for Biosystems Research)
Professor Lawrence R. Sita
?Copyright by
Amy Slover Manoso
2004
ii
DEDICATION
To my parents, Tina and Bill,
husband, Mark
sister and her partner, Betsy and Tanya
and baby Spence
ACKNOWLEDGMENTS
I would like to express my sincerest thanks to my advisor, Professor Philip
DeShong.  Everything that I am today has in some way been influenced by Phil: I am a
better bench chemist, scientific writer, teacher, thinker, chemical professional, public
speaker and?oddly enough?daughter and spouse due to his example.  Thanks for
helping me keep my priorities in order, for insisting that I take myself seriously as a
chemist, and for teaching me not to panic.
iii
My husband, Mark, has provided constant encouragement; I can definitively say
that he has put in double the effort of any other spouse in the history of the DeShong
group, because it has taken me twice as long.  Without him, I could not have made it to
this point.  Thanks for making me finish what I started.
I would also like to thank Dr. Jim Demas (University of Virginia) for encouraging me
to do undergraduate research and to drop my Latin American Studies major.  You were
right: organic chemistry is a highly creative and artistic endeavor, and a liberal art in its
own right; of course you are a physical chemist and I think at the time you meant it as a
snub.  I forgive you.
Dr. James Whitney (Washington and Lee University) taught me that, when in
doubt, the answer is "steric hindrance."  Thank you for introducing me to organic chemistry
and for being the first on a short list of phenomenal science teachers to show me that
excellent science teaching is possible in a large lecture setting.  You are deeply missed.
I am grateful for the support of my colleagues in the DeShong group.  You have
been a valuable source of friendship, advice, and commiseration over the past years.  I
have seen some thirty-odd faces grace the DeShong laboratories, too many to name: ?I
don?t know half of you half as well as I should like; and I like less than half of you half as
well as you deserve.? ?J. R. R. Tolkien.
From the Department, I would like to thank the organic faculty for outstanding
teaching and guidance on matters both chemical and personal.  Dr. Yui-Fai Lam and
Caroline Ladd have provided invaluable assistance in obtaining NMR and mass spectral
data.
And finally, to my parents: this is the culmination of all of your love and effort, and
without you I could not have made it this far.  Thank you.
iv
TABLE OF CONTENTS
List of Tables v
List of Figures vii
List of Schemes viii
List of Abbreviations xiii
Chapter 1: Improved Synthesis of Aryl(triethoxy)silanes for Use in Palladium-Mediated
Cross-Coupling Reactions
Introduction 1
Significance of Aryl(trialkoxy)silanes 1
Synthesis of Natural Products Using Aryl(trialkoxy)silane 7
Derivatives
Research Goal: Synthesis of Aryl(trialkoxy)silane Derivatives 18
Overview of the Synthesis of Aryl Group Transfer Reagents 20
Preparation of Aryl Stille (Tin) Reagents 23
Preparation of Aryl Suzuki (Boron) Reagents 25
Preparation of Aryl Silicon Reagents 30
Results and Discussion 40
Improved Synthesis of Aryl(trialkoxy)silanes via Treatment of Aryl 40
Grignard or Lithium Reagents with Tetraalkoxysilane
Improved Methods for the Synthesis of Aryl(triethoxy)silanes via 59
Palladium(0)-Catalyzed Silylation of Aryl Iodides and
Bromides with Triethoxysilane
Conclusions 77
Epilogue 79
Experimental 81
Chapter 2: Trimethylsilyl Cyanide As A Cyanide Source For Nucleophilic Substitution
Introduction 118
Fluoride Ion Activation of Silicon Bonds 118
Atomic and Molecular Properties of Tetracoordinate and 122
Hypercoordinate Organosilicates
Synthesis, Stability and Characterization of Hypercoordinate 127
Organosilicates
Mechanisms of Nucleophilic Substitution 130
Reactions at Silicon
Fluoride Ion Activation of Silicon Bonds in Organic Synthesis 135
Fluoride Activation of the Si-O Bond 137
Fluoride Activation of the Si-H Bond 140
Fluoride Activation of the Si-C Bond 141
Results and Discussion 145
Background 145
Cyanide Displacements Utilizing Hypercoordinate Cyanosilicate 153
Exploration of the Use of Catalytic Amounts of Fluoride 157
Investigation of Alternative Fluoride Sources 160
Proposed Mechanism 161
Conclusions 170
Epilogue 170
Experimental 175
References 191
v
LIST OF TABLES
Chapter 1
Table 1. Synthesis of Aryl(trialkoxy)silanes via Treatment of Aryl 45
Grignard or Lithium Reagents with Silicon Electrophiles: Review
of the Literature to Date.
Table 2. Optimization of the Synthesis of Arylsiloxanes Using 46
4-Bromomagnesium Anisole.
Table 3. Synthesis of Aryl(trialkoxy)silanes Using Grignard Reagents. 48
Table 4. Optimization of the Synthesis of Arylsiloxanes Using 4-Lithiotoluene. 51
Table 5. Synthesis of Aryl(trialkoxy)silanes Using Lithium Reagents. 53
Table 6. Optimization of the Silylation of 4-Bromoanisole. 61
Table 7. Silylation of Aryl Bromides. 62
Table 8. Silylation of Heteroaryl Bromides. 63
Table 9. Silylation of Aryl Bromides: Effect of Substituent Position. 64
Table 10. Palladium-Catalyzed Silylation of Aryl Iodides. 66
Table 11. Silylation of Aryltriflate Derivatives. 69
Table 12. Silylation of Arylhalides Using Hexamethoxydisilane. 74
Chapter 2
Table 1. Comparison of Atomic Properties of Si and C. 123
Table 2. Atomic and Group Allred-Rochow Electronegativities. 124
Table 3. Approximate Average Bond Dissociation Energies and 123
Bond Lengths for Tetracoordinate C and Si.
Table 4. Comparison of NMR Data for Tetracoordinate and Pentacoordinate 130
Silicates.
Table 5. Reactivity of a Series of Fluorosilicate Complexes in the 147
Fluorination of 1-Bromododecane at 85 ?C.
Table 6. Reaction of Hypercoordinate Silicate 5 with Alkyl Halides. 154
Table 7. Reaction of Benzyl Bromide (64) with Trimethylsilyl 158
Cyanide (3) and Varying Amounts of TBAF.
vi
Table 8. Reaction of Benzyl Bromide (64) and Trimethylsilyl 159
Cyanide (3) with Tetrabutylammonium Nucleophiles.
Table 9. Reaction of Benzyl Bromide (64) and Trimethylsilyl 160
Cyanide (3) with Alternative Fluoride Sources.
Table 10. Reaction of Secondary Alkyl Halides with Trimethylsilyl 161
Cyanide (3) and TBAF or TBAT (1).
Table 11. Comparison of Nitrile Synthesis Using Trimethylsilyl 163
Cyanide (3)/TBAF or Tetrabutylammonium Cyanide (89).
Table 12. 29Si-NMR Spectral Data for Authentic Samples Used In 166
Mechanistic Studies.
vii
LIST OF FIGURES
Chapter 1
Figure 1. Silicon-Based Aryl Group Transfer Reagents. 2
Figure 2. Hypercoordinate Aryl Group Transfer Reagents. 3
Figure 3. Biaryl Natural Product Targets. 7
Figure 4. Model System For the Synthesis of Colchicine: Fitzgerald?s. 8
Compound (23)
Figure 5. Natural Product Targets Featuring the 2,4-Arylpyridine Moiety. 11
Figure 6. Siloxane Derivatives for Application in Natural Product Syntheses. 17
Figure 7. Biaryl Compounds Synthesized Using the Phenyl(trimethoxy)silane 18
Cross-Coupling Methodology.
Figure 8. Silicon-Based Aryl Group Transfer Reagents. 31
Figure 9. Siloxanes Prepared via the Grignard Reaction for Use in 50
Natural Product Syntheses.
Figure 10. Complexes Formed in the Silylation of Pyridinyl Metal Reagents. 55
Figure 11. 5-Indole Siloxanes Prepared from Aryllithium Reagents for Use 56
in Natural Product Syntheses.
Figure 12. Proposed Effect of Substituent Position. 65
Figure 13. Proposed Transition States for the Metathesis Reaction Mechanism. 72
Figure 14. Yields of Siloxanes Using Arylmetalloid Reagents or Palladium- 78
Mediated Silylation.
Figure 15. Siloxane Intermediates for Use In Natural Product Syntheses.. 79
Chapter 2
Figure 1. Hybridization of Tetra-, Penta-, and Hexacoordinate Silicon. 125
Figure 2. Comparison of Rates of Expansion of Coordination. 126
Figure 3. Increase in Silicate Stability Due Chelating Ligands. 128
Figure 4. Reaction Coordinates for Single-Step and Two-Step 133
Substitution Processes.
Figure 5. Angle of Attack by Nucleophiles on Silanes. 135
Figure 6. Triphenylsilyl Cyanide (93) and TBAF (1 equiv), 29Si Spectrum. 167
viii
LIST OF SCHEMES
Chapter 1
Scheme 1 1
Scheme 2 2
Scheme 3 3
Scheme 4 4
Scheme 5 5
Scheme 6 5
Scheme 7 5
Scheme 8 6
Scheme 9 7
Scheme 10 9
Scheme 11 9
Scheme 12 10
Scheme 13 10
Scheme 14 12
Scheme 15 12
Scheme 16 13
Scheme 17 14
Scheme 18 15
Scheme 19 15
Scheme 20 16
Scheme 21 19
Scheme 22 20
Scheme 23 20
Scheme 24 21
Scheme 25 22
ix
Scheme 26 23
Scheme 27 23
Scheme 28 24
Scheme 29 24
Scheme 30 25
Scheme 31 25
Scheme 32 26
Scheme 33 27
Scheme 34 27
Scheme 35 28
Scheme 36 28
Scheme 37 29
Scheme 38 30
Scheme 39 32
Scheme 40 32
Scheme 41 33
Scheme 42 33
Scheme 43 34
Scheme 44 34
Scheme 45 35
Scheme 46 36
Scheme 47 36
Scheme 48 37
Scheme 49 37
Scheme 50 38
Scheme 51 39
Scheme 52 40
Scheme 53 41
x
Scheme 54 47
Scheme 55 49
Scheme 56 50
Scheme 57 54
Scheme 58 56
Scheme 59 57
Scheme 60 59
Scheme 61 67
Scheme 62 70
Scheme 63 70
Scheme 64 71
Scheme 65 72
Scheme 66 73
Scheme 67 73
Scheme 68 75
Scheme 69 75
Scheme 70 76
Scheme 71 77
Scheme 72 80
Chapter 2
Scheme 1 119
Scheme 2 119
Scheme 3 120
Scheme 4 120
Scheme 5 127
Scheme 6 131
Scheme 7 131
xi
Scheme 8 132
Scheme 9 133
Scheme 10 134
Scheme 11 136
Scheme 12 137
Scheme 13 138
Scheme 14 138
Scheme 15 139
Scheme 16 139
Scheme 17 139
Scheme 18 140
Scheme 19 140
Scheme 20 141
Scheme 21 141
Scheme 22 142
Scheme 23 142
Scheme 24 143
Scheme 25 144
Scheme 26 146
Scheme 27 148
Scheme 28 148
Scheme 29 149
Scheme 30 150
Scheme 31 151
Scheme 32 152
Scheme 33 157
Scheme 34 158
Scheme 35 162
xii
Scheme 36 164
Scheme 37 164
Scheme 38 165
Scheme 39 168
Scheme 40 168
Scheme 41 169
Scheme 42 171
Scheme 43 171
Scheme 44 172
Scheme 45 173
xiii
LIST OF ABBREVIATIONS
18-crown-6 1,4,7,10,13,16-Hexaoxacyclooctadecane
Ac acetyl
ap apical
aq. aqueous
Ar aryl
Bn benzyl
BOC t-butyloxycarbonyl
BTAF benzyl(trimethyl)amino fluoride
Bu butyl
Bz benzoyl
cat catecholate
cod cyclooctadienyl
cy cyclohexyl
dba dibenzylideneacetone
DBU 1,8-diazabicyclo[5.4.0]undec-7-ene
DDQ 2,3-dichloro-5,6-dicyano-1,4-benzoquinone
DIEA N,N-diisopropylethylamine
DMAP 4-dimethylaminopyridine
DMF N,N-dimethylformamide
DMSO dimethyl sulfoxide
DOM directed ortho metallation
dppf 1,1'-bis(diphenylphosphino)ferrocene
dppp 1,3-bis(diphenylphosphino)propane
EDG electron donating group
ee enantiomeric excess
eq equatorial
equiv equivalent (s)
xiv
Et ethyl
Et2O diethyl ether
EWG electron withdrawing group
? gyromagnetic ratio
G. C. gas chromatograph
h hour(s)
HMPA hexamethylphosphoramide
HOMO highest-occupied molecular orbital
Hz Hertz
i-Pr isopropyl
IR infrared
J coupling constant
Ln ligand
LUMO lowest-unoccupied molecular orbital
m meta
M+ molecular ion
m/z mass-to-charge ratio
Me methyl
MeCN acetonitrile
MEM 2-methoxyethoxymethyl
MHz megahertz
min minute(s)
MOM methoxymethyl
mp melting point
MS mass spectrometry
Ms methanesulfonyl
Naph naphthyl
NMP 1-methyl-2-pyrrolidinone
xv
NMR nuclear magnetic resonance
o ortho
OAc acetate
p para
Ph phenyl
Pr propyl
pyr pyridinyl
PZ phosphazenium
Rf retardation factor
rt room temperature
SET Single-electron transfer
SN1 substitution nucleophilic unimolecular
SN2 substitution nucleophilic bimolecular
t-Bu tertiary butyl
T1 spin-lattice relaxation time
TAS-F tris(dimethylamino)sulfur(trimethylsilyl)difluoride
TBAF tetrabutylammonium fluoride
TBAT tetrabutylammonium triphenyldifluorosilicate
TBP trigonal bipyramidal
Tf trifluoromethanesulfonyl
THF tetrahydrofuran
TLC thin layer chromatography
TMS trimethylsilyl
tol tolyl
UV ultraviolet
1
Chapter 1.  Improved Synthesis of Aryl(triethoxy)silanes for Use in Palladium-
Mediated Cross-Coupling Reactions
Introduction
Significance of Aryl(trialkoxy)silanes
The metal-catalyzed cross-coupling reaction for the formation of carbon-carbon
bonds between unsaturated centers is an indispensable synthetic tool for the preparation
of useful industrial1 and pharmaceutical2-9 materials.  Of the many combinations of
organometallic nucleophiles and organic electrophiles in the literature,10-12 the Stille
(organostannane) and Suzuki (organoborane) coupling methodologies are the most
widely employed for the synthesis of unsymmetrical biaryl derivatives and substituted
alkenes due to the generally excellent yields, high stereoselectivities, and superior
functional group tolerance (Scheme 1).12-20  Nonetheless, arylsilane derivatives have
emerged as powerful alternatives to conventional arylmetalloids for the Pd(0)-catalyzed
aryl-aryl coupling reaction with organohalides and organo(pseudo)halides because they
avoid the inherent limitations associated with traditional methodologies: the Stille tin
reagents and byproducts are toxic; and the Suzuki boron reagents can be difficult to
synthesize and purify.8,21-59
Scheme 1
X CH3
SnBu3/B(OH)2
CH3
Si(OEt)3
SnBu3/B(OH)2
Si(OEt)3
H3C X H3C
Pd(0)
Pd(0), F-X = I, Br, Cl, OTf
Pd(0)
Pd(0), F-
X = I, Br, Cl, OTf
2
Previous studies from our group21-25 as well as Hiyama,8,26-33 Ito,34,35 Denmark,36-44 and
others45-56 have shown that a variety of silicon derivatives (i.e., compounds 1-4, Figure 1)
undergo fluoride-mediated, Pd(0)-catalyzed aryl group transfer reactions.57-59
SiMeF2
OCH3
Si(OH)2Me
Me
Si
Cl
MeO
Si(OEt)3
O2N
1 2 3 4
Figure 1.  Silicon-Based Aryl Group Transfer Reagents.
Each of the above silicon compounds participates in the Pd-catalyzed cross-
coupling reaction only upon activation by a nucleophile, typically fluoride ion.  The
mechanism of action of these silicon reagents is similar.  As illustrated in Scheme 2, the
process is proposed to involve the in situ formation of the reactive hypercoordinate
intermediate 6 by attack of fluoride on the tetracoordinate aryl silicon reagent 5.9,53,54
Conversion of the neutral tetracoordinate silane 5 to anionic hypercoordinate silicate 6
both lengthens and polarizes the silicon-ligand bonds, placing a large partial positive
charge on silicon and a large partial negative charge on the arene and the other ligands.60-62
Scheme 2
Si
R1
R2
R3
Si R1R2
R3
F
F
65
The overall catalytic cycle for aryl-aryl coupling begins with formation of Pd(II)
species 7 as a result of oxidative addition of Pd(0) into the aryl?X bond of the aryl halide
substrate (Scheme 3).  As described above, unlike the weakly polarized tetracoordinate
precursor 5, the anionic hypercoordinate fluorosilicate 6 undergoes transmetallation with
palladium complex 7 to form the bis-aryl Pd(II) species 9, with loss of R3SiFX? (8).  Lastly,
reductive elimination of Pd(0) regenerates the catalyst, and liberates the biaryl product.
3
Scheme 3
Si
R1
R2
R3
Si R1R
2
R3
F
F
79
X
Pd(II) XPd(II)
R
RR
6 5
Si R1R2
R3
X
F
8
Ln L
n
Pd(0)Ln
R
The most compelling evidence of the participation of a hypercoordinate silicate
intermediate such as 6 is the ability of analogous isolable organosilicates to participate in
the cross-coupling reaction in the absence of additional fluoride.  Silicates 10 and 11 have
been shown to be effective phenylating22 and vinylating63-65 reagents, respectively (Figure
2).  In addition, catecholate derivatives such as 11 have been employed for the transfer of
other groups, for example alkenyl and aryl moieties.65-68
Si OO
O
O
Si PhPh
F
F Bu4N+
Ph Et3NH
11TBAT (10)
Figure 2.  Hypercoordinate Aryl Group Transfer Reagents.
4
The initial studies in the DeShong laboratories concerning the cross-coupling
reactions of silicon reagents employed compound 10, tetrabutylammonium
triphenyldifluorosilicate ([Ph3SiF2]?[Bu4N]+, TBAT).22,67  Under palladium catalysis, good
yields of coupled products were obtained with aryl iodides, most aryl triflates, and
electron-deficient aryl bromides (Scheme 4).  In addition to forming the desired
heterocoupled product 12, small amounts of homocoupled product 13 were also isolated.22
The major limitations of the TBAT cross-coupling methodology are (1) poor atom economy
(under standard reaction conditions only one phenyl group out of three is transferred); and
(2) substituted difluorotriaryl analogs of 10 are not easily synthesized.67
Scheme 4
Si PhPh
F
F
TBAT (10)
Ph
Bu4N+
I Ph
Pd(dba)2
O O
O
O
+ +
12 13
96% 4%
In an effort to overcome the limitations associated with TBAT,
phenyltrimethoxysilane (15, Scheme 5) was investigated as a less wasteful, and more
easily derivatized arylating reagent.21,23-25  Siloxane derivatives such as 15 are non-toxic,
hydrolytically stable compounds, whose synthesis and characterization have been
reported most notably in the fields of polymer and materials chemistry.69,70  Recently, the
DeShong research group described the synthesis of unsymmetrically substituted biaryls
via phenylation of aryl iodides,21,24 bromides and chlorides23,24 with commercially available
phenyltrimethoxysilane (15).  For example, 2-bromopyridine (14) was cross-coupled with
phenyltrimethoxysilane (15) to form biaryl 16 in 76% isolated yield (Scheme 5).23
5
Scheme 5
Si(OMe)3
Pd(OAc)2 / PPh3
TBAFN Br N+
14 15 16
76%
In congruence with the general mechanism depicted in Scheme 3, the assumed
reactive silicon species is hypercoordinate fluorosilicate 17 (Scheme 6).21,67
Scheme 6
SiMeOMeO
OMe
F
17
H3C
I
Pd(dba)2
H3C
F-
Si(OMe)3
15
Recent efforts have focused on the cross-coupling reaction of arylsiloxane
derivatives with aryltriflate substrates.  Aryl triflates, readily derived from the phenol,71 are
often more available than the corresponding aryl halides; however, siloxanes have failed
to undergo efficient cross-coupling with aryl triflates (Scheme 7).  Under standard cross-
coupling conditions, the base TBAF induces triflate hydrolysis by liberating methoxide
from the siloxane starting material.  Preliminary studies indicate that hydrolysis can be
mitigated by the addition of water, which presumably dilutes and solvates the offending
alkoxide.72
Scheme 7
Si(OMe)3
Pd(dba)2 / PR3
TBAF+
15
MeO
OTf
MeO
+
MeO
OH
10% 90%
6
Very recently, siloxane derivatives bearing chelating alkoxy ligands were found to
undergo Pd-catalyzed cross-coupling with aryl and heteroaryl triflates in the presence of a
fluoride source in good to excellent yields.68,72  It is proposed that the alkoxide ligands are
stabilized by the chelate effect, thereby attenuating triflate hydrolysis.  Triethylammonium
(bis)catechol phenyl silicate ([PhSi(cat)2]?[Et3NH]+, 18) and phenyl silatrane (19)
derivatives are synthesized in high yield from the corresponding trialkoxysilane via
transesterification to form crystalline, air and moisture stable complexes (Scheme 8).  The
stability of compounds 18 and 19 to hydrolysis and alcoholysis is well established.73-79
Scheme 8
Si(OMe)3
HO
HO
NEt3
MeOH
N OH 3
toluene
SiOO
N
O
19
Si
OO
O O
18
HNEt3
15
Silicates 18 and 19 were found to participate in the fluoride-activated, Pd-mediated
cross-coupling reaction with aryl iodides, bromides and most notably triflates.68,72  The
reaction tolerates a wide range of electron-withdrawing and electron-releasing
substituents, as well as heteroaromatic systems.  For example, aryl triflate 20 was cross-
coupled with catecholate 18 to form biaryl 21 in 96% isolated yield (Scheme 9).
7
Scheme 9
Si
OO
O O
18
HNEt3
+
OMe
OTf
20
Pd(dba)2 / PR3
TBAF
OMe
96%
21
Synthesis of Natural Products Using Aryl(trialkoxy)silane Derivatives
To further demonstrate the generality of the hypercoordinate silicate cross-coupling
reaction, preliminary studies are underway to apply this technique to the synthesis of
complex biaryl natural products.  Targets include the anti-inflammatory and anti-mitotic
drugs colchicine (22),80,81 and Fitzgerald?s compound (23)82 and the antitumor
2-quinoline-2-pyridyl derivatives streptonigrin (24),83,84 and lavendamycin (25) (Figure
3).85,86
N
O
O
H2N
MeO
N
CH3H2N
CO2H
OMe
OMe
OH
N
O
O
H2N N CO2H
Streptonigrin (24) Lavendamycin (25)
CH3HN
A B
C
D
A B
C
D
E
2 2
4
4
MeO
M eO
M eO
NHAc
OMeO
Colchicine (22)
O OMe
OMe
OMeMeO
Fitzgerald's Compound (23)
Figure 3.  Biaryl Natural Product Targets.
8
Each of these natural product syntheses will have as the key biaryl carbon-
carbon bond forming step a silicon-based cross-coupling reaction.  This, in turn, will
necessitate the synthesis of highly functionalized aryl(trialkoxy)silane and aryl halide
coupling partners.  The biaryl skeletons of colchicine,87-97 Fitzgerald?s compound,98
streptonigrin99-101 and lavendamycin102-109 have been synthesized previously by classical
Stille and Suzuki cross-coupling methodologies; for each target, the previously reported
synthetic approach will serve as a standard for our synthetic plan.
Colchicine (22) is a commonly prescribed drug for the treatment of gout.80  This
alkaloid has more recently been found to have taxol-like antitumor properties, in that it
binds to ?-tubulin preventing cellular spindle formation and division.81  As a synthetic
target, the colchicine skeleton was particularly intriguing to the DeShong group: the
siloxane cross-coupling methodology had never before been used for the formation of
carbon-carbon bonds between arenes and alternative aromatic systems, such as the
tropolone moiety.
Approaches to the synthesis of colchicine (22) in our laboratories have focused on
5-(trimethoxyphenyl)tropolone methyl ether (Fitzgerald?s compound, 23, Figure 4) as a
model system for the formation of the aryl-tropolone bond.  The synthesis of 23 is a
worthwhile endeavor in its own right because Fitzgerald?s compound displays anti-mitotic
properties comparable to those of colchicine.82
O OMe
OMe
OMeMeO
Fitzgerald's Compound (23)
Figure 4.  Model System For the Synthesis of Colchicine: Fitzgerald?s Compound (23).
9
Compound 23 was prepared in excellent yield by Banwell through a Suzuki
reaction employing 5-bromotropolone methyl ether (26) and the trisubstituted aryl boronic
acid 27 (Scheme 10).98  It is noteworthy that attempts to synthesize compound 23 and
simpler analogs via the Stille method consistently gave lower yields than the
corresponding Suzuki approach.  Aryl boronic acids remain the reagent of choice for the
formation of the aryl-tropolone bond.98,110  In most cases, failure of the Stille reaction to
provide the cross-coupled adduct was attributed to steric hindrance by the methoxy
substituent ortho to the desired aryl-tropolone bond.
Scheme 10
O OMe
Br
B(OH)2
OMe
OMe
MeO
Pd(PPh3)4
Na2CO3
92%
+
26 27
O OMe
OMe
OMeMeO
23
A similar tactic is proposed for the synthesis of 23 via the siloxane cross-coupling
technology (Scheme 11).  This approach requires the synthesis of complex aryl siloxane
derivative 28; bromotropolone 26 has been prepared previously.98
Scheme 11
O OMe
Br
Si(OR)3
OMe
OMe
MeO+
26
O OMe
OMe
OMeMeO
23 28
10
Handy111 and Seganish68 in the DeShong laboratories have probed the viability of
using silicon-based reagents for the formation of the phenyl-tropolone bond via Pd(0)-
catalyzed cross-coupling.  To alleviate the steric demand on the cross-coupling of
hindered siloxane 28 (Scheme 11), the simple phenylation of tropolone derivatives was
investigated (Scheme 12).  Handy demonstrated that MEM-protected bromotropolone 29
was unreactive to cross-coupling with phenyltrimethoxysilane (15) under standard and
modified reaction conditions; in all cases, starting material was recovered.111
Scheme 12
O OMEM
Br
29
Si(OMe)3 Pd(0) / PR3
+
15
O OMEM
30
TBAF
X
Seganish reported the high yielding phenylation of 2-tropolone
trifluoromethanesulfonate (31) with triethylammonium (bis)catechol phenyl silicate (18).68
Seganish continues to explore the use of silicon catecholates for the arylation of
substituted tropolone derivatives, with the ultimate goal of completing the total synthesis
of colchicine as outlined in Scheme 11.
Scheme 13
Si
OO
O O
18
HNEt3+ Pd(dba)2 / PPh3
TBAF
89%
O OTf
31
O
32
11
Streptonigrin (24)83,84 and lavendamycin (25)85,86 are structurally similar antitumor
antibiotics: both have at their core a highly substituted pyridine moiety (ring C), bound at
C?2 and C?4 to a functionalized quinone and a substituted arene, respectively (Figure 5).
As a synthetic target, this skeleton was of particular interest to the DeShong group: the
siloxane cross-coupling methodology had not yet been investigated for the formation of
carbon-carbon bonds between two heteroaromatic systems, such as pyridines and
quinones.  More importantly, our goal was to address a major limitation of the Suzuki
reaction, which has been demonstrated to be ineffectual for the cross-coupling of
heteroaromatic derivatives.112  Approaches to the synthesis of streptonigrin (24) and
lavendamycin (25) in our laboratories have concentrated on nitramarine (33) as a model
system for the construction of the 2-quinoline-2-pyridyl systems.  In addition, nitramarine
and lavendamycin have in common the ?-carboline (C?D?E) ring system.
N
O
O
H2N
MeO
N
CH3H2N
CO2H
OMe
OMe
OH
N
O
O
H2N N CO2H
Streptonigrin (24) Lavendamycin (25)
CH3HN
A B
C
D
A B
C
D
E
2 2
4
4
N N
Nitramarine (33)
HN
A B
C
D
E
2 2
4
4
2 2
4
4
Figure 5.  Natural Product Targets Featuring the 2,4-Arylpyridine Moiety.
Focusing on the formation of the quinolinyl-pyridyl (C?2/B?2) bond of nitramarine,
compound 33 was prepared in good yield by Queguiner via Stille coupling of
2-chloropyridine derivative 34 with 2-(trimethylstannyl)quinoline 35 (Scheme 14);
?-carboline ring (ring D) closure of adduct 36 completed the synthesis.113
12
Scheme 14
NCl
F
NH(BOC)
34
N SnMe3
Pd(0)
Ba(OH)2
78%
N
F
NH(BOC)
N
36
?, pyr?HCl
83%+
N N
33
HN
35
A similar tactic is proposed for the synthesis of 33 via the siloxane cross-coupling
technology (Scheme 15).  This approach requires the synthesis of the quinoline siloxane
38; the ?-carboline halides and sulfonates (37) have been prepared previously.113
Alternatively, the complex pyridyl siloxane 39 could be prepared and coupled with the
quinoline halide or sulfonate (40).
Scheme 15
N N
Nitramarine (33)
HN
N
37
HN
N
38
+
TfO/Br
Si(OR)3
N
39
HN
N
40
+
(RO)3Si
Br/OTf
13
Handy,24,111 and Seganish68 in the DeShong laboratories have probed the viability
of using silicon-based reagents for the formation of the C?2/B?2 bond via Pd(0)-
catalyzed cross-coupling.  For these exploratory studies, the simple phenylation of
pyridine and quinoline derivatives was investigated.  Mowery had previously shown that
2-bromo and 3-bromopyridine (41 and 43) readily underwent phenylation using the
fluoride-activated, Pd(0)-catalyzed siloxane methodology (Scheme 16, eqs. a and b).23  In
parallel, 2- and 3-pyridyl triflates were cross-coupled in good yield by Seganish using the
catecholate reagent 18 (Scheme 16, eqs. c and d).68
Scheme 16
[PhSi(cat)2]-[Et3NH]+, 18
TBAF
N OTf N
N
OTf
N
45
46
42
44
Pd(dba)2 / PR3
73%
[PhSi(cat)2]-[Et3NH]+, 18
TBAF
Pd(dba)2 / PR3
78%
N Br N
N
Br
N
41
43
42
44
(a)
(b)
(c)
(d)
PhSi(OMe)3, 15
TBAF
Pd(OAc)2, PPh3
76%
PhSi(OMe)3, 15
TBAF
Pd(OAc)2, PPh3
62%
14
As illustrated in Scheme 17, Handy recently demonstrated the efficient cross-
coupling of phenyltrimethoxysilane (15) and 2-bromoquinoline (47) to form
2-phenylquinoline (48, Scheme 17, eq. a).111  In turn, 2-quinoline triflate 49 was cross-
coupled in excellent yield with (bis)catechol phenyl silicate 21 by Seganish (Scheme 17,
eq. b).68
Scheme 17
N Br
47
PhSi(OMe)3, 15
TBAF
Pd(OAc)2, PPh3
80%
N
48
N OTf
49
[PhSi(cat)2]-[Et3NH]+, 18
TBAF
Pd(OAc)2, PPh3
91%
N
48
(a)
(b)
Encouraged by the initial results demonstrating the successful phenylation of
simple pyridine and quinoline compounds, efforts are underway to develop the cross-
coupling methodology for the formation of the C4?D4 and C2?B2 heteroaryl-heteroaryl
bonds present in both streptonigrin (24) and lavendamycin (25).  For streptonigrin, the
proposed synthesis will have as its key steps (1) the silicon-based pyridyl-aryl cross-
coupling of highly substituted 4-bromopyridine 52 with sterically encumbered arylsiloxane
derivative 53; and (2) the subsequent silicon-based cross-coupling of the complete C?D
ring system (51) with 2-(trialkoxysilylpyridyl)-5,8-quinone 50 (Scheme 18).112
15
Scheme 18
N
OMe
OMe
BOCHN
MeO
N
CH3BOCHN
CO2R
OMe
OMe
OMOM
TfO/Br
Si(OR)3
+
N
CH3BOCHN
CH3
OMe
OMe
MeO
Br
Si(OR)3
+
Streptonigrin (24)
50
51
52
53
OMOM
N
O
O
H 2N
MeO
N
CH3H2N
CO2H
OMe
OMe
OH
A B
C
D
C
D
A B
C
D
For lavendamycin (25), the proposed synthesis will have as its key steps (1) the
silicon-based cross-coupling of highly substituted 4-bromopyridine 57 with ortho-
substituted arylsiloxane derivative 58; and (2) the subsequent silicon-based cross-
coupling of the complete C?D?E ring system (56) with
2-(trialkoxysilylpyridyl)-5,8-quinone 55 (Scheme 19).112
Scheme 19
N
O
O
H2N N R
25, R = COOH, Lavendamycin
54, R = CH3
CH3HN
A B
C
D
E
+ +
N
OMe
OMe
R2N
N CH3
CH3HN
A B
C
D
E
Si(OR)3
55
TfO/Br
56
N CH3
Br
CH3F
C
Cl
57
E
58
BOCHN
Si(OR)3
16
Toward the goal of constructing the C?D ring system (51) of streptonigrin, McElroy
has extended the scope of Pd-catalyzed siloxane coupling to include the efficient
phenylation of functionalized 4-bromopyridines.112  Under palladium catalysis, hindered
4-bromopyridine derivative 59 was cross-coupled in good yield with TBAT (10) (Scheme
20, eq. a); however, when phenyltrimethoxysilane and TBAF were employed as the
phenylating reagent with electron-deficient substrate 59, low yields of adduct 60 were
obtained.  Gratifyingly, electron-rich substrate 61 underwent high yielding phenylation
with phenyltriethoxysilane (Scheme 20, eq. b).
Scheme 20
NH3CO
O2N
CH3
Br
CH3
     TBAT (10)
NH3CO
O2N
CH3
CH3
  Pd(OAc)2, PPh3
67%
59 60
PhSi(OMe)3, 15
TBAF
Pd(OAc)2, PPh3
89%
NH3CO
H3C
CH3
Br
CH3
61
NH3CO
H3C
CH3
CH3
62
(a)
(b)
In conclusion, for these proposed natural product syntheses to be successful, a
general, efficient synthesis of highly functionalized aryl siloxanes is required.  The
siloxanes needed for the synthesis of colchicine (22), Fitzgerald?s compound (23),
streptonigrin (24), lavendamycin (25), and nitramarine (34) are summarized, in Figure 6.
17
N
38
Si(OR)3
N
39
NH Si(OR)3
Si(OR)3
OMe
OMe
MeO
28
OMe
OMe
Si(OR)3
53
OMOM
58
BOCHN
Si(OR)3
N
OMe
OMe
R2N Si(OR)3
55
N
OMe
OMe
BOCHN
MeO
Si(OR)3
50
Figure 6.  Siloxane Derivatives for Application in Natural Product Syntheses.
To date, the DeShong group has demonstrated the Pd-catalyzed fluoride-
activated phenylation by phenyl(trialkoxy)silane derivatives of a range of electron-rich
and electron-deficient aryl halides and triflates, including sterically hindered and
heteroaromatic substrates.21,23-25  A sampling of the biaryl compounds that have been
synthesized in our laboratories is shown in Figure 7.  The syntheses of heteroatomic,
aryloxy, and Lewis basic biaryl derivatives are particularly noteworthy because these
types of compounds are difficult to access via the corresponding Suzuki reaction: the
synthesis and reactions of arylborane reagents in the presence of Lewis basic moieties
are often stymied by their interaction with the highly Lewis acidic boron center.
18
H3C
CH3
O
O
OCH3 CH3
NHR NMe2
HN
R
R = Ac, COOMe
NO2, Cl, CHO
CN, t-Bu
R = H, Ac, Ts
N
S
o, m, p o, m, p
2, 32, 3
N
O
O C16H33
N
OMe
R
CH3
CH3
R = NO2, H, Me
Figure 7.  Biaryl Compounds Synthesized Using the Phenyl(trimethoxy)silane Cross-
Coupling Methodology.
The research described above has already established the relative mildness,
wide ranging functional group compatibility, and ease of work-up of the siloxane-based
cross-coupling process for the transfer of phenyl.21,23-25  However, until the facility of
synthesizing of aryl(trialkoxy)silane derivatives, and the ability of our siloxane
methodology to transfer aryl groups other than phenyl has been established, the
generality of the siloxane-based cross-coupling methodology remains unproven.41
Research Goal: Synthesis of Aryl(trialkoxy)silane Derivatives
The goal of the research described herein has been the development and
optimization of methods for the synthesis of aryl(trialkoxy)silane reagents.  This study
necessitated the synthesis of ortho, meta, and para-substituted, electron-rich and
electron-deficient aryl siloxanes.  Additionally, aryl(trialkoxy)silanes are needed as
19
precursors to the corresponding aryl(biscatecholate) or arylsilatrane derivatives required
for the cross-coupling with aryl triflates.  The penultimate goal is the development of
methods for the synthesis of complex aryl siloxane intermediates needed for the
construction of biaryl natural products.
Scheme 21
X
R
X = I, Br,Cl, OTf
Si(OEt)3
R
SiOO
N
O
Si
OO
O O HNEt
R
R
R
R'
R'
x
Pd(0)
X = I, Br,
Cl, OTf
In their dissertations on the Pd-mediated reactions of hypercoordinate silicates,
Mowery67 and Handy111 reviewed the mechanism and scope of the cross-coupling
reactions of aryl silicon, boron, and tin reagents.  The aim of this chapter is to review
existing methods for the synthesis of aryl trialkoxysilane, boron, and tin reagents for use
in the Pd-mediated cross-coupling reaction.  Finally, the results of studies in the DeShong
lab on improved methods for the synthesis of aryl(trialkoxy)silanes are presented and
discussed.
20
Overview of the Synthesis of Aryl Group Transfer Reagents
Focusing on aryl silicon, boron, and tin reagents, two general approaches exist for
the synthesis of these materials: (1) the most common and economical method is the
treatment of an aryl Grignard or lithium reagent with a silicon, boron or tin electrophile
(Scheme 22);
Scheme 22
H3CO M H3CO B(OEt)2
M = MgBr, Li
H3CO SiXnR3-n
H3CO SnBu3
SiXnR4-n
Cl SnBu3
X = F, Cl, Br
R = alkoxy, alkyl
B(OEt)3
and (2) when an incompatibility with organic functional groups arises, the transition metal-
mediated silylation, borylation or stannylation of an aryl halide (vide infra) (Scheme 23).114
Scheme 23
H3CO X H3CO B(OMe)2
H3CO Si(OEt)3
H3CO SnBu3
Pd(0) or Rh(I)
X = I, Br, Cl, OTf Pd(0)
Pd(0)
(MeO)2B-B(OMe)2
H-Si(OEt)3
Bu3Sn-SnBu3
Other miscellaneous methods have been reported, however, the above methods
remain the most widely employed pathways to the synthesis of aryl cross-coupling
reagents.10  The availability of multiple methods for the synthesis of any given reagent
adds to the versatility and overall strength of the corresponding cross-coupling
methodology.
21
Both approaches (Schemes 22 and 23) have their inherent strengths and
limitations.10  Most notably among their strengths, these methods are regiospecific,
allowing for the direct installment of the desired tin, boron, or silicon electrophile at the site
of the halogen.  Metallation?either via formation of the aryl Grignard or aryl lithium
reagent?is a relatively inexpensive, scalable standard laboratory technique, and the
desired arylmetalloid can be generated conveniently, in typically fair to excellent yields
using previously reported procedures.115  Subsequent treatment of the aryl metalloid
intermediate with a silicon, boron, or tin electrophile gives the desired product in fair to
excellent yield, as described below.
That said, the metalloid reaction is limited by the problems associated with the
synthesis of aryl metalloids having electrophilic functional groups (i.e. esters, ketones,
etc.).116-122  Also, protic functional groups must be protected prior to metallation.  Highly
reactive aryllithium species must be generated at low temperature (between ?78 and
?110 ?C), and often decompose before undergoing further transformation.  The reaction of
multifunctional silicon, boron, or tin electrophiles with highly reactive aryl metalloid
derivatives is typically complicated by the formation of polyarylated products (Scheme
24, eq. a).123  In addition, homocoupling of the arylmetalloid can occur, resulting in the
formation of biaryl contaminants (eq. b), and lithium-halogen exchange can be complicated
by competing alkylation (eq. c).115  This overview will focus on known methods for the
preparation of tin, boron, and silicon cross-coupling reagents; methods for the generation
of aryl Grignard124,125 and lithium126-129 intermediates are reviewed elsewhere.115,130
Scheme 24
B(OMe)3 H3O
+
ArLi Ar B(OH)2 (Ar)2B OH+ +-78 ?CEt
2O
2 Ar-MgBr -78 ?CEt
2O
Ar-Ar
Ar-Br + RLi -78 ?CTHF Ar-R
(a)
(b)
(c)
22
In turn, the Pd-mediated approach summarized in Scheme 23 (above) is relatively
expensive and often limited by the lack of generality (vide infra); for example, different
conditions (catalyst, solvent, base) are typically required for electron-deficient and
electron-rich aryl halide substrates.  In addition, chloroarenes are notoriously unreactive
under typical cross-coupling conditions.  Nevertheless, the Pd-mediated approach is an
invaluable foil to the organometallic approach, given its relative mildness and functional
group tolerance.
Lastly, both methods require an aryl halide starting material: generation of the
aryllithium by metal-halogen exchange, the Grignard under standard or Barbier reaction
conditions, or the reactive Ar?Pd(II)?X intermediate necessitates the synthesis of the
required aryl iodide or bromide precursor (Scheme 25).  The regiospecific halogenation of a
functionalized aromatic system can be problematic, and often requires multiple steps.
Lastly, it is difficult to achieve the regioselective monolithiation of polyhalogenated
aromatics; consequently, multiple products?both regio- and polyfunctionalized
isomers?are obtained upon the addition of the electrophile.126-129
Scheme 25
Br
LiR-Li
MgBrMg0
Pd(0) Pd(II) X
Ln
E+
E+ EMeO
MeO
MeO
MeO
MeO
Y E
Aryllithium reagents can be generated in the absence of a halogen substituent on
the arene substrate by directed ortho metallation (DOM).131-137  The DOM reaction involves
chelation of a lithium transfer reagent to a Lewis basic group; this chelation results in
deprotonation and lithiation at a position ortho to the directing group (Scheme 26).
23
Scheme 26
MeO R-Li E+MeO Li MeO E
As with lithium-halogen exchange, DOM is a powerful method for the
regioselective formation of aryllithium reagents; however, DOM is limited to substrates
with a geometrically available heteroatom.132  Also, the presence of bulky substituents
meta to the desired site of lithiation can compromise the regioselectivity of the reaction
through steric interference;133-137 lastly, other substituents on the substrate which are
capable of chelation can compete as metal-directing groups.  Graduate student Michael
Seganish is currently exploring the synthesis of ortho-substituted aryl(trialkoxy)silane
derivatives utilizing directed ortho metallation.
Preparation of Aryl Stille (Tin) Reagents
Despite their toxicity, organotin reagents are prized for their ease of synthesis,
handling and storage; they are stable to moisture and oxygen, and can be purified by
distillation or C?18 flash column chromatography prior to use.138,139  In addition, aryl
stannanes are compatible with a wide variety of organic functional groups, making the use
of tedious protecting group strategies unnecessary.  Aryltributyl? and ?trimethytin
reagents are typically synthesized from the corresponding aryl halide by the in situ
conversion to a reactive organolithium or organomagnesium species followed by treatment
with trialkyltin chloride (Scheme 27).19,138,140  The synthesis of organotin compounds via
lithium and Grignard reagents has been recently reviewed.138,141-143
Scheme 27
Me2N Br
1. BuLi
   THF, -78 ?C
2. Bu3SnCl
90%
Me2N SnBu3
24
When electrophilic organic functional groups preclude the organometalloid method,
the aryl halide substrate may be cross-coupled under Pd(0) catalysis with
hexaalkyldistannanes (Scheme 28).19,138,144  The coupling approach is generally high-
yielding, albeit limited to aryl iodides and bromides and intolerant of p-nitro and p-amino
substituents on the aryl ring.  The only detectable side reaction is homocoupling of the
electrophile.19
Scheme 28
MeO I
Me3Sn-SnMe3
Pd(PPh3)2Br2
toluene, 115 ?C
96%
MeO SnMe3
In place of a hexaalkyldistannane, tributyltin hydride was recently shown to
couple with most aryl iodides under Pd(0) catalysis in the presence of a weak base
(Scheme 29).145 .  Two byproducts were observed: the homocoupled product (Ar?Ar), and
the reduced (dehalogenated) arene (Ar?H).  Aryl bromides were unreactive.
Scheme 29
H2N I
Bu3Sn-H
PdCl2(PMePh2)2
NMP, 25 ?C
73%
H2N SnBu3
Less common methods for the synthesis of aryl tin derivatives include the photo-
induced stannylation of mono and polychlorobenzenes using trimethylstannylsodium,146-149
and a Diels-Alder approach.143,150  A variety of ortho, meta and para-substituted aryl,
pyridyl, and quinolinyl chlorides are substituted by Me3Sn? ions in liquid ammonia under
irradiation to give the substitution product in high yields (Scheme 30).146  The reaction is
limited to aryl chlorides; aryl bromide and iodide derivatives undergo dehalogenation
(reduction) under the reaction conditions.151  Despite its limited scope, the formation of the
25
tin reagent from the corresponding chloride is noteworthy in that aryl chlorides?which are
more readily obtained than the corresponding bromide or iodide?cannot be readily
converted to the stannane using either the metallation or the coupling approach.
Scheme 30
Z
Cl
+ Na SnMe3 h?NH
3
Z
SnMe3
Cl SnMe3
Z = CH, o-, m-, p-
Z = N, 2,5-, 3,5-, 3,6-
58%, 90%, 88%
88%, 80%, 86%
Lastly, the Diels-Alder reaction between methyl tributylstannylpropiolate (64) and
alkyl substituted 1,3-butadienes (63) forms 1,4-cyclohexadienyl tin derivatives (65) in
good yields; subsequent aromatization (elimination) gives the aryl tin reagent (66)
(Scheme 31).143,150,152  The scope of this reaction is severely narrowed by a number of
factors including (a) the often low regioselectivity of the cycloaddition reaction, and (b)
only simple alkyl-substituted dienes and electron-deficient dienophiles undergo
cyclization.
Scheme 31
+
CO2Me
SnBu3
125 ?C, 50h
71%
CO2Me
SnBu3
DDQ CO2Me
SnBu3
63 64 65 66
Preparation of Aryl Suzuki (Boron) Reagents
Organoboron reagents are a non-toxic alternative to organotin reagents, and have
essentially superceded the use of tin compounds in the Pd-mediated cross-coupling
reaction for the formation of biaryls.153  As with tin reagents, Suzuki reagents are valued for
their ease of handling and storage, due to their stability to moisture and oxygen.139  Unlike
26
tin reagents, organoboranes are more difficult to synthesize and purify (they are often
used as the crude isolate), however much work has been dedicated toward the
development of efficient routes to the formation of these highly useful synthetic
intermediates.10,20,153-155
Methods for the synthesis of arylboronic acids and esters for use in Suzuki
couplings are fundamentally the same as for Stille reagents.  Aryl boron derivatives are
classically synthesized from Grignard or lithium reagents and trialkyl borates; acid
hydrolysis then gives the arylboronic acid (Scheme 32), or where feasible the ester may
be coupled directly.156  The organometalloid approach to the synthesis of organoboron
compounds has been thoroughly reviewed.20,153,155  Unlike the tin electrophile R3Sn?Cl,
which bears only one leaving group, the typical methyl, ethyl or butyl borate electrophile
B(OR)3 can undergo bis- or tris-alkylation leading to the formation of borinic acid (i.e.,
Ar2B(OMe)) or trialkylborane (Ar3B) derivatives, respectively.  Triisopropyl borate has
been shown to sterically temper multialkylation of the borate, and it has become the
electrophile of choice with highly reactive organometalloids.157
Scheme 32
1. n-BuLi, Et2O, -78 ?C
2. B(OBu)3
3. dil. HCl
N
Br
N
B(OH)2
79%
Unlike the traditional organometallic approach, Pd(0)-catalyzed borylation
strategies enable access to boronic acid and ester derivatives in the presence of
electrophilic functionalities such as nitro, ester, ketone and cyano groups.  Aryl halides and
pseudohalides undergo borylation under palladium catalysis using two different types of
boron nucleophiles: alkoxydiboron derivatives, (RO)2B?B(OR)2 or alkoxy boranes,
H?B(OR)2 (Scheme 33).  The Pd(0)-catalyzed cross-coupling approach to the synthesis
of organoboron compounds has been reviewed.158-160
27
Scheme 33
Pd(0)
B-nucleophile
Ar X Ar B(OR)2
Miyaura has pioneered the use of bis(pinacolato)diborane for the borylation of aryl
iodides,161,162 bromides,161,162 chlorides163,164 and triflates165 (Scheme 34).  The reaction
tolerates various functional groups, however ortho-substituents or electron-donating
substituents slow down the reaction significantly, necessitating the use of specialized
catalysts and a higher catalyst loading to achieve reasonable reaction times.163  The major
reaction byproducts are the homocoupled starting material (believed to arise from the
Suzuki reaction of the arylboronate product and unreacted aryl halide starting material),
and reduced starting material (attributed to hydrolytic photodeboronation,166 a particular
problem with boronic acids and esters adjacent to a heteroatom).163
Scheme 34
OMe
X
PdCl2(dppf), KOAc
solvent, 80 ?C, 2-24 h
82%, X = I, DMSO
68%, X = Br, DMSO
93%, X = OTf, dioxane OMe
B B
O
OO
O
B OO Pd(dba), PCy3, KOAc
dioxane, 80 ?C, 6 h
B B
O
OO
O
OMe
Cl
92%
Strongin has extended the scope of the methodology to aryldiazonium salts: the
Pd-catalyzed cross-coupling of bis(pinacolato)diborane and most para-substituted
aryldiazonium salts proceeds efficiently in moderate to excellent yields (42?96%)(Scheme
35).167  This reaction is notable in that the tetrafluoroborate salts are prepared from
relatively inexpensive, readily available anilines.  Also, this methodology features
comparatively mild conditions, an environmentally-friendly alcohol solvent, and no added
base; homocoupled contaminants were not observed (and no other byproducts were
reported).167
28
Scheme 35
N2BF4
PdCl2(dppf)
MeOH, 25-40 ?C, 8 h
B B
O
OO
O
B OO
81%O OMe
O OMe
Masuda discovered that the coupling reaction of pinacolboron hydride with aryl
iodides, bromides, or triflates in the presence of a catalytic amount of PdCl2(dppf) or
PdCl2(PPh3), together with triethylamine afforded aryl boronates in good to excellent yields
(Scheme 36).168,169  Since the initial report by Masuda, the reaction has not been greatly
improved upon, although several variations of the reaction have appeared in the
literature:170-173  Baudoin demonstrated that the reaction is catalyzed by Pd(OAc)2 and
Buchwald?s phosphine (PCy2(o-biphenyl));170 and LeFloch employed a novel
phosphinine-Pd complex as an alternative catalyst.171
Scheme 36
AcHN OTf
77%
PdCl2(dppf), Et3N
dioxane, 100 ?C, 4 hB H
O
O
B
O
O
AcHN+
The cross-coupling reaction employing pinacolboron hydride tolerates a variety of
electron-rich and -deficient functional groups and is relatively insensitive to solvent
(dioxane, toluene, dichloroethane, and acetonitrile were all equally accommodated).168-171
Ortho, meta, and para substituted substrates undergo equally efficient conversion to the
boronate.  As with the cross-coupling reactions using alkyl diboranes, aryl iodides are
much more reactive than bromides or triflates, which require extended reaction times and
elevated temperatures to reach completion.  The major byproduct is the reduced substrate
29
Ar?H; when triethylamine is substituted by H?nig?s base, pyridine, KOAc, or DBU, the
reduced species predominates.
Less common methods for the synthesis of aryl boron derivatives include the
rhodium or iridium-catalyzed borylation of arenes via C?H bond activation174 and the
regioselective D?tz annulation of Fischer carbene complexes with alkynyl boronates.175
Both of these techniques are noteworthy in that each provides arylboronic acids without
relying on the availability of the appropriate aryl halide.  The former technique employs
either pinacolboron hydride or bis(pinacolato)diborane, and was reviewed by Ishiyama in
2003.174  An example of this method is shown in Scheme 37.176  C?H bond activation
suffers from the requirement for harsh reaction conditions, polyborylation, and often poor
regioselectivity with mono or unsubstituted substrates; only disubstituted arenes and
substituted heteroaromatics exhibit regiocontrol.
Scheme 37
[IrCl(COD)]2+dibpy
(3 mol%)
B B
O
OO
O
N
(i-Pr)3Si N
(i-Pr)3Si
B
O
O
octane / 80 ?C / 16 h
+ H2+
N
(i-Pr)3Si
B
O
O
B
O
O
79% 10%
The benzannulation technique has some unexpected strengths: both the Fischer
complexes and alkynyl boronates are readily accessible; and alkynyl boronates exhibit
high regiospecificity in the D?tz annulation reaction, in stark contrast to the corresponding
alkynylsilanes and -stannanes.175  The reaction tolerates alkyl and phenyl substituents on
the alkynyl boronate substrate; however the presence of bulky alkynyl substituents
leads to the exclusive formation of cyclobutenone products.  Harrity developed and
applied this technique to the synthesis of a novel class of quinone and hydroquinone
boronic acids (Scheme 38).175  Aryl complex 67 and alkyne 68 underwent smooth
30
cycloaddition to provide arylboronate 69; regioisomer 71 was not detected.  The remaining
yield was of quinone 70, formed by the photodeborylation of the arylboronate product 69.
Scheme 38
Cr(CO)5
OMe
Ph B
O
O
O
O
Ph
B
O
O
O
O
Ph
B O
O
O
O
Ph
1.  THF, 45 ?C
2.  Ce(IV)
67
68
70
12%
69
57%
71
+ +
Preparation of Aryl Silicon Reagents
Previous studies from our group21-25 as well as Hiyama,8,26-33 Ito,34,35 Denmark,36-44 and
others45-56 have shown that a variety of silicon derivatives (i.e., compounds 72-78, Figure
7) undergo fluoride-mediated, Pd(0)-catalyzed aryl group transfer reactions.57-59  The Pd-
catalyzed cross-coupling reaction of organosilicon compounds has largely been studied
by Hiyama and Hatanaka (aryl(alkyl)dihalosilanes 72-73),8,26-33 and Shibata116 and
DeShong21-25 (aryl(trialkoxy)silanes 74): all results to date indicate that these organosilicon
derivatives participate in the cross-coupling reaction with similar efficiency and functional
group tolerance as aryl stannanes and boranes.139  While initial reports demonstrate that
Denmark?s36-44 arylsilacyclobutanes (75), and Mori?s28,31,52,56 arylsilanols (76-78) will
participate in the aryl-aryl cross-coupling process, the scope and utility of these reactions
have yet to be demonstrated.  In addition, the potential application of the silanol
31
methodology is limited by the need for stoichiometric amounts of silver(I) oxide as an
activator.139  Silacyclobutanes and silanols will not be discussed further.
SiRX2
OCH3
Si(OH)2Et
Me
Si
Cl
MeO
Si(OEt)3
O2N
72, X = F, R = Et, Me, i-Pr
73, X = Cl, R = Et
77
7574
Si(OH)(CH3)2
Me
76
Si(OH)3
78
Figure 8.  Silicon-Based Aryl Group Transfer Reagents.
Aryl(trialkoxy) and aryl(alkyl)dihalo silicon reagents (Ar?Si(OR)3 and Ar?Si(R)X2,
respectively) possess many of the strengths, but few of the limitations associated with
their tin and boron counterparts (vide infra).8,21-59  Cross-coupling prowess aside, it is the
ease of working with these silicon reagents that has led to the flurry of interest in silicon-
based aryl-group transfer reagents.  Organosilicon derivatives?like boronic acids?are
non-toxic relative to the tin compounds.26  Organosilanes are readily available, stable to
air and moisture, and?unlike many boronic acids and esters?can undergo purification by
distillation or column chromatography, and are stable to most reaction conditions employed
in synthetic chemistry.26  Lastly, organosilicon compounds hold the promise of being more
easily prepared than the notoriously problematic organoboron derivatives.
Hiyama and Hatanaka have pioneered the use of aryl(alkyl)dihalosilanes in the
Pd-catalyzed cross-coupling reaction with aryl halides (Scheme 39).26,177,178  A range of
silanes (Ar?SiR3-nXn) has been shown to participate in the cross-coupling, among which
the optimal reagents are the aryl(alkyl)difluoro-1,8,177,179,180 and aryl(alkyl)dichlorosilanes.29,30
The non-transferable ?dummy? alkyl ligand on silicon is typically methyl, ethyl or propyl,
32
although under certain conditions the methyl group is also capable of being transferred in
the cross-coupling reaction, in competition with the aryl group.26,177,178
Scheme 39
Me
DMF
100 ?C
67%
+
NC
I
NC
Si(Et)F2 Me
(?3-C3H5PdCl)2
KF
The organofluorosilane derivatives are synthesized from the corresponding
organochlorosilanes in moderate yield (50-60%), using antimony trifluoride (SbF3) (Swarts
reaction)1,181-185 or CuF2 (Scheme 40).1,9  This conversion has also been reported to occur in
moderate yield with HF, although few applications of this technique to the synthesis of
aryl(alkyl)difluorosilanes have appeared in the literature.181,186-188  Miscellaneous other
methods for the formation of organofluorosilane derivatives via the cleavage of Si?X
bonds other than chloride have been reported (i.e., X = OH, OR, H), but are of limited
scope.119,185,188-190  Hiyama and Hatanaka have since developed a cross-coupling protocol
employing aryl(alkyl)dichlorosilanes directly, thus avoiding an additional synthetic step,
and the handling of the toxic and moisture-sensitive SbF3 and CuF2.29,30
Scheme 40
H3C
Si(Et)Cl2 1. SbF
3, -70 ?C ? 25 ?C, neat
2. 100 ?C, 2h
65%
H3C
Si(Et)F2
In parallel to the preparation of aryl tin and boron reagents, aryl(alkyl)dichlorosilane
derivatives are traditionally synthesized from the corresponding aryl Grignard or lithium
reagent and trichloro(alkyl)silane electrophiles (Scheme 41).1,29,33,181,183,187,190-195  No
systematic study of the synthesis of aryl(alkyl)dichlorosilanes via the organometallic
method has been reported, and little data exists in the literature: of the few reports stating
33
yields of purified product,33,193 a range of 33-88% (average yield of 50-60%) is given, and
in no cases are the byproducts of the metallation reaction discussed or characterized.
Hiyama and Hatanaka have demonstrated that crude aryl(alkyl)dichlorosilane derivatives
prepared via metallation may be used without further purification for Pd-catalyzed cross-
coupling, and report quantitative yields of crude silane via the metallation reaction.1,181
Scheme 41
1. Mgo, THF, 0 ?C
2. EtSiCl3
88%
Br
MeO
Si(Et)Cl2
MeO
Ortho substitution of the aryl Grignard or lithium species strongly impacts the yield
of the metallation reaction (Scheme 42).33,193  Hiyama demonstrated that silylation of p- and
m-bromotoluene with Et?SiCl3 occurred in good yield relative to o-bromotoluene.33  The
more sterically compact alkyltrifluorosilane electrophiles (R?SiF3) have been shown to
react with very hindered organometallic reagents where R?SiCl3 failed to react;191 however
this approach has never been applied to the systematic synthesis of ortho-substituted
aryl(alkyl)difluorosilanes.
Scheme 42
1. Mgo, THF, 0 ?C
2. Et-SiCl3Me
Br
Me
Si(Et)Cl2
o-Me, 35%
m-Me, 72%
p-Me, 62%
A second, less common method for the synthesis of aryl(alkyl)dichlorosilanes is
silylative decarbonylation of aryl acid chlorides, as reported by Rich.196  Again, this Pd-
catalyzed cross-coupling technique is a good foil to the metallation reaction where
electrophilic organic functional groups prohibit the organometalloid method.  The palladium-
catalyzed reaction of sym-tetrachlorodimethyldisilane(Cl2(Me)Si?Si(Me)Cl2) with benzoyl
chloride derivatives was shown to form aromatic chlorosilanes in generally good yield
(Scheme 43).  The best yields were obtained with electron-deficient, p- and m-substituted
34
aromatic acid chlorides.  The reaction failed for 2,6-pyridine dicarboxylic acid chloride (no
reaction was observed), apparently due to complexation of the pyridine to the palladium
catalyst.  With few exceptions, the corresponding cross-coupling reaction of aryl halide
substrates and Cl2(Me)Si?Si(Me)Cl2 fails.45,196-198
Scheme 43
O
Cl +
Cl2Si SiCl2
MeMe
(PhCN)2PdCl2
PPh3
Si(Me)Cl2
+ CO MeSiCl3+
69%NO2
NO2
neat, 145 ?C, 13h
Miscellaneous other preparations of aryl(alkyl)dihalo silane derivatives have been
reported, but are of limited scope or are only practical in the industrial laboratory.184,199-203  An
efficient synthesis of ortho-substituted aryl(alkyl)dihalo silane derivatives has not been
described.
In addition to functioning as aryl group transfer reagents, aryl(trialkoxy)silane
derivatives (Ar-Si(OR)3) are important synthetic intermediates for the formation of hybrid
organic-inorganic materials, such as synthetic glasses, ceramics, coatings or fibers
prepared by sol-gel chemistry.118,204  These compounds are often called alkoxysilane
?monomers,? in reference to the polymerization of organosilanes into water-soluble
oligomers.204  Despite the multidisciplinary utility of arylsiloxanes, few practical methods for
the preparation of trialkoxysilyl or trihalogenosilyl derivatives have been reported.
In analogy to the corresponding preparations of Stille and Suzuki reagents, the
traditional method for the synthesis of aryl siloxanes is the treatment of an aryl Grignard or
lithium reagent with a silicon electrophile (SiCl4, Cl-Si(OR)3, or Si(OR)4) (Scheme 44).
Scheme 44
OCH3
M
OCH3
Si(OR)3
M = MgBr, Li
Si(OR)4
Cl-Si(OR)3
1. SiCl4 
2. ROH
35
Aryl metals will react with silicon atoms bearing leaving groups other than chloride
and alkoxy, including ?CN, ?H, ?OSiR3, ?NR2, and ?OAc, however these reactions are of
limited practicality: not only are the electrophiles tedious to prepare and purify, but in the
case of H?Si(OR)3, the pyrophoric byproduct silane (SiH4) is produced upon reaction
with strong bases such as organometallic reagents.204,205  Other organometallic reagents
generated by metal-halogen exchange have been employed in this transformation, as
well, however they are of limited scope.121,204
The first organometalloid method for the synthesis of arylsiloxane derivatives
involves a two-step process: (1) the silylation of an arylmetalloid with commercially-
available, inexpensive silicon tetrachloride (SiCl4) to form the aryl(trichloro)silane
intermediate; and then (2) alcoholysis (Scheme 45).116,206-214  Shibata synthesized a series
of aryl(triethoxy)silanes in ?acceptable? yields using Grignard or lithium reagents (the
choice of metal was dictated by the ease of forming the carbanion).116
Scheme 45
Pr
SiCl3
MeOH 
pyridine
65%
Pr
Si(OMe)3
Pr
Br
1. Mgo
2. SiCl4, 0-25 ?C, 17h
Pr
I
1. BuLi, hexane, -70 ?C
2. SiCl4, -70 to 25 ?C, 17h
The use of SiCl4 as the silicon electrophile is of limited practicality for a number of
reasons which include (a) moderate to poor product yield for the overall, two step
conversion, (b) the difficult transfer and handling of moisture-sensitive reagents and
intermediates, and (c) multiple substitution results in the formation of difficult to separate
byproducts (Scheme 46).206,210  Large quantities of electrophile (20+-fold excess) have
been employed to mitigate polyarylation, however this leads to difficulties in product
isolation and HCl contamination.210
36
Scheme 46
SiCl4, 1.2 equiv
heptane/THF
reflux 2h
MgCl SiCl3
+
Cl2
Si
48% 17%
Treatment of the arylmetalloid with Cl?Si(OR)3 should favor the formation of
monoaryl siloxanes by preferential displacement of chloride from silicon.118,210,215,216  Not only
are the yields somewhat better than the SiCl4/alcoholysis technique, but the reaction
involves a single step from the formation of the organometalloid (i.e., Scheme 47).216
However, use of Cl?Si(OR)3 as the silicon electrophile still has several significant
drawbacks: (1) unlike SiCl4, Cl?Si(OR)3 compounds are not commercially available, and
are tedious to prepare;121,217,218 (2) while less reactive than the tetrachloride,
chloro(trialkyl)silane reagents still require careful handling to avoid hydrolysis of the
reactive Si?Cl bond; and (3) surprisingly, even when excess electrophile is used, or low
temperatures are employed, over-arylation of silicon occurs, resulting in inseparable di-
and tri-arylated byproducts.204,210
Scheme 47
Cl-Si(OMe)3, 1.0 equiv
THF
reflux, 1h
MgBr Si(OMe)3
60%
Br Br
Treatment of the arylmetalloid with the less reactive electrophile Si(OEt)4 should
favor the formation of monoaryl siloxanes because alkoxide is more difficult to displace
from silicon than chloride; typically, the reaction of organometallic reagents with alkoxy
silanes is more selective than the reaction with chlorosilanes.204  As with the arylation of
Cl?Si(OR)3, the typical yields of the silylation of organometallic reagents with Si(OEt)4 are
superior than the SiCl4/alcoholysis method, and this technique is more efficient because it
involves only a single step from the formation of the organometalloid.116-120,209,214,219,220
37
For example in Scheme 48, conversion of the series of bromotoluene regioisomers
to the Grignard reagent, followed by treatment with 2 equiv of tetraethoxysilane afforded
acceptable yields of the corresponding ortho- and para-(triethoxysilyl)toluene isomers; the
low yield of m-(triethoxysilyl)toluene was attributed to the lowered nucleophilicity of the
carbanion (electronic effect) .120
Scheme 48
Si(OEt)4, 2.0 equiv
THF
reflux, 16 h
o-, 68%
m-, 29%
p-, 48%
MgBr
CH3
Si(OEt)3
CH3
The use of Si(OR)4 for the one-step preparation of arylsiloxanes via the
organometallic approach has several advantages including the commercial availability, low
cost, and ease of handling and storage of tetraalkoxysilanes.204  Polyarylation still occurs,
however, lowering the yield of monoarylated silane, and necessitating careful fractional
distillation or chromatography to isolate the desired product.  For example, Frohn was able
to make perfluorinated siloxane 80 in 55% yield from the Grignard reagent and Si(OEt)4,
where the modest yield was due to the formation of di- and triarylated products 81 and 82,
respectively (Scheme 49).220
Scheme 49
1. Mgo
2. Si(OEt)4, 2.0 equiv
Br
F
F
F
F
F
Si(OEt)3
F
F
F
F
F
+ (C6F5)2Si(OEt)2 (C6F5)3Si(OEt)+
80
55%
81
35%
82
trace
79
Masuda has reported the Pd(0)-catalyzed silylation of aryl iodides using
triethoxysilane (H?Si(OEt)3) (Scheme 50).58,221  The reaction was achieved with
38
triethoxysilane and Pd2(dba)3?CHCl3 with the addition of 2 equiv of tris(o-tolyl)phosphine
and a base such as i-Pr2NEt.  Excellent yields of aryl siloxane were obtained with
electron-rich, para-substituted aryl iodides.  In contrast to aryl iodides, aryl bromides were
reported to provide low yields of aryl siloxane under identical conditions.  In addition, the
silylation of ortho- or meta-substituted aryl iodides/bromides was not reported.
Scheme 50
H3CO
Si(OEt)3
H3CO
I
H3CO
H
+
83 84 85
H-Si(OEt)3
i-Pr2NEt / NMP
Pd(dba)2?CHCl3
P(o-tol)3
The major byproduct was the reduced substrate Ar?H (85); in contrast to the
polyarylated silane byproducts formed using the organometallic technique, the reduced
byproduct is readily separated by distillation or column chromatography.  When H?nig?s
base was substituted by triethylamine, pyridine, KOAc, or left out of the reaction
completely, the reduced species predominated.19  Electron-withdrawing groups not only
slowed the reaction significantly, necessitating higher reaction temperatures and longer
reaction times, but facilitated the transfer of hydride from the silane to give the reduced
arene as the major product.19,159  With few exceptions, the corresponding cross-coupling
reaction of aryl halide substrates and Cl3Si?SiCl3 fails,45,196,197 and silylation employing
hexaalkoxydisilanes ((RO)3Si?Si(OR)3) has not been reported.198
The Masuda method is an interesting alternative to the organometalloid approach
in that the yields of the cross-coupling reaction are far superior than the metallation reaction
with para-substituted electron-rich aryl halide substrates.221  In addition, where the cross-
coupling technique fails with ortho-substituted arenes, the metallation method works
optimally.  The Masuda technique is limited to aryl iodides, unlike the metallation method,
which typically employs the more available aryl bromides (and sometimes chlorides).
Unfortunately, neither the organometallic approach nor the silylation technique is effective
for the silylation of arenes bearing electron-withdrawing, electrophilic moieties.
39
In conclusion, existing methods for the synthesis of aryl siloxanes fall into two
categories (Scheme 51): (1) treatment of an aryl Grignard or lithium reagent with a silicon
electrophile ; and (2) silylation of an aryl iodide by triethoxysilane (H?Si(OEt)3) in the
presence of a palladium catalyst as reported by Masuda.221
Scheme 51
H-Si(OEt)3
Pd(0), PR3
Masuda
OCH3
Si(OEt)3
OCH3
I
OCH3
M
M = MgBr, Li
OCH3
X
X = I, Br
Si(OEt)4
Metallation
Both methods, as presently constituted, have their limitations.  The metalloid
reaction is limited by the generally inferior yields of monoarylsiloxane, as well as the
problems associated with the synthesis of aryl metalloids having electrophilic functional
groups (i.e. esters, ketones, etc.).116-122  A general method for the synthesis of
arylsiloxanes from aryl lithium or magnesium reagents has not been reported, nor has a
systematic study of this reaction been performed.  Our first goal was to evaluate the
metallation method, and to develop a practical, general synthetic technique utilizing
standard organometallic reagents for the synthesis of aryl(trialkoxy)silanes.  Ideally our
method would employ the inexpensive, commercially available tetraethoxysilane, or its
methoxy analog.
The Pd-mediated silylation protocol of Masuda is limited to electron-rich iodo
arenes.221  Masuda reported that electron-rich, para-substituted aryl iodides gave excellent
yields of aryl siloxane.  In contrast to aryl iodides, aryl bromides were reported to provide
low yields of aryl siloxane under identical conditions.  In addition, the silylation of ortho- or
meta-substituted aryl iodides/bromides was not reported.  Accordingly, the goals of this
study were to extend the Masuda silylation reaction to aryl bromides and chlorides, and to
evaluate the Masuda methodology for the synthesis of ortho- and meta-substituted aryl
siloxanes.
40
Results and Discussion
Improved Synthesis of Aryl(trialkoxy)silanes via Treatment of Aryl Grignard or
Lithium Reagents with Tetraalkoxysilane
Numerous methods for the formation of the aryl C?Si bond appear in the literature,
the vast majority of which describe the trimethylsilylation of organic molecules.204,222,223  In
contrast, few systematic studies of the synthesis of aryl(trialkoxy)silanes have been
described, partly because the synthetic usefulness and interesting material properties of
aryl(trialkoxy)silanes have only recently been discovered (vide supra).204  Our laboratory
has focused specifically on aryl(trialkoxy)silanes as surrogates for Stille or Suzuki
reagents (Scheme 52).  Although initially described in a single paper by Shibata in
1997,116 the Pd-catalyzed fluoride-activated phenylation by phenyl(trialkoxy)silane
derivatives has been independently cultivated into a practical synthetic technique by the
DeShong group.21,23-25  The scope of the cross-coupling reaction now encompasses
phenylation of a range of electron-rich and electron-deficient aryl halides and triflates,
including sterically hindered arenes and heteroaromatic substrates.21,23-25  Having
demonstrated the efficient phenylation, we wished to study the transfer of substituted aryl
groups to ascertain the scope and limitations of the methodology.  This study
necessitated the synthesis of ortho-, meta-, and para-substituted, electron-rich and
electron-deficient aryl siloxanes.
Scheme 52
X
H3C
SnR3/B(OH)2
H3C
Si(OR)3
Pd(0)
Pd(0), F-X = I, Br, Cl
41
The most common approach to the formation of siloxanes is silylation of an aryl
lithium or magnesium (Grignard) reagent (Scheme 53); Table 1 summarizes the literature to
date.  Although definitive conclusions cannot be drawn from this data, some
generalizations can be made including (a) the yields are typically poor to modest, most
likely due to competing formation of di- and tri- arylated products (over-arylation) (entries 1
and 26); (b) the choice of metal (Li or Mg) is dictated by the ease of forming the carbanion,
although aryllithium reagents are much more reactive than the corresponding
arylmagnesium reagents, requiring lower temperatures and shorter reaction times; (c)
although SiCl4, Cl?Si(OR)3 and Si(OR)4 all perform similarly in the silylation reaction, the
modest yield of the alcoholysis reaction of aryl(trichloro)silane derivatives limits the utility
of SiCl4 (entry 30); (d) heteroaromatic systems are particularly problematic (entries10-12
and 31) and (e) the reaction tolerates a variety of aryl halides (o-, m-, and p-substituted,
electron-rich as well as deficient arenes undergo silylation).
Scheme 53
OCH3
M
OCH3
Si(OR)3
M = MgBr, Li
Si(OR)4
Cl-Si(OR)3
1. SiCl4 
2. ROH
Toward our goal of synthesizing a variety of highly functionalized siloxane
derivatives for use in aryl coupling reactions, it was necessary to determine the scope
and limitations of the synthesis of aryl siloxanes from standard organometallic reagents.
For our studies, 4-bromomagnesiumanisole 87, Table 2) was selected as the initial
nucleophile to be investigated in the metallation methodology.  The inexpensive,
commercially available electrophiles tetramethoxysilane (Si(OMe)4), tetraethoxysilane
(Si(OEt)4) and tetrachlorosilane (SiCl4) were each evaluated for their efficacy in the
formation of the Si?Ar bond.  The results are summarized in Table 2.
42
Ar X metallationconditions Ar M Ar Si(OR)3silylationconditions
SiL4
Conditions
Product Substrate Metallation Silylation Yielda
Entry Ar-Si(OR)3 Ar-X Ar-M Ar-M SiL4 (equiv) %
1224 Si(OMe)
3
Br Ar-MgBrb Mg?/I2
Et2O/THF
reflux
Si(OMe)4 (1.5)
Et2O/THF
25 ?C
35c
2225 Si(OEt)
3MeO
Br Ar-MgBrb Mg?/I2
THF
65 ?C/2 h
Si(OEt)4 (4.0)
THF
65 ?C/12 h
74
3225 Si(OEt)
3F
I Ar-MgIb Mg?/I2
THF
65 ?C/2 h
Si(OEt)4 (4.0)
THF
65 ?C/12 h
68
4118 Si(OEt)3
(EtO)3Si
1-Br
4-Br
(1,4)-bis
MgBrb
Mg?/I2
THF
65 ?C/2 h
Si(OEt)4 (5.0)
THF
65 ?C/1 h
55
5118 Si(OEt)3
(EtO)3Si
1-Br
4-Br
(1,4)-bis
Ar-Li
t-BuLi
Et2O
-78 ?C/4 h
Cl-Si(OEt)3
(2.5)
Et2O
-78 to 25 ?C
32
6118 Si(OEt)3
(EtO)3Si 2
4-Br
4?-Br
(4,4?)-bis
MgBrb
Mg?
THF
65 ?C/2 h
Si(OEt)4 (5.0)
THF
65 ?C/5 d
34
7118 Si(OEt)3
(EtO)3Si 3
4-Br
4?-Br
(4,4?)-bis
Ar-Li
t-BuLi
Et2O
-78 ?C/4 h
Cl-Si(OEt)3
(2.5)
Et2O
-78 to 25 ?C
24
8118 Si(OEt)3
Si(OEt)3
4-Br
4?-Br
(4,4?)-bis
Ar-Li
t-BuLi
Et2O
-78 ?C/4 h
Cl-Si(OEt)3
(2.5)
Et2O
-78 to 25 ?C
24
9226 Si(OEt)
3
N N Ph I Ar-Li BuLi
THF
-105?C
Cl-Si(OEt)3
(1.2)
THF
0?C/12 h
75
10227 N Si(OEt)
3
Br ArLi BuLi
Et2O
-78?C/45min
Si(OEt)4 (2.0)
Et2O
-78 to 0?C
10
43
Ar X metallationconditions Ar M Ar Si(OR)3silylationconditions
SiL4
Conditions
Product Substrate Metallation Silylation Yielda
Entry Ar-Si(OR)3 Ar-X Ar-M Ar-M SiL4 (equiv) %
11227 N Si(OEt)
3
Br ArLi BuLi
Et2O
-78?C/1h
Si(OEt)4 (2.0)
Et2O
-78 to 0?C
16
12227
N
Si(OEt)3 Br ArLi BuLi
Et2O
-78?C/15min
Si(OEt)4 (2.0)
Et2O
-78 to 0?C
21
13119
NMe2
Si(OEt)3 Hd ArLi BuLi
Et2O
25?C/60 h
Si(OEt)4 (1.3)
Et2O
25?C/12h
56
14219 Si(OMe)
3
Br ArMgBr Mg?
Et2O
25?C/4h
Si(OMe)4 (1.0)
Et2O
25?C/ 3 h
43
15216 Si(OMe)
3Br
Br ArMgBr Mg?
THF
Cl-Si(OMe)3
(1.0)
THF
25?C/12h
65?C/1h
50
16120
Si(OEt)3
Br ArMgBr Mg?
Et2O/THF
reflux
Si(OEt)4 (2.0)
Et2O/THF
reflux/16 h
69
17120
Si(OEt)3
Br ArMgBr Mg?
Et2O/THF
reflux
Si(OEt)4 (2.0)
Et2O/THF
reflux/36 h
29
18120 Si(OEt)
3
Br ArMgBr Mg?
Et2O/THF
reflux
Si(OEt)4 (2.0)
Et2O/THF
reflux/36 h
48
19208 SiCl
3Me2N
Br ArMgBr Mg?
THF
40?C
SiCl4 (2.0)
THF/
heptane
40?C
40
20208 SiCl
3MeO
Br ArMgBr Mg?
THF
40?C
SiCl4 (2.0)
THF/
heptane
40?C
32
44
Ar X metallationconditions Ar M Ar Si(OR)3silylationconditions
SiL4
Conditions
Product Substrate Metallation Silylation Yielda
Entry Ar-Si(OR)3 Ar-X Ar-M Ar-M SiL4 (equiv) %
21208 SiCl
3Cl
Br ArMgBr Mg?
THF
40?C
SiCl4 (2.0)
THF/
heptane
40?C
39
22214 SiCl3 Me
N
NMe
Hd ArLi BuLi
Et2O
-30 to 0?C
SiCl4 (1.3)
Et2O
25?C/12h
91
23214 (MeO)3Si Me
N
NMe
Hd ArLi BuLi
Et2O
25?C/60 h
Si(OMe)4 (1.3)
Et2O
25?C/12h
17
24214 (MeO)3Si Me
N
NMeCl
Hd ArLi BuLi
Et2O
25?C/6 d
Si(OMe)4 (1.3)
Et2O
25?C/12h
17
25207 SiCl
3
Br MgBr Mg?
Et2O
SiCl4 (1.5)
Et2O/
benzene
25?C/12h
59
26206 SiCl
3
Cl MgCl Mg?
THF
SiCl4/(1.1)
THF/
heptane
reflux/2h
47e
27116 Si(OMe)
3R
R = 4-(Pr)-cyh-
Br Ar-MgBr Mg?
THF
50?C/2h
1. SiCl4 (1.5)
    THF
    25?C/17h
2. MeOH
    pyr/0?C
64f
28116 Si(OMe)
3R
R = 4-(Pr)-cyh-
Br Ar-MgBr Mg?
THF
50?C/2h
Si(OMe)4 (1.5)
THF
25?C/17h
35
45
Ar X metallationconditions Ar M Ar Si(OR)3silylationconditions
SiL4
Conditions
Product Substrate Metallation Silylation Yielda
Entry Ar-Si(OR)3 Ar-X Ar-M Ar-M SiL4 (equiv) %
29116 Si(OMe)
3R
R = 4-(Pr)-cyh-
I Ar-Li BuLi
THF
-70?C/2h
1. SiCl4 (2.0)
    THF
    25?C/17h
2. MeOH
    pyr/0?C
66f
30213
NMeNMe2
Si(OEt)3 Hd Ar-Li BuLi/TMEDA
Hexane
25?C/2d
1. SiCl4 (1.1)
    hexane
    25?C/12h
2. NaOEt
    THF/2d
6f
(22)h
31210 N
Si(OEt)3
Br Ar-Li BuLi
Et2O
-78?C/30min
1. SiCl4 (2.0)
    Et2O
    25?C/3h
2. EtOH/TEA
15f
a Yields are after distillation.  Byproducts were not reported.  Unless otherwise indicated,
the organometalloid (Ar-MgBr or Ar-Li) was first generated, and then combined with the
indicated silicon electrophile SiL4 (Si(OR)4, Cl-Si(OEt)3, or SiCl4).  b Grignard generated
under Barbier conditions: Mg?, I2 (if used), the silicon electrophile SiL4 (Si(OR)4,
Cl-Si(OEt)3, or SiCl4) and solvent were combined and brought to the indicated
temperature with stirring; the arylbromide was added at such a rate as to maintain reflux,
and then the reaction was stirred at the given temperature until the reaction was complete.
c A 41% yield of the diaryl(dialkoxy)silane and trace amounts of the triaryl(alkoxy) silane
were isolated.  d Aryl lithium generated by directed ortho metallation.  e A 17% yield of the
diaryl(dialkoxy)silane and a 10% yield of biphenyl were isolated.  f The overall yield of
Ar-Si(OR)3 after alcoholysis of Ar-SiCl3, based on the amount of substrate (Ar-X or Ar-H).
g The major product was the diaryl(dialkoxy)silane.  h The yield in parentheses indicates
the yield of Ar-SiCl3.
Table 1.  Synthesis of Aryl(trialkoxy)silanes via Treatment of Aryl Grignard or Lithium
Reagents with Silicon Electrophiles SiL4: Review of the Literature to Date.
46
MgBr Si(OR)3
Si(OR)4, THF
Br
OCH3 OCH3 OCH3
86 88
+
89
Mg?, I2 (cat)
87
1. SiCl4, THF
2. EtOH, pyr, 0 ?C
ORTHFreflux
Ar2Si(OR)2
Conditionsa Yield (%)b,c
Entry Silane / Equiv T (?C) 88 89
1 Si(OMe)4 / 3.0 25 47 47
2 Si(OMe)4 / 3.0 -30 76 3
3 Si(OMe)4 / 1.5 -30 65 4
4 Si(OEt)4 / 3.0 0 72 23
5 Si(OEt)4 / 3.0 -10 70 23
6 Si(OEt)4 / 3.0 -30 83 3
7 Si(OEt)4 / 1.5 -30 76 2
8 Si(Cl)4 / 3.0d -30 70d 3
a Reactions of p-methoxy magnesium bromide 87 (1.0 equiv) with Si(OR)
4 orSiCl
4 (1.5 to 3.0 equiv) were allowed to stir at the given temperature in THF.The reaction mixture was stirred at the indicated temperature for 1 h, and then
at room temperature for 12 h.  b GC yields are based on amount of
4-bromoanisole (86).  c The remainder of the product was of anisole.  d Yield of
4-(triethoxysilyl)anisole (88).  The crude, concentrated 4-(trichlorosilyl)anisole
was converted to the siloxane 88 by dropwise addition of the chlorosilane to
EtOH/pyridine at 0 ?C.
Table 2.  Optimization of the Synthesis of Arylsiloxanes Using 4-Bromomagnesium
Anisole.
The temperature at which the Grignard reagent was added to the electrophile had
a marked effect on the reaction.  As seen in entries 1, 4 and 5, at temperatures above
?30 ?C a significant amount of the diaryl(dialkoxy)silane impurity 89 was formed, although
no triaryl(alkoxy)silane was observed over the tested temperature range.  The remainder
of the reaction mixture was anisole, which can result from the aqueous quench of
unreacted arylmagnesium bromide.  However, longer reaction time or elevated temperature
did not improve the yield.  Also, the amount of anisole remained constant irrespective of
the electrophile.  It is likely that reduction occurs at least in part during the in situ formation
47
of the Grignard reagent, and is an inherent limitation of the metallation approach to the
synthesis of siloxanes.
The best result was obtained when the Grignard reagent was treated at ?30 ?C
with 3.0 equiv of the electrophile Si(OEt)4 (83% yield, entry 6); under identical reaction
conditions, Si(OMe)4 (76% yield, entry 2) and SiCl4 (followed by alcoholysis) (70%,
entry 8) also performed well (the yields were determined by G.C. analysis).  In contrast,
Shibata observed a 60% yield of siloxane using the two-step SiCl4/alcoholysis method
for the silylation of p-(4-propylcyclohexyl)phenylmagnesium bromide (Scheme 54, also
above in Table 2, entries 27 and 28), but only a 35% yield of siloxane via direct silylation
with Si(OMe)4.  The reaction conditions employed by Shibata were addition of the
Grignard reagent to 1.5 equiv of silane at 0 ?C.116  In our study, a two-fold decrease in the
concentration of the electrophile slightly decreased the yield of the desired monoarylated
silane, but surprisingly did not stimulate the formation of diarylated byproduct (Table 3,
entries 3 and 7).
Scheme 54
Pr
Si(OMe)3
Pr
MgBr
1. SiCl4 (1.5 equiv)
    THF, 0-25 ?C, 17h
64%
THF
0-25 ?C, 17h
35%
Si(OMe)4 (1.5 equiv)
2. MeOH, pyridine
Preliminary studies performed by Arash Soheili (an undergraduate) using
commercial phenylmagnesium bromide indicated that increasing the concentration of the
electrophile from 3 to 5 to 30 equiv did not improve the reaction outcome, and only served
to complicate product isolation.  Soheili also observed little reaction improvement with
alternative ether solvents, and poorer results with toluene or hexane.  Ultimately, THF
48
rather than lower-boiling Et2O was employed as the solvent in order to facilitate in situ
formation of the Grignard reagent (which required heating to progress efficiently).228
In order to demonstrate the scope of the Grignard reaction, a variety of substituted
aryl bromides was examined (Table 3).  The isolated yields obtained in our laboratories
were generally better than those reported in the literature.  Only trace amounts of
diaryl(dialkoxy)silane contaminants were observed for all entries.  Again, the remaining
yield was of reduced (dehalogenated) aryl halide.  As expected, tetramethoxysilane and
tetraethoxysilane worked equally well (entries 1 and 2, and 6 and 7).
MgBr Si(OR')3
R R
THF
Si(OR')4
Br
R
THF
Mg?
90 9291
Entry Aryl Siloxane Yield (%)a,b Entry Aryl Siloxane Yield (%)a,b
1
Si(OEt)3
OCH3
88 6
Si(OEt)3
CH3
81
2
Si(OMe)3
OCH3
83 7
Si(OMe)3
CH3
71
3
Si(OEt)3
H3CO
84 8
Si(OEt)3
H3C
75
4 H3CO Si(OEt)3 82 9 H3C Si(OEt)3 86
5
O
O
Si(OEt)3
74 10 Si(OEt)3 55
a Reactions of arylmagnesium bromide 91 (1.0 equiv) with Si(OEt)
4 or Si(OMe)4 (3.0equiv) were allowed to stir at ?30 ?C in THF.  The reaction mixture was stirred at ?30 ?C
for 1 h, and then at room temperature for 12 h.  b Yields of 92 are after distillation (purity
>95%).  The remainder of the product was of the reduced (dehalogenated) arene.
Table 3.  Synthesis of Aryl(trialkoxy)silanes Using Grignard Reagents.
49
Surprisingly, the results were comparable with o-, m-, and p-substituted anisyl
and tolyl Grignard reagents (entries 2-4, and 7-9, respectively); all yields were
approximately 80%.  This result contradicts the findings of Selin and co-workers (Scheme
55, also above in Table 2, entries 15-17), who observed acceptable yields of o- and p-,
but not m-(triethoxysilyl)toluene; the reaction conditions employed by Selin entailed
addition of the Grignard reagent to 2.0 equiv of tetraethoxysilane at reflux.120
Scheme 55
Si(OEt)4, 2.0 equiv
THF
reflux, 16 h
o-, 68%
m-, 29%
p-, 48%
MgBr
CH3
Si(OEt)3
CH3
Several researchers have reported acceptable yields of arylsiloxane using Barbier
reaction conditions?the in situ formation of the reactive Grignard intermediate in the
presence of the silicon electrophile (Scheme 56, and Table 2, entries 1-4,
and 6).118,130,224,225  Ideally, Barbier conditions are a method of controlling multiple substitution
at silicon, because the Grignard reagent is immediately consumed, and never present in
excess.  For example, Shea and co-workers combined magnesium metal, a crystal of
iodine, 4 equiv of tetraethoxysilane and THF, and brought the mixture to reflux (Scheme
56).  A solution of p-bromoanisole (86) in THF was then added slowly, and the mixture
was allowed to reflux for 12 h; a 74% isolated yield of 4-(triethoxysilyl)anisole (88) was
obtained without mention of byproducts.225  This result was not reproducible in our
laboratories: under identical Barbier reaction conditions, only 50% yield at 80% conversion
was achieved; although no diarylated silane was observed, the remaining yield was of
reduced arene.
50
Scheme 56
Si(OEt)3
Br
H3CO
H3CO
88
1. Mg?, I2, THF, reflux
2.
   THF, reflux, 12h
86
74% (50%)Si
OEt
OEt
EtO OEt
As shown in Table 3 (entry 5), 3,4-(methylenedioxy)bromobenzene underwent
smooth conversion to the siloxane (93, 74% yield).  Siloxane 93 was chosen as a model
for siloxane 28, which is a synthetic intermediate in the synthesis of Fitzgerald?s
compound 23 (Figure 4).  Since the completion of this study, Correia in the DeShong
laboratories has applied the Grignard methodology described herein toward the
preparation of siloxane 94 in 50% yield from the corresponding bromide.229
Si(OEt)3
OMe
OMe
MeO
28
Si(OEt)3
O
O
93
Si(OEt)3
OMe
O
O
94
Figure 9.  Siloxanes Prepared via the Grignard Reaction for Use in Natural Product
Syntheses.
In continuing pursuit of our goal of synthesizing a variety of highly functionalized
siloxane derivatives for use in aryl coupling reactions, we turned our efforts to determining
the scope and limitations of the synthesis of aryl siloxanes from lithium reagents.  For our
studies, 4-lithiotoluene (96, Table 4) was selected as the initial nucleophile for
investigation of the formation of the Si?Ar bond.  The electrophile tetraethoxysilane
(Si(OEt)4) was chosen for initial study, in lieu of tetramethoxysilane (Si(OMe)4), which
freezes at the low temperatures required for the formation of aryllithium reagents, or
tetrachlorosilane (SiCl4), because the subsequent alcoholysis step had proven to be
problematic (low yielding and complicated by polymerization).  Both ether and THF were
51
evaluated for their suitability in the silylation of aryl lithium intermediates, although ether
was the solvent of choice for practical reasons.  The higher-boiling ethereal solvent was
preferred for the Grignard protocol because it allowed for heating the reaction to initiate
formation of the Grignard, or to drive silylation.  The more reactive lithium reagents
decompose above low temperatures and do not require higher-boiling solvents.  The
results of the silylation reactions are shown in Table 4.
Li Si(OEt)3
Si(OEt)4
Br
CH3 CH3 CH3
95 97
+ Ar2Si(OEt)2  +  Ar3Si(OEt)
98 99
n-BuLi
96
Conditionsa Yield (%)b,c
Entry Equiv Si(OEt)4 Solvent T (?C) 97 98 99
1 1.5 THF 0 7 25 54
2 1.5 THF -30 74 12 1
3 1.5 Et2O -30 77 6 0
4 1.5 THF -78 81 9 0
5 1.5 Et2O -78 82 5 1
6 3.0 Et2O -78 86 3 1
a Reactions of p-tolyl lithium 96 (1.0 equiv) with Si(OEt)
4 (1.5 to 3.0 equiv) wereallowed to stir at the given temperature; the reaction was complete in 1 h.  b GC
yields are based on amount of 4-bromotoluene (95).  c The remainder of the
product was toluene.
Table 4.  Optimization of the Synthesis of Arylsiloxanes Using 4-Lithiotoluene.
Like the Grignard approach, the temperature at which the lithium reagent was
added to the electrophile dramatically effected the reaction outcome.  As seen in entries 1-
3, at temperatures above ?78 ?C a significant amount of the diaryl(dialkoxy)silane impurity
98 was formed.  In addition, trialkylated product 99 was observed.  Note that the
analogous transformation employing Grignard reagents did not lead to the formation of
52
trialkylated products, because of the significantly lower reactivity of Grignard reagents.  At
0 ?C (entry 1), the major product was tris-p-tolyl(ethoxy)silane (99).  In contrast, at
?30 ?C (entries 2 and 3) and ?78 ?C (entries 4-6) formation of the trialkylated silane 99
was effectively suppressed, although diarylated silane 98 was formed.  As in the
Grignard reaction, reduction (dehalogenation) of the starting material also was observed.
At low temperature, the reaction was essentially insensitive to the solvent (Et2O and THF
were tolerated, entries 4 and 5) and only a small excess of the electrophile was needed
(1.5-3.0 equiv were equally effective, entries 5 and 6).
The best result was obtained when the lithium reagent in ether was treated at
?78 ?C with 3.0 equiv of the electrophile Si(OEt)4 (86% yield, entry 6).  Experience
garnered applying these reaction conditions to other substrates would show that more
than 1.5 equiv were unnecessary to achieve the optimum yield of siloxane.  The
electrophile and the lithium reagent were allowed to stir at ?78 ?C until the reaction ceased
to progress.  Visiting Scientist Dr. Chuljin Ahn made the discovery that quenching the
reaction at ?78 ?C before allowing the mixture to slowly warm to room temperature
mitigated formation of di- and tri- arylated byproducts.
In order to demonstrate the scope of the optimized silylation reaction, a variety of
substituted aryl bromides was examined (Table 5).  The isolated yields obtained were
generally better than those reported in the literature.  Only trace amounts of
diaryl(dialkoxy)silane contaminants were observed for most entries; again, the remaining
yield was of reduced (dehalogenated) aryl halide.  The best results were obtained with
less reactive (less electron-rich) aryl lithium derivatives: the less electron-rich tolyl series
(entries 1-3) and electron-neutral phenyl (entry 4) outperformed the more electron-rich
anisyl/thioanisyl series (entries 5-8).  Bearing two electron-donating substituents, the
3,4-(methylenedioxy)phenyllithium intermediate (entry 9) proved to be highly reactive: the
major product was the diarylated silane.  Reducing the temperature to ?110 ?C, or
increasing the concentration of Si(OEt)4 failed to improve the yield.  Note that the
analogous Grignard reagent underwent clean silylation (Table 3, entry 5), forming 74% of
53
triethoxy(3,4-methylenedioxyphenyl)silane.  Again as with magnesium reagents, the
reaction using aryllithium intermediates was insensitive to the position of substituents: o-,
m-, and p-substituted arenes underwent silylation with equal efficiency (Table 5, entries
1-3, and 5-8).
Li Si(OEt)3
R R
Si(OEt)4
Br
R
Et2O
-78 ?C
n-Bu Li
90 92100
Et2O
-78 ?C
Entry Aryl Siloxane (92) % Yielda,b Entry Aryl Siloxane (92) % Yielda,b
1 Si(OEt)3
CH3
79 7 H3CO Si(OEt)3 67
2 Si(OEt)3
H3C
71 8 Si(OEt)3MeS 50
3 H3C Si(OEt)3 85 9
O
O
Si(OEt)3
30c
4 Si(OEt)3 74 10
S
Si(OEt)3
50
5 Si(OEt)3
OCH3
60 11
O Si(OEt)3
22d
6 Si(OEt)3
H3CO
66 12
N Si(OEt)3
0
a Reactions of aryl lithium 100 (1.0 equiv) with Si(OEt)
4 (1.5 equiv) were allowed to stir at?78 ?C for 1 h in Et
2O.  
b Yields of 92 are after distillation or chromatography (purity
>95%).  c The major product was Ar2Si(OEt)2.  d G.C. analysis indicated a 2:1:1 ratio of
mono:di:tri arylalkoxysilanes.
Table 5.  Synthesis of Aryl(trialkoxy)silanes Using Lithium Reagents.
54
Mixed results were obtained for silylation of heteroaromatic systems (entries 10-
12).  For example, an acceptable yield of 3-(triethoxysilyl)thiophene was obtained from
the corresponding bromide (entry 10), whereas silylation of 2-bromofuran was inefficient
and 2-bromopyridine failed to give any of the desired siloxane (entries 11 and 12).  The
yield of 2-(triethoxysilyl)furan was compromised by the formation of di- and triarylated
products, indicating that 2-lithiofuran was successfully formed in situ, but was highly
reactive.  In contrast, attempted silylation of 2-bromopyridine led to exclusive formation of
pyridine, indicating successful formation of the organolithium intermediate, but unsuccessful
silylation.  Dr. Chuljin Ahn confirmed the nearly quantitative formation of 2-lithiopyridine
under our reaction conditions by capture with the more reactive electrophiles TMS-Cl and
benzaldehyde.228  In an effort to increase the nucleophilicity of the pyridine metalloid,
silylation of 3-bromo-4-methoxypyridine (101) was attempted with dramatic results.
Handy isolated 25% of the desired monopyridinyl siloxane 102, in addition to significant
quantities of dipyridinyl- and tripyridinyl siloxanes 103 and 104.111
Scheme 57
NMeO
Br
NMeO
Si(OEt)3
1. BuLi, Et2O, -78 ?C
2. Si(OEt)4, -78 ?C
3. H2O, -78 ?C to 25 ?C
+
102, 25%101
NMeO
Si(OEt)4-n
n
103, n = 2, 25%
104, n = 3, 20%
Scheme 57
The results with pyridine derivatives were not surprising given the literature
precedence.  Using analogous reaction conditions, Schmidbaur and co-workers
synthesized 2- and 3-(triethoxysilyl)pyridine in 10% and 16% yield, respectively (Table
2, entries 10 and 11).227  Zeldin carefully examined the synthesis of 3-pyridinyl substituted
ethoxysilane monomers, focusing on the preparation of
diethoxy(methyl)(3-pyridinyl)silane (PyrSiMe2(OEt)).210  A variety of silicon electrophiles
were evaluated, most notably MeSiCl3 (followed by alcoholysis), MeSi(OEt)2Cl, and
55
MeSi(OEt)3, under different metallation conditions.  Three significant conclusions were
drawn: (1) MeSi(OEt)3 (3 equiv) was ideal for the methyl(diethoxy)silylation of 3-pyridinyl
magnesium bromide, yielding 45% of the desired mono substitution product, and no
diarylated adduct; (2) in contrast, a 20-fold excess of MeSiCl3 was required to mitigate
multiple substitution by 3-lithiopyridine, and as with MeSi(OEt)2Cl, still yielded a
significant amount of the diarylated silane and led to the formation of mixed silanes and
silicates, for example 105 and 106 (Figure 10); and (3) the use of pyridinyllithium reagents
led to the formation of a pentacoordinate anionic species between the silane product and
LiOEt formed in the displacement reaction (107).  The decomposition of complexes 105-
107 during distillation was blamed for the very low product yields.210
N
Si N
SiMeX2
X
Me
Cl- Si
N
X
Me
X
SiMeX2
Si
OEt
Me
EtO Li+
N
105, X = OEt, Cl 106, X = OEt, Cl
OEt N
107
Figure 10.  Complexes Formed in the Silylation of Pyridinyl Metal Reagents.
Zeldin obtained the best results when the pyridinyl Grignard reagent was
generated under Barbier conditions (Scheme 58, eq. a); in fact, when the preformed
3-pyridinyl magnesium bromide was treated with MeSi(OEt)3, no reaction was
observed.210  Given that pyridinyl Grignard reagents are reputed to be unreactive toward
most electrophiles,230,231 Zeldin?s result is striking.  Unfortunately in our laboratories, using
the Barbier reaction conditions reported by Zeldin, but substituting Si(OEt)4 as the
electrophile, preparation of 3-(triethoxy)pyridine failed.  The only products obtained were
the homocoupled product 3,3?-dipyridyl (109) and pyridine (Scheme 58, eq. b).
Homocoupling (Wurtz-type coupling) is a common side-reaction of organomagnesium
reagents.115
56
Scheme 58
N
SiMe(OEt)2
N
Br
108
45%
1. Mg?, I2, THF, reflux
2.
   THF, reflux, 8 h
43
Si
OEt
OEt
Me OEt (a)
N
N
Br
109
30%
1. Mg?, I2, THF, reflux
2.
   THF, reflux, 8 h
43
Si
OEt
OEt
EtO OEt (b)N
Since the completion of this study, Handy and Correia applied the general method
for the synthesis of arylsiloxanes from aryllithium reagents outlined in Table 5 to prepare
indole derivatives 110 and 111 in 70% and 60% yield, respectively.24,229  These 5-indole
siloxanes are synthetic intermediates in the preparation of biologically-interesting
tryptamines and tetrahydropyridylindoles.111,232  For the synthesis of siloxane 110, Handy
first converted 5-bromoindole to the potassium salt using KH; subsequent lithiation and
treatment with Si(OEt)4 afforded the siloxane.24,111
NH
Si(OEt)3
110
NMe
Si(OEt)3
111
Figure 11.  5-Indole Siloxanes Prepared from Aryllithium Reagents for Use in Natural
Product Syntheses.
With both Grignard and lithium reagents, the formation of di- and triarylated silanes
was best controlled by employing reduced reaction temperatures.  In contrast, change of
solvent or the use of large excesses of the electrophile had relatively little impact on the
reaction outcome.  It is unlikely that the temperature effect observed in the arylation is due
solely to the attenuation of organometalloid reactivity at reduced temperature.  Contrary to
57
expectation, lower temperatures have been shown to increase the reactivity of the
organometallic species toward electrophiles by causing deaggregation of the
organometalloid.115  This phenomenon would clearly favor multiple arylation of the silane.
Instead, a reduction in diarylation was observed when the temperature was reduced;
therefore, the reactivity of the nucleophile must not be greatly altered within the
temperature range studied.  In fact, it has been observed that phenyllithium does not
change its aggregation state until temperatures as low as ?100 ?C are reached.115
The relative rates of reaction of alkoxysilanes with organometallic reagents follows
the order of silane electrophilicity: Si(OEt)4 > RSi(OEt)3 > R2Si(OEt)2 > R3Si(OEt); the
same order is observed with chlorosilanes.204  Given the relative reactivities, polyarylation
should be stoichiometrically controllable, or mitigated by slow addition of the organometallic
reagent to the electrophile.  On the contrary, even at low temperature, with less than 1
equiv of organometallic reagent, diarylated and even triarylated byproducts are observed,
suggesting that other factors are at play than organometalloid reactivity or electrophile
electronics.122
The excepted mechanism of alkylation comprises formation of pentacoordinate
adduct 113 as shown in Scheme 59.122,204,233  Diarylation is the result of either direct attack
of a second aryl nucleophile on the pentacoordinate silicate 113 to form hexacoordinate
intermediate 115, or attack on the tetracoordinate monoaryl silane 114.
Scheme 59
OEt
Si
EtO OEtOEt Si OEt
OEt
OEt
OEt
Si OEtOEt
OEt
OEt
Ph
Ph
Ph
Ph-Li
fast
113112
115
Li+
2Li+
2-
slow
Ph
Si
Ph OEtOEt
116
OEt
Si
Ph OEtOEt
114
+
+
2 LiOEt
LiOEt
Ph-Li     fastPh-Li     slow
58
Again, it was observed that at lower temperatures the formation of diaryl products
was minimal.  We propose that at reduced temperature, the pentacoordinate silicate 113
formed by initial attack of the metalloid reagent does not decompose (with loss of alkoxide)
to give the neutral monoaddition product 114.  The stable, anionic monoaryl silicate 113 is
less reactive than its neutral monoaryl silane counterpart 114; in effect, the monoaryl silane
114 is ?protected? as the pentacoordinate silane against multiple arylation.  This result is
quite different than what has been observed for chlorosilanes, where the analogous
pentacoordinate tetrachloroaryl silicate (Ar-SiCl4-) has been found to be more reactive than
the neutral tetracoordinate monoaryl silane (Ar-SiCl3).122,204,233
In conclusion, general reaction conditions for the synthesis of aryl(trialkoxy)silanes
from aryl Grignard and lithium reagents and functional silanes have been developed.
Although examples in the literature have described the use of a range of silicon
electrophiles (including SiCl4 and Cl?Si(OR)3), tetraalkyl orthosilicates (Si(OR)4) allow for
the most direct and convenient synthesis of arylsiloxanes, in that they are commercially
available, inexpensive, and air and moisture stable.  Using the reaction conditions
developed herein, o-, m- and p-substituted bromoarenes underwent equally efficient
metallation and silylation.  Mixed results were obtained with heteroaromatic substrates:
3-bromothiophene, 3-bromo-4-methoxypyridine, 5-bromoindole, N-methyl-5-bromoindole
all underwent silylation in good yield, whereas low yields of siloxanes were obtained from
2-bromofuran, and 2-bromopyridine failed to be silylated.  Lower temperatures allowed for
the formation of predominantly mono arylated siloxanes, without requiring more than 1.5-
3.0 equiv of the electrophile.
Several important issues remain unresolved.  Irrespective of the electrophile, the
synthesis of aryl(trialkoxy)silane derivatives using Grignard or lithium reagents is plagued
by modest yields caused by the formation of reduced (dehalogenated) substrate, and
multiply arylated byproducts.  These limitations are most likely inherent to the
methodology: reduction of the organometalloid presumably occurs during the metallation
step (and thus occurs in all reactions employing Grignard or lithium species); and multiple
59
alkylation stems from the high susceptibility toward nucleophilic attack of the
hypercoordinate monoaryl(tetraethoxy)silicate intermediate.
Improved Methods for the Synthesis of Aryl(triethoxy)silanes via Palladium(0)-
Catalyzed Silylation of Aryl Iodides and Bromides with Triethoxysilane
An alternative to the preparation of arylsilanes from organomagnesium or lithium
intermediates was reported by Masuda and co-workers in 1997: the silylation of aryl
iodide derivatives by triethoxysilane (H?Si(OEt)3) in the presence of a Pd catalyst
(Scheme 60).221  Masuda reported that electron-rich, para-substituted aryl iodides gave
excellent yields of aryl siloxane.  The major byproduct of the reaction was the reduced
arene (119).  In contrast to aryl iodides, aryl bromides were reported to provide low yields
of aryl siloxane under identical conditions.  In addition, the silylation of ortho- or meta-
substituted aryl iodides/bromides was not reported.  Accordingly, the goals of this study
were to extend the Masuda silylation reaction to aryl bromides and chlorides, and to
evaluate the Masuda methodology for the synthesis of ortho- and meta-substituted aryl
siloxanes.
Scheme 60
H3CO
Si(OEt)3
H3CO
I
H3CO
H
+
117 118 119
H-Si(OEt)3
i-Pr2NEt / NMP
Pd(dba)2?CHCl3
P(o-tol)3
Toward our goal of synthesizing a variety of highly functionalized siloxane
derivatives for use in aryl coupling reactions, it was necessary to determine whether
Masuda conditions could be modified, and the scope extended to encompass silylation of
aryl bromide derivatives.  Standard optimization approaches involving change of solvent,
reaction temperature, catalyst, base, and catalyst:ligand ratio failed to provide improved
yields of siloxane.  As reported by Masuda, the silylation reaction of phenyl bromide
60
under these conditions afforded the reduced arene rather than the desired siloxane
derivative (see Scheme 60).221
Previous studies in our laboratory23 had shown that incorporation of Buchwald's
phosphine 120 into Pd-catalyzed reactions resulted in dramatically improved yields of
adducts.234-238  The use of Buchwald's and related phosphine derivatives in the silylation
reaction was investigated and the results are summarized in Table 6.  Entries 1 and 2 are
the results obtained employing the standard conditions reported by Masuda and show
that the silylation provided a low yield of the desired aryl siloxane.
The major product was the reduced arene.  Substitution of Buchwald's
ligand (120) as the phosphine resulted in a marked improvement in the
yield of siloxane obtained (entry 10).  Similarly, inclusion of
tributylphosphine (entries 6 and 7) , as reported by Fu,239 had a less significant effect, and
showed an appreciable difference in yield depending on the solvent.  Subsequent
studies were performed with the Buchwald ligand because of its inherent ease of
handling, thus avoiding the air-sensitive nature of tributylphosphine.  A variety of other
ligands was investigated including mono- and bidentate phosphines (dppp, dppf, etc.),
Buchwald?s 2-(dicyclohexylphosphino)biphenyl, and triphenylarsine; however, these
ligands failed to provide siloxane in acceptable yields.  Similarly, additives such as
tetraalkylammonium iodides, copper iodide, silver(I) salts, thallium acetate, or the inclusion
of molecular sieves failed to improve the reaction outcome.
Solvents that are either less polar than NMP, or that can coordinate with the
catalyst resulted in dramatically reduced yields of the siloxane (Table 6, entries 12-14).
An amine base was required for silylation.  In the absence of base, slow reduction of the
starting material was observed (entry 15).  Triethylamine (entry 16) gave more reduced
material when compared to diisopropylethylamine, possibly due to its ability to coordinate
as a ligand.  Pyridine (entry 17) and 2,6-lutidine (entry 18) slowed the reaction
dramatically and resulted in reduction preferentially.  Replacement of the amine base by
weak alkali bases such as KOAc (entry 20) and CsCO3 (entry 21) was ineffective.
(t-Bu)2P
Ph
120
61
Br
OCH3
H Si(OEt)3
Si(OEt)3
OCH3
H
OCH3
+ +
Pd(dba)2
ligand
base
solvent
86 118 119
Conditionsa Yield (%)b,c
Ligand Base Solvent
Entry (10 mol %) (3 mmol) (4 mL) 118 119
1 P(o-tol)3 i-Pr2NEt NMP 21 79
2 P(o-tol)3 i-Pr2NEt DMF 15 70
3 none i-Pr2NEt DMF 14 86
4 PPh3 i-Pr2NEt DMF 0 5
5 dppf i-Pr2NEt NMP 0 8
6 P(t-Bu)3 i-Pr2NEt NMP 59 41
7 P(t-Bu)3 i-Pr2NEt DMF 45 55
8 P[(2,4,6-OMe)Ph]3 i-Pr2NEt NMP 8 92
9 P(cy)2(o-biphenyl) i-Pr2NEt NMP 17 83
10 P(t-Bu)2(o-biphenyl) i-Pr2NEt NMP 75 25
11 P(t-Bu)2(o-biphenyl) i-Pr2NEt DMF 36 64
12 P(t-Bu)2(o-biphenyl) i-Pr2NEt THF 6 54
13 P(t-Bu)2(o-biphenyl) i-Pr2NEt CH3CN 6 93
14 P(t-Bu)2(o-biphenyl) i-Pr2NEt toluene 3 19
15 P(t-Bu)2(o-biphenyl) none NMP 0 4
16 P(t-Bu)2(o-biphenyl) Et3N NMP 55 45
17 P(t-Bu)2(o-biphenyl) pyridine NMP 0 5
18 P(t-Bu)2(o-biphenyl) 2,6-lutidine NMP 32 26
19 P(t-Bu)2(o-biphenyl) DBU NMP 0 57
20 P(t-Bu)2(o-biphenyl) KOAc NMP 22 78
21 P(t-Bu)2(o-biphenyl) Cs2CO3 NMP 3 97
a Reactions of 4-bromoanisole (86) (1.0 equiv) with H-Si(OEt)
3 (1.5 equiv) wereallowed to stir at room temperature for 12 h in 4 mL of solvent by using Pd(dba)
2 (5 mol%), phosphine (10 mol %), and base (3.0 equiv).  b GC yields are based on amount of
4-bromoanisole.  c Remaining percentage was unreacted starting material.
Table 6.  Optimization of the Silylation of 4-Bromoanisole.
In order to demonstrate the scope of the modified silylation reaction, a variety of
substituted aryl bromides was examined (Table 7).  The best yields of siloxane were
obtained for electron-rich aryl bromides (entries 1-7) although the yields obtained are
generally modest.  This trend was not unexpected based on the report from Masuda with
62
iodides.221  Silylation of bromobenzene or electron-poor aryl bromides was unsuccessful
(entries 8-10), exclusively resulting in dehalogenation of the starting material.
Br
H Si(OEt)3
Si(OEt)3 H
R R R
+ +Pd(dba)2
P(t-Bu)2(o-biphenyl)(120)
i-Pr2NEt
NMP
90 92 121
Entry Aryl Bromide
(90)
% Yielda-c
(92)
Entry Aryl Bromide
(90)
% Yielda-c
(92)
1 Br OCH3 68 6 Br OAc 30
2 Br CH3 43 7 Br OH 28d,e
3
O
O
Br
44 8 Br 5
4 Br NHAc 33 9 Br
O
0
5 Br NH2 38d,e 10 Br Cl 0
a Reactions of arylbromide (90) (1.0 equiv) with H-Si(OEt)
3 (1.5 equiv) were allowed to stirat 60 ?C for 12 h in NMP by using 3 mol % Pd(dba)
2, (t-Bu)2P(o-biphenyl)(120) (6 mol %),and i-Pr
2NEt (3 equiv).  
b Isolated yield of purified (>95%) product.  c Unless otherwise
indicated, remaining percentage was reduced starting material (121).  d Reaction allowed to
stir at room temperature.  e Reaction stopped at 2 h.
Table 7.  Silylation of Aryl Bromides.
Mixed results were obtained for heteroaromatic systems (Table 8).  For example, a
satisfactory yield of 2-(triethoxysilyl)thiophene was obtained from the corresponding
bromide (entry 1), whereas, silylation of 2- and 3-bromopyridine and 2- and
3-bromoquinoline failed (entries 2-5), probably due in part to nitrogen functioning as a
ligand for the metal (vide infra).  Support for this hypothesis is that use of Pd(0)/pyridine
as a catalyst system for the silylation of 4-bromoanisole (Table 1, entry 17) resulted in a
63
dramatic reduction in the rate of silylation.  Not surprisingly, the more electron-rich
substituted pyridine derivative 3-bromo-4-methoxypyridine was converted to the
siloxane in fair yield  (Table 8, entry 6).
H Si(OEt)3Ar-Br Ar-Si(OEt)3 Ar-H+
Pd(dba)2
P(t-Bu)2(o-biphenyl)(120)
i-Pr2NEt
NMP122 123 124
+
Entry Heteroaryl Bromide
(122)
% Yielda-c
(123)
Entry Heteroaryl Bromide
(122)
% Yielda-c
(123)
1
S Br
43 4
N Br
0
2
N Br
0d 5
N
Br
0
3
N
Br
0 6
N
Br
MeO
57
a Reactions of heteroarylbromide (122) (1.0 equiv) with H-Si(OEt)
3 (1.5 equiv)
were allowed to stir at 60 ?C for 12 h in NMP by using 3 mol % Pd(dba)2,
(t-Bu)2P(o-biphenyl)(120) (6 mol %), and i-Pr2NEt (3 equiv).  b Isolated yield of
purified (>95%) product.  c Unless otherwise noted, the remaining percentage was
reduced starting material (124).  d Trace amounts of 2,2?-dipyridyl were observed
by G.C. analysis.
Table 8.  Silylation of Heteroaryl Bromides.
Given that the yield of silylated arene was dependent upon the electron-rich
character of the arene system, it was expected that 4-bromo-1,2-(methylenedioxy)
benzene (Table 7, entry 3) would give a comparable (or greater) yield of siloxane than
4-bromoanisole (entry 1).  Surprisingly, the opposite was observed.  It was proposed
that the presence of a substituent at the meta position resulted in the lower yield.  Further
exploration of the effect of substituent placement on the silylation of bromoanisoles was
undertaken and the results are summarized in Table 9.  The yield of siloxane rapidly
declined as the methoxy substituent shifted from the para (68%) to meta (25%) to ortho
64
(0%) position.  Attempts to improve the yield of meta- or ortho-aryl siloxanes by altering
the phosphine ligand were unsuccessful.
Br
H Si(OEt)3
Si(OEt)3 H
R R R
+ +Pd(dba)2
P(t-Bu)2(o-biphenyl)(120)
i-Pr2NEt
NMP
90 92 121
Entry Aryl Bromide (90) % Yield (92)a-c Entry Aryl Bromide (90) % Yield (92)a-c
1 Br OCH3 68 4 Br CH3 43
2 Br
OCH3
25 5 Br
CH3
10
3 Br
H3CO
0 6 Br
H3C
0
a Reactions of arylbromide (90) (1.0 equiv) with H-Si(OEt)
3 (1.5 equiv) were allowed to
stir at 60 ?C for 12 h in NMP using 3 mol % Pd(dba)2,(t-Bu)2P(o-biphenyl) (120) (6 mol
%), and i-Pr2NEt (3 equiv).  b Yields are isolated yields of purified (>95%) product.
c Remaining yield was of reduced starting material (121).
Table 9.  Silylation of Aryl Bromides: Effect of Substituent Position.
There are several possible explanations for the effect of ortho and meta
substitution on the silylation reaction.  It was initially thought that coordination of the Lewis
basic oxygen lone pair of the methoxy substituent to palladium or silicon was responsible
for this outcome (Figure 12).  However, a non-coordinating ortho-methyl substituent also
prevented silylation (Table 9, entry 6) indicating that steric interference also had a
significant role.  Additionally, coordination of the ortho-methoxy oxygen to silicon was not
observed by either 29Si or 19F-NMR,111 although this result does not rule out the possibility
that the dative bond in the hypercoordinate system 127 forms under the reaction
conditions.  Sterically hindered ortho- and meta-substituted aryl silanes have been shown
to be more susceptible to acid240-244 and base229,245-248-catalyzed protodesilylation than the
65
less hindered para-substituted analogs, regardless of the nature of the ortho substituent.
Truthfully, it is proposed that both steric and electronic factors are responsible for the
decreased yields in this reaction.  The potential effects of substituent position on the
mechanism of the silylation reaction are discussed in detail below.
OMe
Si
OMeOMe
MeO
OMe
Si
OMe
OMe
OMe
Si
OMe
OMe
125 126 127
MeO
MeO
Figure 12.  Proposed Effect of Substituent Position.
The modified reaction conditions were also applied to a variety of substituted aryl
iodides in order to demonstrate the generality of the new ligand system and to determine
the impact of arene substituent location on the silylation of iodides (Table 10).  In
agreement with the report of Masuda, electron-rich para-substituted aryl iodides
underwent silylation more efficiently than the corresponding aryl bromides.221  Similar yields
of siloxanes were achieved with aryl iodides when either the
Pd(dba)2/P(t-Bu)2(o-biphenyl)(120) system or Masuda's Pd2(dba)3?CHCl3/P(o-tol)3
system was employed.
Aryl iodides were less sensitive to the electronic nature of the activating group
than the corresponding bromides.  For example, both 4-bromo (Table 10, entry 8) and
4-chloroiodobenzene (entry 9) gave comparable yields of siloxane to electron-rich aryl
iodides (i.e., O-, N-, and alkyl-substituted).  In contrast, only electron-rich aryl bromide
analogs underwent silylation under these conditions.  In the case of 4-bromo-iodobenzene
(entry 8), the reaction required close monitoring for consumption of starting material
because dehalogenation of the desired product, 4-(triethoxysilyl)-bromobenzene,
occurred under these conditions.  Protection of other functionalities was unnecessary as
shown by the excellent yields obtained with 4-iodoaniline (entry 11) and 4-iodophenol
(entry 13).  Prolonged reaction of iodoaniline not only lowered the yield of siloxane, but
also affected silylation of the unprotected amine nitrogen.
66
H Si(OEt)3Ar-I Ar-Si(OEt)3 Ar-H+
Pd(dba)2
P(t-Bu)2(o-biphenyl)(120)
i-Pr2NEt
NMP128 123 124
+
Entry Aryl Iodide (128) % Yield (123)a-c Entry Aryl Iodide (128) % Yield (123)a-c
1 I OCH3 86 10 I NHAc 68e
2
I
OCH3
52 11 I NH2 77e
3 I
H3CO
10 12 I OAc 75e
4 I CH3 80 13 I OH 70d
6
I
CH3
65 14 I
O
24
7
I
H3C
0d 15
N I
0d,g
8 I Br 68e,f 16
N
I
10
9 I Cl 75e 17
S I
92
a Reactions of aryliodide (128) (1.0 equiv) with H-Si(OEt)
3 (1.5 equiv) were allowed to stirat 60 ?C for 12 h in NMP using Pd(dba)
2 (3 mol %), (t-Bu)2P(o-biphenyl) (120) (6 mol %),and i-Pr
2NEt (3 equiv).  
b Yields shown in parentheses are GC yields; all other yields are
isolated yields of purified (>95%) product.  c Unless noted otherwise, the remaining
percentage was of reduced starting material (124).  d Yield confirmed by GCMS.
e Reaction allowed to stir at room temperature.  f Reaction stopped at 2 h.  g Dipyridyl was
isolated in 15% yield.
Table 10.  Palladium-Catalyzed Silylation of Aryl Iodides.
67
In contrast to the electron-rich aryl iodide systems, 4-iodoacetophenone was
silylated in only 24% yield (entry 14) (see other examples in Masuda221).  Recall that the
bromo analog failed to be silylated under these conditions (Table 7, entry 9).  It is
noteworthy that even the low yield was a triumph since this acetophenone analog cannot
be synthesized by the organometallic approach (vide supra) due to the presence of the
reactive carbonyl group.  Once again, the position of the substituent greatly impacted the
reaction outcome: ortho-iodoanisole (Table 9, entry 3) or toluene (entry 7) gave poor
yields of product (10%, and 0%, respectively); whereas their meta- and para-iodo arene
counterparts gave acceptable yields.
The results from silylation of 2- and 3-iodopyridine are notable.  While in all
previous examples the Pd-mediated silylation reaction yielded either aryl siloxane or
reduced starting material (Scheme 60), homocoupling of 2-iodopyridine was observed.
The homocoupled product [2,2']Bipyridinyl (130, Scheme 61) was isolated in 15% yield
from the attempted silylation of 2-iodopyridine (the reaction went to completion, with
pyridine as the only other product).  The homocoupling of 2-halopyridines in the presence
of a palladium catalyst is a known reaction.249-251  As a control, 2-iodopyridine was exposed
to the standard silylation conditions in the absence of triethoxysilane, and [2, 2']dipyridyl
(130) was isolated in quantitative yield (Scheme 61).  In contrast, when 2-bromopyridine
was used in the control experiment, only a trace amount of the homocoupled product 130
was formed.  The remainder of the reaction mixture was starting material.  The results of
the control experiments explain why no homocoupled product was observed in the
attempted silylation of 2-bromopyridine, whereas homocoupling was a significant side-
reaction in the silylation of 2-iodopyridine.
Scheme 61
N X N Ni-Pr2NEt / NMP
129, X = I
42, X = Br
130
X = I, 99%
X = Br, 6%
Pd(dba)2
P(t-Bu)2(o-biphenyl)(120)
68
Attempts to silylate 3-iodopyridine were problematic also, although no
homocoupled adduct was observed.  We obtained only 10% of the desired product using
either Masuda's conditions or our modified reaction conditions (Table 10, entry 16).  These
results were surprising because Masuda reported a 56% yield of
3-(triethoxysilyl)pyridine using Pd2(dba)3?CHCl3/P(o-tol)3 in NMP (1h, 80 ?C).221  Again it
appears that the metal coordinating ability of the pyridine nucleus is the culprit since
2-iodothiophene was readily silylated (92% yield, Table 9, entry 17).
Aryl triflates are appealing substrates for silylation since they are readily derived
from the phenol,71 and are often more available than the corresponding aryl halides.
However, aryl triflates failed to undergo efficient silylation under the standard conditions
used for aryl iodides and bromides (Table 11).  As seen in entries 1 and 9, electron-rich
and deficient aryl triflates underwent reduction upon treatment with excess Hunig?s base
and triethoxysilane with catalytic Pd(dba)2/P(t-Bu)2(o-biphenyl)(120).  A base was
required for complete reaction turnover (entries 2,4,10, and 12), and the reaction tolerated
both polar and non-polar solvents.  The electron-rich substrate 4-methoxyphenyl triflate
underwent reduction most efficiently using the alternative Buchwald ligand,
P(cy)2(o-biphenyl) (entry 8), whereas the electron-deficient substrate 4-nitrophenyl triflate
tolerated a range of phosphine ligands: P(t-Bu)2(o-biphenyl) (120), P(cy)2(o-biphenyl),
and PPh3 all affected efficient reduction.
69
OTf
R
H Si(OEt)3
Si(OEt)3
R
H
R
+ +
Pd(dba)2
ligand
base
solvent
131 92 121
Conditionsa Yield (%)b,c
Entry R Ligand Base Solvent 92 121
1 OMe P(t-Bu)2(o-biphenyl) i-Pr2NEt NMP 3 90
2 OMe P(t-Bu)2(o-biphenyl) none NMP 0 5
3 OMe P(t-Bu)2(o-biphenyl) i-Pr2NEt dioxane 2 96
4 OMe P(t-Bu)2(o-biphenyl) none dioxane 0 7
5 OMe PPh3 i-Pr2NEt NMP 0 5
6 OMe PPh3 i-Pr2NEt dioxane 0 24
7 OMe P(cy)2(o-biphenyl) i-Pr2NEt NMP 1 32
8 OMe P(cy)2(o-biphenyl) i-Pr2NEt dioxane 1 99
9 NO2 P(t-Bu)2(o-biphenyl) i-Pr2NEt NMP 0 100
10 NO2 P(t-Bu)2(o-biphenyl) none NMP 0 22
11 NO2 P(t-Bu)2(o-biphenyl) i-Pr2NEt dioxane 0 100
12 NO2 P(t-Bu)2(o-biphenyl) none dioxane 0 15
13 NO2 PPh3 i-Pr2NEt NMP 0 100
14 NO2 PPh3 i-Pr2NEt dioxane 0 100
15 NO2 P(cy)2(o-biphenyl) i-Pr2NEt NMP 0 100
16 NO2 P(cy)2(o-biphenyl) i-Pr2NEt dioxane 0 100
a Reactions of aryltriflate (131) (1.0 mmol) with H-Si(OEt)
3 (1.5 mmol) were performed atroom temperature for 12h in 4 mL of solvent by using Pd(dba)
2 (5 mol %), phosphine (10mol %), and base (3 mmol).  b GC yields are based on amount of aryltriflate (131).
c Remaining percentage was unreacted starting material.
Table 11.  Silylation of Aryltriflate Derivatives.
The Pd-catalyzed reduction of aryl triflates using triethylsilane (Et3Si?H) was
reported by Kotsuki in 1995 (Scheme 62).252  Under mild conditions, a variety of aryl
triflates underwent deoxygenation in excellent yield.  It was observed that triethylamine
increased the reaction rate.  With further optimization, triflate deoxygenation using
H-Si(OEt)3 in dioxane (or other volatile, low-polarity solvents such as THF or toluene)
under our conditions could prove to be synthetically useful, and more attractive than
existing methods, which require DMF.252
70
Scheme 62
H-SiEt3
Pd(OAc)2
dppp
DMF
100%
OTf H
Two mechanisms have been proposed for the palladium-catalyzed silylation
reaction, both of which account for the formation of reduced arene byproducts.221  Both the
C-X bond of aryl halides and the Si-H bond of silanes are known to undergo oxidative
addition to Pd(0) complexes.45,253-258  Thus, two logical mechanisms have been proposed,
one with Ar-Pd(II)-X, and the other with R3Si-Pd(II)-H as the key intermediate,
respectively.
Scheme 63 illustrates a reasonable mechanism for the oxidative addition of the aryl
halide to Pd(0), to form Ar-Pd(II)-X complex 132.  Transmetallation with the silane forms
four-centered palladium intermediate 133, which in turn undergoes reductive elimination to
liberate aryl silane and regenerate the Pd(0) catalyst.  Support for this mechanism was
provided by Chatgilialoglu, who demonstrated that organic halides underwent oxidative
addition to Pd(0) catalysts more readily than hydrosilanes.255  Additionally, it was shown
that the mechanism did not involve the intermediacy of carbenium ions or free-radical
species.
Scheme 63
H(EtO)3Si
Ar I
(EtO)3Si
Ar
Ln Pd(II) I
Ar
HI
Pd(II) I
Ln
H
(EtO)3Si Pd I
H
Ar
Pd(0)Ln
132134
133
71
A mechanism involving oxidative addition of the hydrosilane followed by ?-bond
metathesis has been proposed by Kunai and Ishikawa for the exchange of the Si-H and
C-I bonds of alkyl and aryl iodides and hydrosilanes in the presence of a Pd(0) catalyst
(Scheme 64).258  The mechanism for silylation begins with formation of a Si-Pd bond by
oxidative addition of Pd(0) to the silane.  Silylation of the aryl halide results from ?-bond
metathesis, for overall Si-H/C-I bond exchange and regeneration of the Pd(0) catalyst.
Scheme 64
H(EtO)3Si
Ar I(EtO)3Si
Ar
Pd(0)Ln
(EtO)3Si Pd(II) H
Ln
(EtO)3Si Pd H
IAr
Ln
HI
Pd(II) H
Ln
I 135134
136
Both mechanisms account for the formation of dehalogenated aryl halide substrate
when ortho substituents are present on the arene.  Reductive elimination of silylated
arene (Ar-Si(OEt)3) from 4-coordinate Pd intermediate 133 requires that the ?Si(OEt)3 and
the ?Ar ligands adopt a cis geometry, as shown above in Scheme 64.  Steric bulk on the
arene will disfavor the cis conformation, and isomerization of the complex reorients the two
largest substituents to the trans geometry on the palladium complex (137, Scheme 65).
As a consequence, the Ar- and H- ligands are placed preferentially cis, and Ar-H is formed
upon reductive elimination from palladium.
72
Scheme 65
137133
(EtO)3Si Pd I
H
Ar
(EtO)3Si Pd Ar
H
I
Ar H (EtO)3Si I+
Similarly, for the proposed mechanism entailing ?-bond metathesis, steric bulk on
the arene will disfavor the approach of Ar-X on the R3Si-Pd(II)-H intermediate which
places the large arene adjacent to the bulky ?SiR3 ligand, as shown in transition state 136
in Figure 13.  Instead, the less sterically demanding approach 139 should be favored, and
formation of Ar-H in lieu of the desired Ar-SiR3 results.
(EtO)3Si Pd H
IAr
Ln
136
(EtO)3Si Pd H
ArI
Ln
139
Figure 13.  Proposed Transition States for the Metathesis Reaction Mechanism.
In order to determine which of the above two mechanisms most likely is at play in
this process, Masuda demonstrated that neither silylation nor reduction occurred when a
preformed Ar-Pd(II)-I complex was treated with (EtO)3SiH and triethylamine, indicating that
the mechanism of reaction likely does not involve initial oxidative addition to the aryl
halide.221  Instead, the latter mechanism entailing initial oxidative addition into the silane,
followed by ?-bond metathesis seems the most likely pathway for the formation of aryl
siloxane product.
In an effort to circumvent formation of reduced arene byproducts, the silylation
reaction was attempted using hexamethoxydisilane ((MeO)3Si-Si(OMe)3) (Scheme 66).
Alkylchloro- and alkylalkoxydisilanes had been shown previously to participate in the Pd-
mediated silylation of aryl halides (vide supra).45,197,198,257,259-267  It is notable that the
73
analogous Pd-mediated process using hexachlorodisilane did not yield trichlorosilyl arenes
(which could be converted to the siloxane upon alcoholysis).265
Scheme 66
(MeO)3Si Si(OMe)3 +
X
R
Pd(0)
Si(OMe)3
R
X-Si(OMe)3
Unfortunately, aryl halides failed to undergo silylation using hexamethoxydisilane
under the conditions used for the silylation of aryl iodides and bromides with hydrosilane
(Table 12).  Under standard silylation conditions, no reaction was observed with electron-
rich p-haloanisole derivatives (entries 1-4).  In contrast, the electron-deficient system of
4-bromoacetophenone underwent complete reduction using standard as well as modified
silylation conditions (entries 5 to 9).
Hatanaka reported the palladium-mediated, fluoride-induced trimethylsilylation of
electron-rich and electron-neutral aryl iodides with hexamethyldisilane (Scheme 67).
Under the same conditions reported by Hatanaka using hexamethoxysilane, no reaction
was observed (Table 12, entries 10-12).  Finally, the best results were obtained under
forced reaction conditions (entry 13): treatment of bromobenzene with
hexamethoxydisilane for 72 hours in a sealed tube at 140 ?C in the presence of catalytic
Pd(0) yielded 27% of the desired silane, as well as reduced arene and biphenyl
contaminants.
Scheme 67
Me3Si-SiMe3
Pd(PPh3)4 (20 mol%)
TASF
HMPA, 25 ?C
100%
IMe SiMe3Me
74
X
(MeO)3Si Si(OMe)3
Si(OMe)3 H
R R R
+ +
Pd(0)
ligand
base
solvent
139 92 121
Substrate Conditionsa Yield
(%)b,c
Entry X R Ligand Pd catalyst / base solvent T
(?C)
92 121
1 I OMe P(t-Bu)2(o-biphenyl) Pd(dba)2 / i-Pr2NEt NMP 25 0 0
2 I OMe P(o-tol)3 Pd(dba)2?CHCl3/i-Pr2NEt NMP 25 0 2
3 Br OMe P(t-Bu)2(o-biphenyl) Pd(dba)2 / i-Pr2NEt NMP 25 0 0
4 Cl OMe P(t-Bu)2(o-biphenyl) Pd(dba)2 / i-Pr2NEt NMP 25 0 0
5 Br Ac P(t-Bu)2(o-biphenyl) Pd(dba)2 / i-Pr2NEt NMP 100 0 100
6 Br Ac P(t-Bu)2(o-biphenyl) Pd(dba)2 / i-Pr2NEt DMPU 100 0 100
7 I Ac P(t-Bu)2(o-biphenyl) Pd(dba)2 / KF (aq) DMPU 75 0 100
8 Br Ac P(t-Bu)2(o-biphenyl) Pd(dba)2 / KF (aq) DMPU 75 0 100
9 Br OMe P(t-Bu)2(o-biphenyl) Pd(dba)2 / K2CO3 (aq) DMPU 75 0 0
10 I OMe Pd(PPh3)4 / TBAF NMP 25 0 0
11 I Me Pd(PPh3)4 / TBAF DMF 25 0 3
12 I Me Pd(PPh3)4 / TBAF HMPA 25 0 3
13d,e Br H Pd(PPh3)4 toluene 140 27 10
a Reactions of aryl halide 139 (1.0 equiv) with (MeO)
3Si-Si(OMe)3 (2.0 equiv) wereperformed using the indicated temperature and solvent for 12h-48h by using the given
palladium catalyst (5 mol %), phosphine (10 mol %), and base (3 equiv).  b GC yields are
based on amount of aryl halide 139.  c Unless otherwise noted, remaining percentage was
unreacted starting material (139).  d Reaction was performed in a sealed tube for 72h.
e Biphenyl was observed in 7% yield.
Table 12.  Silylation of Arylhalides Using Hexamethoxydisilane.
The results of the silylation reaction employing hexamethoxydisilane are
surprising.  In the absence of a hydride source, it was anticipated that reduction of the aryl
halide would be suppressed.  One possible hydrogen atom source is methoxide, which
can be generated upon decomposition of the disilane under the harsh reaction
conditions.198  Previous researchers have demonstrated the catalytic dehalogenation of a
large variety of aryl chlorides and bromides with sodium or potassium methoxide mediated
by Pd(0) (Scheme 68).268
75
Scheme 68
Pd(dba)2, KOMe, 140
dioxane, 100 ?C, 1h
100%
Cl
O O N N
140
The proposed mechanism of dehalogenation by methoxide under palladium
catalysis is depicted in Scheme 69.268  The mechanism begins with oxidative addition of
the aryl halide to Pd(0) to form the Ar-Pd(II)-X intermediate 132, followed by methoxide
attack with displacement of the halide to give key intermediate 141.  Then, ?-hydride
elimination and liberation of formaldehyde gives the palladium-hydride complex 134, which
can reductively eliminate reduced arene and regenerate the catalyst.
Scheme 69
Ar X
Pd(0)Ln
Ln Pd(II) X
Ar
132
MeO
XLn Pd(II) OMe
Ar
141
H H
O
Ln Pd(II) H
Ar
134
Ar H
76
Rich pioneered the use of aryl acyl chloride derivatives as substrates for silylation
(Scheme 70).196,269,270  For example, treatment of m-nitrobenzoyl chloride (142) with
1,1,2,2-dichlorodimethyldisilane under palladium catalysis resulted in decarbonylative
silylation to form aryl silane 143.196
Scheme 70
MeCl2Si-SiCl2Me
(PhCN)2PdCl2
PPh3
145 ?C, 20h
69%
SiCl2MeO2NO
2N Cl
O
+     CO     +     MeCl2Si-Cl
142 143
Rich demonstrated the efficient silylation of para and meta-substituted electron rich
and deficient aromatic acid chlorides utilizing methylchlorodisilanes; ortho-substituted acid
chlorides failed to undergo carbonylative silylation.196  It is notable that the analogous
method using hexachlorodisilane did not successfully form trichlorosilyl arenes (which
could be converted to the siloxane upon alcoholysis).  Rich reported that
hexachlorodisilane underwent decomposition under the conditions of the reaction.  Lastly,
a number of byproducts were observed, including benzil and diarylketone derivatives,
especially when electron-deficient substrates were employed.
The decarbonylative silylation reaction as reported by Rich was attempted in our
laboratories, using hexamethoxydisilane (Scheme 71, eqn. a).  Benzoyl chloride was
heated without solvent in a sealed tube with hexamethoxydisilane and (PhCN)2PdCl2 in
the presence of triphenylphosphine.  However, none of the desired product was formed;
instead, quantitative formation of methylbenzoate was observed.  Clearly, the harsh
reaction conditions elicited formation of methoxide via decomposition of the disilane,
resulting in the methanolysis of the acyl chloride moiety.  The thermal decomposition of
chloro196 and alkoxy198 disilanes was reported, previously.  Formation of arylsilane was
observed when a different catalyst was employed (Scheme 71, eqn. b), however
formation of the methyl ester was still a significant side-reaction.  Less harsh reaction
77
conditions resulted in no reaction.  Efforts to employ the disilane for the synthesis of aryl
siloxanes from aryl halides and acyl chlorides were abandoned in light of the poor results
of these preliminary studies, the expense of the disilane reagent, and the harsh reaction
conditions.
Scheme 71
(MeO)3Si-Si(OMe)3
(PhCN)2PdCl2
PPh3
145 ?C, 20h
Si(OMe)3
Cl
O
+ OMe
O
0 % 100 %
(MeO)3Si-Si(OMe)3
Pd(PPh3)4
145 ?C, 20h
Si(OMe)3
Cl
O
+ OMe
O
45 % 55 %
(a)
(b)
In summary, the Pd-mediated silylation of electron-rich aryl halides has been
extended to include both iodides and bromides.  For bromo arenes, the inclusion of
Buchwald's phosphine ligand (120) is crucial.  Although aryl iodides remain the substrates
of choice for silylation, an acceptable yield of arylsiloxane may be obtained from the
corresponding bromide.  This is an advantage since aryl bromides are generally less
expensive and more widely available than the analogous aryl iodides.
Conclusions
The scope of the silylation protocol has been fully defined: the synthesis of aryl
and heteroaryl siloxanes using H-Si(OEt)3 and a Pd catalyst is limited generally to
electron-rich, para- and meta-substituted aryl bromides and iodides.  Aryl chlorides were
inert under the reaction conditions, and triflates were poor substrates for silylation, instead
undergoing highly efficient reductive deoxygenation.  The optimum silylation reagent is
triethoxysilane.  This silylation method is an excellent companion to the more traditional
organometallic approach to the formation of the Ar-Si bond.  Case in point, ortho-
substituted aryl siloxanes are readily synthesized from the Grignard or lithium reagent.
78
Unlike the metallation approach, the Pd-catalyzed silylation technique can be performed in
the presence of a wide range of functional groups, including carbonyl-containing
electrophiles, and protic moieties such as phenols or primary amines.
To date, a large variety of simple aryl and heteroaryl halides has been shown to
undergo silylation by one or both of the above protocols (Figure 14).24,25,68,111,229
70% 64% 65% 74% 68% 71%
Br
OMe
Br OMe Br
OMe
Br
Me
Br Me Br
Me
43% 50% 22% 70% 60%
S
Br
O Br N
57%
Br
OMe
Br Br
HN MeN
33% 38% 30% 28% 55%
Br
NHAc
Br Br Br
OH
Br
NH2 OAc
S Br
86% 52% 10% 80% 65%
I
OMe
I OMe I
OMe
I
Me
I Me
92% 68% 77% 75% 70%
I
NHAc
I I I
OHNH2 OAcS I N
10%
I
80%
I
Ac
Figure 14.  Yields of Siloxanes Using Arylmetalloid Reagents or Palladium-Mediated
Silylation.
The siloxane derivatives synthesized by the methods described herein have
been utilized in palladium-catalyzed cross-coupling.  The synthesis of aryl siloxanes has
been shown to be comparable in yield to the synthesis of aryl boron reagents.  In
79
contrast to the Suzuki reagents, siloxanes are easily purified by chromatography,
distillation, or even recrystalization (in the case of aryl catecholates and silatranes).
Although aryl tin reagents remain the easiest to synthesize, the silicon-based cross-
coupling technique is an attractive alternative to Stille coupling, due to the low toxicity of
the siloxane cross-coupling reagents.
Application of these methodologies to the synthesis of complex, biologically active
materials has been investigated in our laboratory.  For example, the synthesis of a variety
of highly functionalized siloxane derivatives has been accomplished.  Coupling of these
siloxanes to provide intermediates in the total synthesis of pancratistatin, streptonigrin,
lavendamycin, and colchicine are being investigated by other members of the group and
these results will be reported in due course.  A sample of highly functionalized siloxanes
prepared by these methods includes 93, 94, 142 and 143 (Figure 15).
O
O
Si(OEt)3
93, 74%
O
O
Si(OEt)3
94, 50%
OMe
MeO
MeO
Si(OEt)3
142, 50%
OMOM N OMeMe
Me
Si(OEt)3
143, 30%
Figure 15.  Siloxane Intermediates for Use In Natural Product Syntheses.
Epilogue
Since the publication of the above method for aryl siloxane synthesis via Pd(0)-
catalyzed silylation of aryl bromides and iodides in 2001,271 Masuda reported the Rh(I)-
catalyzed silylation of aryl iodides and bromides (Scheme 72).272  The silylation is
analogous to the Pd(0) silylation, in that the reaction requires a tertiary amine and polar
amide solvent.  Again, dehalogenation of the aryl halide starting material was the major
side-reaction.  Significantly, the substitution of Rh(I) for Pd(0) as the catalyst allowed for
the silylation of electron-deficient aryl halides, as well as hindered, ortho?substituted
silanes.  The Rh(I)-catalyzed process is limited by expense of, and the need to
80
synthesize the [Rh(cod)MeCN)2]BF4 catalyst, but nonetheless presents a general method
of silylation, encompassing electron-rich as well as electron-deficient aryl halides, including
ortho-substituted arenes.  The silylation of chloro arenes remains elusive.
Scheme 72
Br
Et3N
Bu4NI
90%
+ H-Si(OEt)3
Si(OEt)3[Rh(cod)(MeCN)2]BF4
EtO2C
I
Et3N
81%
+ H-Si(OEt)3
Si(OEt)3[Rh(cod)(MeCN)2]BF4
Me Me
EtO2C
81
Experimental
General.  Thin layer chromatography (TLC) was performed on 0.25 mm Merck silica-
coated glass plates treated with a UV-active binder, with the compounds being visualized
in one or more of the following manners: UV (254 nm), iodine, or vanillin/sulfuric acid
charring.  Flash chromatography was performed using thick-walled glass columns and
medium-pressure silica gel (Davisil? 200-425 mesh) as described by Still.273  Flash
chromatography data is reported as: (column diameter in mm, column height in cm,
solvent).
Infrared spectra were recorded on a Nicolet 5DXC FT-IR spectrophotometer with
the samples prepared as stated.  Band positions are given in reciprocal centimeters (cm-1)
and relative intensities are listed as br (broad), vs (very strong), s (strong), m (medium),
or w (weak).
Melting points were taken in Kimax soft glass capillary tubes using a Thomas-
Hoover Uni-Melt capillary melting point apparatus (Model 6406K) equipped with a
calibrated thermometer.  Melting points are corrected.
Nuclear magnetic resonance (1H, 13C) spectra were recorded on a Bruker DRX-400
spectrometer.  Chemical shifts are reported in parts per million (?) downfield from
tetramethylsilane (TMS).  Coupling constants (J values) are reported in Hertz (Hz), and
spin multiplicities are indicated by the following symbols: s (singlet), d (doublet), t (triplet),
q (quartet), m (multiplet), br s (broad singlet).
Low resolution (MS) and high resolution mass spectra (HRMS) were obtained on
a VG-7070E magnetic sector instrument equipped with a 486 PC-based data system.
GCMS was performed on a Shimadzu QP5000MS coupled with a GC17A gas
chromatograph.
Gas chromatography was performed on a Hewlett Packard 5890 GC equipped
with a flame ionization detector using a 25 m methyl silicon column.
82
Methylene chloride (CH2Cl2), tetraethyl orthosilicate (Si(OEt)4), tetramethyl
orthosilicate (Si(OMe)4), methyl sulfoxide (DMSO), dimethyl formamide (DMF),
1-methyl-2-pyrrolidinone (NMP), toluene, pyridine, and acetonitrile (MeCN) were each
distilled from calcium hydride.  Tetrahydrofuran (THF), dioxane and diethyl ether (Et2O)
were each distilled from sodium-benzophenone ketyl.  Methanol (MeOH) and ethanol
(EtOH) were stored over molecular sieves.
Palladium(II) acetate (Pd(OAc)2), bis(dibenzylideneacetone)palladium (Pd(dba)2),
dichlorobis(triphenylphosphine)palladium(II) (PdCl2(PPh3)2), and
tetrakis(triphenylphosphine)palladium(0) (Pd(PPh3)4) were purchased from Acros and
used as received.
Tri-o-tolylphosphine (P(o-tol)3) was purchased from Acros and used as received.
Triphenylphosphine (PPh3) was purchased from Aldrich and recrystallized from hexanes
prior to use.  2-(Di-t-butylphosphino)biphenyl (120) (P(t-Bu)2(o-biphenyl)) was
purchased from Strem and recrystallized from methanol (MeOH) prior to use.  The ligand
2-(Dicyclohexylphosphino)biphenyl (P(cy)2(o-biphenyl)) was purchased from Strem and
recrystallized from absolute ethanol (EtOH) prior to use.  Tri-t-butylphosphino (P(t-Bu)3)
was purchased from Strem as a 10 wt% solution in hexane and stored under argon.  All
other phosphines and triphenylarsine were purchased from Aldrich, stored under argon,
and used as received.
Aryl halides, heteroaryl halides and alkyl halides were prepared by literature
procedure as noted, or purchased from Acros or Aldrich and purified using the method of
Perrin274 prior to use.  N-(4-Bromophenyl) acetamide275, 4-acetoxybromobenzene276,
4-acetoxyiodobenzene276, 2-iodopyridine277, 3-iodopyridine278, 2-bromoquinoline279,
3-bromoquinoline280, and 5-bromo-2-methoxypyridine281 were each prepared according to
the literature procedure.  In the case aryl sulfonates, the appropriate sulfonate was
synthesized from the phenol immediately before use using the literature method283,284 and
the crude isolated sulfonate was used without further purification.  Triethoxysilane
83
(H-Si(OEt)3), and diisopropylethylamine (i-Pr2NEt), were purchased from Aldrich, stored in
a dessicator, and used as received.  Triisopropoxysilane (H-Si(O-i-Pr)3) and
hexamethoxydisiloxane ((MeO)3Si-Si(OMe)3) were purchased from Gelest, stored in a
dessicator, and used as received.  Tetrabutylammonium fluoride (TBAF) was purchased
from Acros as a 1.0 M solution in THF and used as received.  Tetrabutylammonium
triphenyldifluorosilicate (TBAT) was prepared according to the literature procedure.285
n-Butyllithium (1.6 M solution in hexane), and t-butyllithium (1.5 M solution in
pentane) were purchased from Acros and used as received.  The alkyllithium
concentration was confirmed by titration with diphenylacetic acid using the method of
Kofron.286  Magnesium turnings were cleaned as follows: enough turnings were placed in a
beaker to form a thin layer.  Dilute HCl solution (0.1 M) was added to just cover the
magnesium turnings.  The turnings were stirred until bubbling ceased and then the solution
was decanted off and the process repeated three times or until the metal had a shiny
mirror appearance.  The turnings were then washed in the beaker three times each with
water, ethanol, and diethyl ether.  Finally, the turnings were dried in an oven at 120 ?C for
five minutes.
Glassware used in the reactions described below was dried for a minimum of 12 h
in an oven at 120 ?C.  All reactions were run under an atmosphere of nitrogen or argon at
room temperature unless otherwise noted.
All compounds were determined to be >95% pure by 1H NMR unless otherwise
noted.
84
General Procedure for the Optimization of the Synthesis of 4-
(Triethoxysilyl)anisole (88) Using 4-Bromomagnesium anisole (87) (Table 2).  A 10
mL, 3-neck pear-shaped flask was fitted with an addition funnel, a reflux condenser, a
rubber septum, and a stirbar.  The flask was then charged with freshly washed
magnesium turnings (134 mg, 5.50 mmol), flame-dried under vacuum, and back-filled with
argon.  THF (1.0 mL) was added to the magnesium turnings via syringe.  The addition
funnel was charged with 4-bromoanisole (86) (935 mg, 628 ?L, 5.00 mmol) in 2.0 mL THF.
The reaction was initiated by addition of 5-10 drops of the bromoanisole solution to the
magnesium turnings with stirring, followed by gentle heating.  The rest of the bromoanisole
solution was then added at such a rate that the THF maintained a moderate reflux.  Upon
final addition, the solution was allowed to stir at room temperature for 1 h, at which point
GC analysis of a quenched aliquot of the reaction mixture indicated complete consumption
of 4-bromoanisole.  The 4-(bromomagnesium)anisole solution was then transferred via
cannula to a second flame-dried addition funnel, to which was fitted a 50 mL round-bottom
flask containing the indicated silane (1.5-3.0 equiv) and the internal standard naphthalene
(64 mg, 0.50 mmol) in 10.0 ml of THF.  The silane solution was cooled to the indicated
temperature, and then the 4-(bromomagnesium)anisole solution was added dropwise (1
drop per second).  The solution was allowed to stir at the indicated temperature for 1 h,
and then at room temperature for 12 h.  Progress was monitored by GC analysis of
aliquots of the quenched reaction mixture.  GC response factors relative to the internal
naphthalene standard were determined, and the observed percentages of products were
normalized accordingly.  The reduced product anisole was identified by comparison of the
GC retention time to that of an authentic sample.  Diarylated products were identified by
GCMS; triarylated products were not observed.  Aliquots of the crude, concentrated
4-(trichlorosilyl)anisole were converted to the siloxane by dropwise addition (1 drop per
second) of the chlorosilane to EtOH/pyridine at 0 ?C.
85
MgBr Si(OR)3
Si(OR)4, THF
Br
OCH3 OCH3 OCH3
86 88
+
89
Mg?, I2 (cat)
87
1. SiCl4, THF
2. EtOH, pyr, 0 ?C
ORTHFreflux
Ar2Si(OR)2
Conditionsa Yield (%)b,c
Entry Silane / Equiv T (?C) 88 89
1 Si(OMe)4 / 3.0 25 47 47
2 Si(OMe)4 / 3.0 -30 76 3
3 Si(OMe)4 / 1.5 -30 65 4
4 Si(OEt)4 / 3.0 0 72 23
5 Si(OEt)4 / 3.0 -10 70 23
6 Si(OEt)4 / 3.0 -30 83 3
7 Si(OEt)4 / 1.5 -30 76 2
8 Si(Cl)4 / 3.0d -30 70d 3
a Reactions of p-methoxy magnesium bromide 87 (1.0 equiv) with Si(OR)
4 orSiCl
4 (1.5 to 3.0 equiv) were allowed to stir at the given temperature in THF.The reaction mixture was stirred at the indicated temperature for 1 h, and then
at room temperature for 12 h.  b GC yields are based on amount of
4-bromoanisole (86).  c The remainder of the product was of anisole.  d Yield of
4-(triethoxysilyl)anisole (88).  The crude, concentrated 4-(trichlorosilyl)anisole
was converted to the siloxane 88 by dropwise addition of the chlorosilane to
EtOH/pyridine at 0 ?C.
Table 2.  Optimization of the Synthesis of Arylsiloxanes Using 4-Bromomagnesium
Anisole.
General Procedure for Synthesis of Siloxanes from Grignard Reagents (Table 3).
Unless otherwise indicated, all reactions were performed on a 5 mmol scale.  A 10 mL, 3-
neck pear-shaped flask was fitted with an addition funnel, a reflux condenser, a rubber
septum, and a stirbar.  The flask was then charged with freshly washed magnesium
turnings (134 mg, 5.50 mmol), flame-dried under vacuum, and back-filled with argon.  THF
(1.0 mL) was added to the magnesium turnings via syringe.  The addition funnel was
charged with the aryl halide (5.00 mmol) in 2.0 mL THF.  The reaction was initiated by
addition of 5-10 drops of the aryl halide solution to the magnesium turnings with stirring,
86
followed by gentle heating.  The rest of the aryl halide solution was then added at such a
rate that the THF maintained a moderate reflux.  Upon final addition, the solution was
allowed to stir at room temperature until GC analysis of a quenched aliquot of the reaction
mixture indicated complete consumption of aryl halide.  The aryl magnesiumhalide solution
was then transferred via cannula to a second flame-dried addition funnel, to which was
fitted a 50 mL round-bottom flask containing tetraethyl orthosilicate or tetramethyl
orthosilicate (15.00 mmol) in 10.0 ml of THF.  The silane solution was cooled to ?30 ?C,
and then the 4-arylmagnesiumhalide solution was added dropwise (1 drop per second).
The solution was allowed to stir at the indicated temperature for 1 h, and then at room
temperature for 12 h.  The crude reaction mixture was then poured into 50 mL of pentane
in a 200 mL separatory funnel.  The amber solution was washed with 3 x 25 mL water to
remove the excess tetraalkoxysilane, dried over MgSO4, filtered, and concentrated in
vacuo.  Purification of the residue by bulb-to-bulb distillation yielded the siloxane.
2-(Triethoxysilyl)anisole (Table 3, entry 1).  The general
procedure for synthesis of siloxanes from Grignard reagents was
followed using 2-bromoanisole (935 mg, 623 ?L, 5.00 mmol),
magnesium turnings (134 mg, 5.50 mmol), and tetraethyl orthosilicate (3.13 g, 3.35 mL,
15.0 mmol) in THF.  Bulb-to-bulb distillation (125 ?C, 0.5 torr) afforded 1.19 g (88%) of
2-(triethoxysilyl)anisole as a colorless oil.  IR (neat) 3067 (m), 2967 (s), 2922 (s, 2891
(s), 2829 (m), 2780 (w), 2762 (w), 1590 (s), 1569 (s), 1459 (s), 1241 (s) cm-1; 1H (NMR)
(CDCl3) ? 1.21 (t, J = 7.2, 9H), 3.79 (s, 3H), 3.84 (q, J = 7.2, 6H), 6.83 (d, J = 8.2, 1H),
6.95 (t, J = 7.2, 1H), 7.38 (m, 1H), 7.63 (dd, J = 1.6, 7.2, 1H); 13C (NMR) (CDCl3) ? 18.2,
55.1, 58.7, 109.6, 119.2, 120.5, 132.2, 137.5, 164.3; MS (m/z) 271 (M++1, 42), 225 (100),
195 (21), 181 (36), 139 (25), 119 (21), 91 (24), 77 (14); HRMS for C13H23O4Si calcd
271.1366 (M++1), found 271.1354.
Si(OEt)3
OCH3
87
MgBr Si(OR')3
R R
THF
Si(OR')4
Br
R
THF
Mg?
90 9291
Entry Aryl Siloxane Yield (%)a,b Entry Aryl Siloxane Yield (%)a,b
1
Si(OEt)3
OCH3
88 6
Si(OEt)3
CH3
81
2
Si(OMe)3
OCH3
83 7
Si(OMe)3
CH3
71
3
Si(OEt)3
H3CO
84 8
Si(OEt)3
H3C
75
4 H3CO Si(OEt)3 82 9 H3C Si(OEt)3 86
5
O
O
Si(OEt)3
74 10 Si(OEt)3 55
a Reactions of arylmagnesium bromide 91 (1.0 equiv) with Si(OEt)
4 or Si(OMe)4 (3.0equiv) were allowed to stir at ?30 ?C in THF.  The reaction mixture was stirred at ?30 ?C
for 1 h, and then at room temperature for 12 h.  b Yields of 92 are after distillation (purity
>95%).  The remainder of the product was of the reduced (dehalogenated) arene.
Table 3.  Synthesis of Aryl(trialkoxy)silanes Using Grignard Reagents.
2-(Trimethoxysilyl)anisole (Table 3, entry 2).  The general
procedure for synthesis of siloxanes from Grignard reagents was
followed using 2-bromoanisole (935 mg, 623 ?L, 5.00 mmol),
magnesium turnings (134 mg, 5.50 mmol), and tetramethyl orthosilicate (2.28 g, 2.21 mL,
15.0 mmol) in THF.  Bulb-to-bulb distillation (125 ?C, 0.5 torr) afforded 948 mg (83%) of
2-(trimethoxysilyl)anisole as a colorless oil.  IR (1H (NMR) (CDCl3) ? 3.61 (s, 9H), 3.80 (s,
3H), 6.87 (d, J=8.3, 1H), 6.97 (t, J=7.2, 1H), 7.42 (m, 1H), 7.59 (dd, J=1.7, 7.2, 1H); 13C
NMR (CDCl3) ? 50.4, 54.9, 109.4, 117.7, 120.3, 132.2, 137.0, 164.1; MS (m/z) 228 (100),
196 (61) 167 (55), 137 (18), 121 (44), 91 (45), 58 (29); HRMS for C10H16O4Si calcd
228.0818, found 228.0809.
Si(OMe)3
OCH3
88
3-(Triethoxysilyl)anisole (Table 3, entry 3).  The general
procedure for synthesis of siloxanes from Grignard reagents was
followed using 3-bromoanisole (935 mg, 633 ?L, 5.00 mmol),
magnesium turnings (134 mg, 5.50 mmol), and tetraethyl orthosilicate (3.13 g, 3.35 mL,
15.0 mmol) in THF.  Bulb-to-bulb distillation (125 ?C, 0.5 torr) afforded 1.14 g (84%) of
3-(triethoxysilyl)anisole as a colorless oil.  IR (neat) 2975 (s), 2927 (m), 2887 (m), 1572
(m), 1482 (w), 1410 (w), 1391 (w), 1284 (w), 1249 (m), 1234 (m), 1167 (m), 1078 (vs)
cm-1; 1H (NMR) (CDCl3) ? 1.25 (t, J = 7.0, 9H), 3.81 (s, 3H), 3.87 (q, J = 7.0, 6H), 6.96-
6.98 (m, 1H), 7.21-7.33 (m, 3H); 13C (NMR) (CDCl3) ? 18.3, 55.1, 58.8, 116.1, 119.8,
127.1, 129.2, 132.4, 159.0; MS (m/z) 270 (100), 256 (12), 255 (70), 226 (28), 225 (64),
211 (23), 197 (13), 182 (11), 181 (41), 169 (37), 168 (13), 167 (29), 163 (10), 154 (16),
153 (27), 149 (22), 147 (61), 139 (20), 137 (14), 136 (55), 135 (95); HRMS for C13H22O4Si
calcd 270.1287, found 270.1282.
4-(Triethoxysilyl)anisole (Table 3, entry 4).  The general
procedure for synthesis of siloxanes from Grignard reagents
was followed using 4-bromoanisole (935 mg, 626 ?L, 5.00
mmol), magnesium turnings (134 mg, 5.50 mmol), and tetraethyl orthosilicate (3.13 g, 3.35
mL, 15.0 mmol) in THF.  Bulb-to-bulb distillation (125 ?C, 0.5 torr) afforded 1.11g (82%) of
4-(triethoxysilyl)anisole as a colorless oil.  IR (neat) 2975 (s), 2926 (m), 2894 (m), 1597
(s), 1505 (m), 1282 (m), 1249 (m), 1167 (s), 1127 (vs), 1104 (vs), 1080 (vs) cm-1; 1H
(NMR) (CDCl3) ? 1.24 (t, J = 7.0, 9 H), 2.34 (s, 3H), 3.86 (q, J = 7.0, 6 H), 6.92 (d, J =
8.6, 2 H), 7.61 (d, J = 8.6, 2 H); 13C (NMR) (CDCl3) ? 18.1, 54.9, 58.6, 113.6, 122.0,
136.4, 161.4; MS (m/z) 270 (52), 255 (53), 225 (38), 211 (25), 181 (28), 169 (27), 149
(22), 147 (100), 135 (32); HRMS for C13H22O4Si calcd 270.1287, found 270.1261.  The IR,
1H and 13C NMR data were identical to published spectral data.221
(EtO)3Si OCH3
Si(OEt)3
H3CO
89
4-(Triethoxysilyl)-1,2-(methylenedioxy)benzene (Table 3,
entry 5).  The general procedure for synthesis of siloxanes from
Grignard reagents was followed using 4-bromo-1,2-
(methylenedioxy)benzene (1.01 g, 602 ?L, 5.00 mmol), magnesium turnings (134 mg,
5.50 mmol), and tetraethyl orthosilicate (3.13 g, 3.35 mL, 15.0 mmol) in THF.  Bulb-to-bulb
distillation (125 ?C, 0.5 torr) afforded 1.00 g (74%) of 4-(triethoxysilyl)-1,2-
(methylenedioxy)benzene as a colorless oil.  IR (CCl4) 2976 (s), 2926 (m), 2886 (s),
1613 (w), 1503 (w), 1487 (m), 1422 (m), 1237 (m), 1168 (m), 1080 (s), 1045 (m)
cm-1; 1H (NMR) (CDCl3) ? 1.24 (t, J = 6.8, 9H), 3.85 (q, J = 6.8, 6H), 5.95 (s, 2H), 6.86 (d,
J = 7.6, 1H), 7.12 (s, 1H), 7.19 (d, J = 7.6, 1H); 13C (NMR) (CDCl3) ? 18.1, 59.9, 100.8,
108.8, 114.2, 123.9, 129.6, 147.6, 149.7; MS (m/z) 284 (100), 239 (39), 226 (28), 211
(10), 195 (14), 183 (25), 167 (18), 153 (13), 149 (24), 148 (14), 147 (75), 135 (12);
HRMS for C13H20O5Si calcd 284.1080, found 284.1083.
2-(Triethoxysilyl)toluene (Table 3, entry 6).  The general
procedure for synthesis of siloxanes from Grignard reagents was
followed using 2-bromotoluene (855 mg, 601 ?L, 5.00 mmol),
magnesium turnings (134 mg, 5.50 mmol), and tetraethyl orthosilicate (3.13 g, 3.35 mL,
15.0 mmol) in THF.  Bulb-to-bulb distillation (125 ?C, 0.5 torr) afforded 1.03 g (81%) of
2-(triethoxysilyl)toluene as a colorless oil.  IR (CCl4) 3054, 2971, 2922, 2881, 1442, 1393,
1283, 1162, 1079 cm-1; 1H NMR (CDCl3) ? 1.26 (t, J=7.0, 9H), 2.26 (s, 3H), 3.87 (q,
J=7.0, 6H), 7.17 (m, 2H), 7.32 (m, 1H), 7.74 (m, 1H); 13C NMR (CDCl3) ? 18.2, 22.4, 58.5,
124.7, 129.7, 129.9, 130.5, 136.5, 144.5, MS (m/z) 254 (48), 209 (44), 208 (19), 162 (55),
147 (100), 119 (51), 91 (50), 79 (15); HRMS for C13H22O3Si calcd 254.1349, found
254.1338.  The IR, 1H and 13C NMR data were identical to published spectral data.120
2-(Trimethoxysilyl)toluene (Table 3, entry 7).  The general
procedure for synthesis of siloxanes from Grignard reagents was
O
O
Si(OEt)3
Si(OEt)3
CH3
Si(OMe)3
CH3
90
followed using 2-bromotoluene (855 mg, 601 ?L, 5.00 mmol), magnesium turnings (134
mg, 5.50 mmol), and tetramethyl orthosilicate (2.28 g, 2.21 mL, 15.0 mmol) in THF.  Bulb-
to-bulb distillation (125 ?C, 0.5 torr) afforded 754 mg (71%) of 2-(trimethoxysilyl)toluene
as a colorless oil.  IR (neat) 3052 (w), 3008 (w), 2942 (s), 2840 (s), 1592 (m), 1471 (m),
1456 (m) cm -1; 1H NMR (CDCl3) ? 2.48 (s, 3H), 3.61 (s, 9H), 7.17 (m, 2H), 7.31 (m, 1H),
7.67 (d, J=7.5, 1H); 13C NMR (CDCl3) ? 22.2, 50.4, 124.7, 128.4, 129.7, 130.6, 136.3,
144.4; MS (m/z) 212 (61), 151 (16), 121 (100), 60 (73); HRMS for C10H16O3Si 212.0869,
found 212.0859.
3-(Triethoxysilyl)toluene (Table 3, entry 8).  The general
procedure for synthesis of siloxanes from Grignard reagents was
followed using 3-bromotoluene (855 mg, 607 ?L, 5.00 mmol),
magnesium turnings (134 mg, 5.50 mmol), and tetraethyl orthosilicate (3.13 g, 3.35 mL,
15.0 mmol) in THF.  Bulb-to-bulb distillation (125 ?C, 0.5 torr) afforded 954 mg (75%) of
3-(triethoxysilyl)toluene as a colorless oil.  IR (neat) 2975 (s), 2926 (s), 2885 (s), 1577
(w), 1480 (w), 1442 (m), 1390 (m), 1295 (w), 1225 (w), 1167 (s), 1104 (vs), 1079 (vs)
cm-1; 1H (NMR) (CDCl3) ? 1.25 (t, J = 7.2, 9H), 2.36 (s, 3H), 3.87 (q, J = 7.2, 6H), 7.23-
7.29 (m, 2H), 7.46-7.48 (m, 2H); 13C (NMR) (CDCl3) ? 18.4, 21.7, 58.9, 128.0, 130.8,
131.4, 132.0, 135.6, 137.4; MS (m/z) 254 (41), 239 (6), 209 (52), 195 (6), 162 (44), 147
(100), 119 (53), 91 (42), 66 (6); HRMS for C13H22O3Si calcd 254.1338, found 254.1331.
4-(Triethoxysilyl)toluene (Table 3, entry 9).  The general
procedure for synthesis of siloxanes from Grignard reagents
was followed using 4-bromotoluene (855 mg, 638 ?L, 5.00
mmol), magnesium turnings (134 mg, 5.50 mmol), and tetraethyl orthosilicate (3.13 g, 3.35
mL, 15.0 mmol) in THF.  Bulb-to-bulb distillation (125 ?C, 0.5 torr) afforded 1.09 g (86%) of
4-(triethoxysilyl)toluene as a colorless oil.  IR (CCl4) 2975 (s) , 2926 (m), 2885 (m),
1167(s), 1124 (vs), 1103 (vs), 1080 (vs) cm -1 ; 1H (NMR) (CDCl3) ? 1.24 (t, J = 7.0, 9
Si(OEt)3
H3C
H3C Si(OEt)3
91
H), 2.36 (s, 3 H), 3.86 (q, J = 7.0, 6 H), 7.19 (d, J = 7.9, 2 H), 7.57(d, J = 7.9, 2 H); 13C
(NMR) (CDCl3) ? 18.2, 21.5, 58.6, 127.4, 128.6, 134.8, 140.2; MS (m/z) 254 (23), 209
(38), 181 (5), 165 (16), 162 (30), 153 (19), 147 (100), 135 (17); HRMS for C13H22O3Si
calcd 254.1363, found 254.1338.  The IR, 1H and 13C NMR data were identical to
published spectral data.221
Triethoxyphenylsilane (Table 3, entry 10).  The general procedure
for synthesis of siloxanes from Grignard reagents was followed using
bromobenzene (785 mg, 527 ?L, 5.00 mmol), magnesium turnings (134 mg, 5.50 mmol),
and tetraethyl orthosilicate (3.13 g, 3.35 mL, 15.0 mmol) in THF.  Bulb-to-bulb distillation
(125 ?C, 0.5 torr) afforded 661 mg (55%) of triethoxyphenylsilane as a colorless oil.
Spectral data is reported above.  IR (CCl4) 3140 (w), 2976 (s), 2928 (m), 2941 (m), 1431
(m), 1391 (m), 1129 (s), 1102 (s), 1094 (s), 1080 (s) cm-1; 1H (NMR) (CDCl3) ? 1.25 (t, J
= 7.0, 9 H), 3.88 (q, J = 7.0, 6 H), 7.3-7.5 (m, 3 H), 7.6-7.8 (m, 2 H); 13C (NMR) (CDCl3) ?
18.1, 58.7, 127.8, 130.2, 131.1, 134.7; MS (m/z) 240 (16), 195 (38), 181 (13), 162 (28),
147 (100), 139 (33), 135 (33); HRMS for C12H20O3Si calcd 240.1182, found 240.1141.
The IR, 1H and 13C NMR data were identical to published spectral data.221
General Procedure for the Optimization of the Synthesis of 4-
(Triethoxysilyl)toluene (97) Using 4-Lithioanisole (96) (Table 4)  A solution of
n-BuLi (1.5 M in pentane, 3.33 mL, 5.00 mmol) was added dropwise (1 drop per second)
to a stirring solution of 4-bromotoluene (97) (855 mg,615 ?L, 5.00 mmol) in Et2O (15.0 mL)
at room temperature.  After 1 h, the solution was cooled to ?78 ?C and added via cannula
to a stirring solution of tetraethyl orthosilicate (1.5-3.0 equiv) and the internal standard
biphenyl (77 mg, 0.50 mmol) in Et2O (15.0 mL) at ?78 ?C.  Progress was monitored by
GC analysis of aliquots of the quenched reaction mixture.  GC response factors relative to
the internal naphthalene standard were determined, and the observed percentages of
products were normalized accordingly.  The reduced product toluene was identified by
Si(OEt)3
92
comparison of the GC retention time to that of an authentic sample.  Polyarylated products
were identified by GCMS.
Li Si(OEt)3
Si(OEt)4
Br
CH3 CH3 CH3
95 97
+ Ar2Si(OEt)2  +  Ar3Si(OEt)
98 99
n-BuLi
96
Conditionsa Yield (%)b,c
Entry Equiv Si(OEt)4 Solvent T (?C) 97 98 99
1 1.5 THF 0 7 25 54
2 1.5 THF -30 74 12 1
3 1.5 Et2O -30 77 6 0
4 1.5 THF -78 81 9 0
5 1.5 Et2O -78 82 5 1
6 3.0 Et2O -78 86 3 1
a Reactions of p-tolyl lithium 96 (1.0 equiv) with Si(OEt)
4 (1.5 to 3.0 equiv) wereallowed to stir at the given temperature; the reaction was complete in 1 h.  b GC
yields are based on amount of 4-bromotoluene (95).  c The remainder of the
product was toluene.
Table 4.  Optimization of the Synthesis of Arylsiloxanes Using 4-Lithiotoluene.
General Procedure for Synthesis of Siloxanes from Lithium Reagents Using
n-BuLi (Table 5).  Unless otherwise indicated, all reactions were performed on a 5 mmol
scale.  A solution of n-BuLi (1.6 M in pentane, 3.1 mL, 5.0 mmol) was added dropwise (1
drop per second) to a stirring solution of the aryl halide (5.00 mmol) in Et2O or THF (7.0
mL) at room temperature.  After 1 h, the solution was cooled to ?78 ?C and added via
cannula to a stirring solution of tetraethyl orthosilicate (1.56 g, 1.68 mL, 7.50 mmol) in Et2O
or THF (7.0 mL) at ?78 ?C.  After 1 h, the reaction was quenched with H2O (5 drops) at
?78 ?C and allowed to slowly warm to room temperature.  The crude reaction mixture was
then extracted with 3 x 50 mL Et2O.  The combined organic extracts were dried over
MgSO4, filtered, and concentrated in vacuo.  The residue was purified by either column
chromatography or by bulb-to-bulb distillation.
93
Li Si(OEt)3
R R
Si(OEt)4
Br
R
Et2O
-78 ?C
n-Bu Li
90 92100
Et2O
-78 ?C
Entry Aryl Siloxane (92) % Yielda,b Entry Aryl Siloxane (92) % Yielda,b
1 Si(OEt)3
CH3
79 7 H3CO Si(OEt)3 67
2 Si(OEt)3
H3C
71 8 Si(OEt)3MeS 50
3 H3C Si(OEt)3 85 9
O
O
Si(OEt)3
30c
4 Si(OEt)3 74 10
S
Si(OEt)3
50
5 Si(OEt)3
OCH3
60 11
O Si(OEt)3
22d
6 Si(OEt)3
H3CO
66 12
N Si(OEt)3
0
a Reactions of aryl lithium 100 (1.0 equiv) with Si(OEt)
4 (1.5 equiv) were allowed to stir at?78 ?C for 1 h in Et
2O.  
b Yields of 92 are after distillation or chromatography (purity
>95%).  c The major product was Ar2Si(OEt)2.  d G.C. analysis indicated a 2:1:1 ratio of
mono:di:tri arylalkoxysilanes.
Table 5.  Synthesis of Aryl(trialkoxy)silanes Using Lithium Reagents.
2-(Triethoxysilyl)toluene (Table 5, entry 1).  The general
procedure for synthesis of siloxanes from lithium reagents was
followed using n-BuLi (1.6 M in pentane, 3.1 mL, 5.0 mmol),
Si(OEt)3
CH3
94
2-bromotoluene (855 mg, 601 ?L, 5.00 mmol), and tetraethyl orthosilicate (1.56 g, 1.68 mL,
7.50 mmol) in Et2O.  Bulb-to-bulb distillation (125 ?C, 0.5 torr) afforded 1.00 g (79%) of
2-(triethoxysilyl)toluene as a colorless oil.  Spectral data is reported above.
3-(Triethoxysilyl)toluene (Table 5, entry 2).  The general
procedure for synthesis of siloxanes from lithium reagents was
followed using n-BuLi (1.6 M in pentane, 3.1 mL, 5.0 mmol),
3-bromotoluene (855 mg, 607 ?L, 5.00 mmol), and tetraethyl orthosilicate (1.56 g, 1.68 mL,
7.50 mmol) in Et2O.  Bulb-to-bulb distillation (125 ?C, 0.5 torr) afforded 903 mg (71%) of 3-
(triethoxysilyl)toluene as a colorless oil.  Spectral data is reported above.
4-(Triethoxysilyl)toluene (Table 5, entry 3).  The general
procedure for synthesis of siloxanes from lithium reagents was
followed using n-BuLi (1.6 M in pentane, 3.1 mL, 5.0 mmol), 4-bromotoluene (855 mg, 638
?L, 5.00 mmol), and tetraethyl orthosilicate (1.56 g, 1.68 mL, 7.50 mmol) in Et2O.  Bulb-to-
bulb distillation (125 ?C, 0.5 torr) afforded 1.08 g (81%) of 4-(triethoxysilyl)toluene as a
colorless oil.  Spectral data is reported above.
Triethoxyphenylsilane (Table 5, entry 4).  The general procedure
for synthesis of siloxanes from lithium reagents was followed using
n-BuLi (1.6 M in pentane, 3.1 mL, 5.0 mmol), bromobenzene (785 mg, 527 ?L, 5.00 mmol),
and tetraethyl orthosilicate (1.56 g, 1.68 mL, 7.50 mmol) in Et2O.  Bulb-to-bulb distillation
(125 ?C, 0.5 torr) afforded 889 mg (74%) of triethoxyphenylsilane as a colorless oil.
Spectral data is reported above.
2-(Triethoxysilyl)anisole (Table 5, entry 5).  The general
procedure for synthesis of siloxanes from lithium reagents was
followed using n-BuLi (1.6 M in pentane, 3.1 mL, 5.0 mmol),
Si(OEt)3
OCH3
Si(OEt)3
H3C
H3C Si(OEt)3
Si(OEt)3
95
2-bromoanisole (935 mg, 623 ?L, 5.00 mmol), and tetraethyl orthosilicate (1.56 g, 1.68 mL,
7.50 mmol) in Et2O.  Bulb-to-bulb distillation (125 ?C, 0.5 torr) afforded 811 mg (60%) of
2-(triethoxysilyl)anisole as a colorless oil.  Spectral data is reported above.
3-(Triethoxysilyl)anisole (Table 5, entry 6).  The general
procedure for synthesis of siloxanes from lithium reagents was
followed using n-BuLi (1.6 M in pentane, 3.1 mL, 5.0 mmol),
3-bromoanisole (935 mg, 633 ?L, 5.00 mmol), and tetraethyl orthosilicate (1.56 g, 1.68 mL,
7.50 mmol) in Et2O.  Bulb-to-bulb distillation (125 ?C, 0.5 torr) afforded 892 mg (66%) of
3-(triethoxysilyl)anisole as a colorless oil.  Spectral data is reported above.
4-(Triethoxysilyl)anisole (Table 5, entry 7).  The general
procedure for synthesis of siloxanes from lithium reagents was
followed using n-BuLi (1.6 M in pentane, 3.1 mL, 5.0 mmol),
4-bromoanisole (935 mg, 626 ?L, 5.00 mmol), and tetraethyl orthosilicate (1.56 g, 1.68 mL,
7.50 mmol) in Et2O.  Bulb-to-bulb distillation (125 ?C, 0.5 torr) afforded 906 mg (67%) of
4-(triethoxysilyl)anisole as a colorless oil.  Spectral data is reported above.
 4-(Triethoxysilyl)thioanisole (Table 5, entry 8).  The
following experiment was performed by Correia.228  The general
procedure for synthesis of siloxanes from lithium reagents was
followed using n-BuLi (1.6 M in pentane, 6.1 mL, 9.8 mmol), 4-bromothioanisole (1.99 g,
9.80 mmol), and tetraethyl orthosilicate (6.13 g, 6.56 mL, 29.4 mmol) in Et2O (20 mL).
Extraction and flash chromatography (30 mm, 15 cm, 33% CH2Cl2/hexanes) afforded 1.40
g (50%) of 4-(triethoxysilyl)thioanisole as a colorless oil.  TLC Rf = 0.25 (33%
CH2Cl2/hexanes); IR (CCl4) 2976 (m), 2925 (m), 1585 (m), 1487 (m), 1440 (m), 1103 (s),
1080 (s) cm-1; 1H NMR (CDCl3) ? 1.24 (t, J = 6.8, 9H), 2.48 (s, 3H), 3.86 (q, J = 6.8, 6H),
7.25 (d, J = 7.9, 2H), 7.58 (d, J = 7.9, 2H); 13C NMR (CDCl3) ? 15.0, 18.2, 58.7, 125.3,
Si(OEt)3
H3CO
(EtO)3Si OCH3
Si(OEt)3MeS
96
126.7, 135.1, 141.4; MS (m/z) 287 (M++1, 22), 286 (100), 241 (19), 227 (17), 195 (19),
147 (49), 124 (17), 119 (17); HRMS for C13H22O3SSi calcd 286.1059, found 286.1063.
4-(Triethoxysilyl)-1,2-(methylenedioxy)benzene (Table 5,
entry 9).  The general procedure for synthesis of siloxanes from
lithium reagents was followed using n-BuLi (1.6 M in pentane, 3.1
mL, 5.0 mmol), 4-bromo-1,2-(methylenedioxy)benzene (1.01 g, 602 ?L, 5.00 mmol), and
tetraethyl orthosilicate (1.56 g, 1.68 mL, 7.50 mmol) in Et2O.  Bulb-to-bulb distillation (125
?C, 0.5 torr) afforded 427 mg (30%) of 4-(triethoxysilyl)-1,2-(methylenedioxy)benzene as
a colorless oil.  Spectral data is reported above.
3-(Triethoxysilyl)thiophene (Table 5, entry 10).  The following
experiment was performed by Correia.228  The general procedure for
synthesis of siloxanes from lithium reagents was followed using n-BuLi
(1.6 M in pentane, 7.50 mL, 12.0 mmol), 3-bromothiophene (1.96 g, 1.12 mL, 12.0 mmol),
and tetraethyl orthosilicate (7.50 g, 8.05 mL, 36.0 mmol) in Et2O (20 mL).  Extraction and
flash chromatography (30 mm, 15 cm, 17% CH2Cl2/hexanes) gave 1.48 g (50%) of
3-(triethoxysilyl)thiophene as a colorless oil.  TLC Rf = 0.25 (17% CH2Cl2/hexanes); IR
(CCl4) 2975 (m), 2926 (m), 1553 (m), 1542 (m), 1103 (s), 1081 (s) cm-1; 1H NMR (CDCl3)
? 1.24 (t, J = 7.2, 9H), 3.87 (q, J = 7.2, 6H), 7.29 (d, J = 4.8, 1H), 7.40 (dd, J = 4.8, 2.0,
1H), 7.74 (d, J = 2.0, 1H); 13C NMR (CDCl3) ? 18.2, 58.7, 125.7, 131.7, 131.8, 135.5; MS
(m/z) 247 (M++1, 17), 246 (100), 202 (30), 201 (46), 158 (51), 145 (30), 135 (73); HRMS
for C10H18O3SSi calcd 246.0746, found 246.0743.
2-furyltriethoxysilane (Table 5, entry 11).  The following experiment
was performed by Ahn.228  A solution of t-BuLi (1.50 M in pentane,
16.00 mL, 24.00 mmol) was added dropwise (1 drop per second) to a
O
O
Si(OEt)3
O Si(OEt)3
S
Si(OEt)3
97
stirring solution of the furan (1.36 g, 1.46 mL, 20.0 mmol) and TMEDA (2.32 g, 3.02 mL,
20.0 mmol) in Et2O (40.0 mL) at 0 ?C.  After 2 h, the solution was cooled to ?78 ?C and
tetraethyl orthosilicate (6.25 g, 6.69 mL, 30.0 mmol) was added dropwise (1 drop per
second).  After 1 h, the reaction was quenched with H2O (1 mL) at ?78 ?C and allowed to
slowly warm to room temperature.  The crude reaction mixture was then extracted with 2 x
200 mL Et2O.  The combined organic extracts were dried over MgSO4, filtered, and
concentrated in vacuo.  Purification of the residue by flash chromatography (30 mm, 15 cm,
10% EtOAc/hexanes) gave 1.01 g (22%) of 2-furyltriethoxysilane as a colorless oil.  TLC
Rf = 0.71 (10% EtOAc/hexane); IR (CCl4) 2974 (s), 2926 (s), 2891 (s), 1455 (m), 1390
(m), 1169 (s), 1100 (s), 1079 (s), 965 (m); 1H (NMR) (CDCl3) ? 1.23 (t, J = 7.0, 9H), 3.87
(q, J = 7.0, 6H), 6.39 (dd, J = 1.3, 3.3, 1H), 6.87 (d, J = 3.3, 1H), 7.65 (d, J = 1.3, 1H);
13C (NMR) (CDCl
3) ? 18.1, 59.0, 109.3, 123.2, 147.4, 151.3; MS (m/z) 231 (M
++1, 5), 230
(M+, 28), 215 (100), 203 (14), 185 (28), 147 (80), 119 (52), 113 (55), 79 (47), 63 (27);
HRMS for C10H18O4Si calcd 230.0979, found 230.0974.
5-Triethoxysilyl-2-methoxypyridine (102).  The following
experiment was performed by Handy.111  The general procedure
for synthesis of siloxanes from lithium reagents was followed
using n-BuLi (1.4 M in pentane, 6.5 mL, 8.8 mmol), 5-bromo-2-methoxypyridine (101)
(1.66 g, 1.14 mL, 8.83 mmol), and tetraethyl orthosilicate (2.76 g, 2.95 mL, 13.3 mmol) in
Et2O (20 mL).  Extraction and flash chromatography (9:1 hexanes/EtOAc) afforded 527
mg (22%) of 102 as a colorless oil.  TLC Rf =0.28 (9:1 hexanes/EtOAc); IR (CCl4) 2976
(s), 2927 (m), 2887 (m), 1589 (s), 1491 (w), 1442 (m), 1390 (w), 1356 (m), 1286 (s),
1082 (vs) cm-1; 1H (NMR) (CD3CN) ? 1.20 (t, J = 7.0, 9H), 3.83 (q, J = 7.0, 6H), 3.87 (s,
3H), 6.73-6.75 (m, 1H), 7.76-7.78 (m, 1H), 8.32-8.35 (m, 1H); 13C (NMR) (CD3CN) ? 18.6,
53.9, 59.5, 111.5, 130.8, 118.2, 145.5, 154.3, 166.5; MS (m/z) 272 (100), 240 (13), 226
(31), 170 (11), 163 (11), 136 (15), 119 (6), 91 (5), 79 (14); HRMS for C12H22ONSi calcd
272.1318, found 272.1311.
N
Si(OEt)3
MeO
98
5-(Triethoxysilyl)indole (110).  The following experiment was
performed by Handy.111  To a solution of KH (35% dispersion in
mineral oil, 292 mg, 2.55 mmol) in THF (5.0 mL) was added
dropwise (1 drop per second) a solution of 5-bromoindole (498 mg, 2.54 mmol) in THF
(5.0 mL).  The reaction mixture was stirred for 15 min then cooled to ?78 ?C.  A solution of
t-BuLi (1.7 M in pentane, 3.0 mL, 5.0 mmol) was then added via cannula.  A white
precipitate immediately formed.  The mixture was stirred for 10 min, followed by dropwise
(1 drop per second) addition of a solution of tetraethyl orthosilicate (1.06 g, 1.13 mL, 5.08
mmol) in THF (2 mL).  The reaction mixture was stirred for 30 min at -78 ?C, and then
allowed to slowly warm to room temperature.  The reaction mixture was poured into 10 mL
ice water, then extracted with ether (3 ? 15 mL).  The combined organic extracts were
dried over MgSO4, then concentrated in vacuo.  Column chromatography (4:1
hexanes/EtOAc) afforded 497 mg (70%) of 110 as a pale yellow oil; TLC Rf =0.32 (4:1
hexanes/EtOAc); IR (CCl4) 3489 (s), 2976 (s), 2926 (m), 1885 (m) cm-1; 1H NMR (CDCl3)
? 8.38 (br s, 1H), 8.03 (s, 1H), 7.48 (d, J=8.1 Hz, 1H), 7.39 (d, J=8.1 Hz, 1H), 7.16 (t,
J=2.6 Hz, 1H), 6.56 (s, 1H), 3.89 (q, J=7.0, 6H), 1.26 (t, J=7.0, 9H); 13C NMR (CDCl3) ?
137.2, 128.5, 127.7, 127.6, 124.2, 120.0, 110.9, 102.7. 58.6, 18.2; MS (m/z) 280 (70), 234
(42), 206 (14), 190 (21), 163 (100), 144 (78), 117 (58); HRMS for C14H21NO3Si calcd
280.1369, found 280.1381.
5-(Triethoxysilyl)-1-methyl-indole (111).  The following
experiment was performed by Correia.228  A solution of t-BuLi (1.50
M in pentane, 3.76 mL, 5.64 mmol) was added dropwise (1 drop
per second) to a stirring solution of 5-bromo-1-methylindole (987 mg, 4.70 mmol) in Et2O
(10.0 mL) at -78 ?C.  After 15 min, the solution was added dropwise (1 drop per second)
via cannula to a solution of tetraethyl orthosilicate (6.25 g, 6.69 mL, 30.0 mmol) in 5 mL of
Et2O cooled to ?78 ?C.  After 1 h, the reaction was allowed to slowly warm to room
temperature.  The reaction mixture was quenched by the addition of 50 mL of water.  The
N
Me
Si(OEt)3
NH
Si(OEt)3
99
crude reaction mixture was then extracted with 4 x 50 mL Et2O.  The combined organic
extracts were dried over Na2SO4, filtered, and concentrated in vacuo.  Purification of the
residue by flash chromatography (30 mm, 15 cm, 33% CH2Cl2/hexane) gave 840 mg
(60%) of 111 as a yellow oil.  TLC Rf = 0.37 (33% CH2Cl2/hexane); IR (CCl4) 2975 (s),
2923 (m), 2882 (m), 1611 (m), 1556 (s), 1518 (m), 1480 (m), 1104 (s), 1080 (s) cm-1; 1H
NMR (CDCl3) ? 1.25 (t, J = 7.2, 9H), 3.79 (s, 3H), 3.88 (q, J = 7.2, 6H), 6.52 (d, J = 2.8,
1H), 7.05 (d, J = 2.8, 1H), 7.36 (d, J = 7.9, 1H), 7.52 (d, J = 7.9, 1H), 8.00 (s, 1H); 13C
NMR (CDCl3) ? 18.2, 32.6, 58.5, 101.3, 108.9, 119.4, 127.3, 128.2, 128.6, 128.8, 137.9;
MS (m/z) 294 (M++1, 29), 293 (M+, 100), 278 (10), 131 (23).  HRMS for C15H23NO3Si
calcd 293.1447, found 293.1439.
General Procedure for the Optimization of the Silylation of 4-Bromoanisole (86)
(Table 6).  All siloxanes were synthesized using modifications of the procedure reported
by Masuda.221  4-Bromoanisole (86)(187 mg, 125 ?L, 1.00 mmol, 1.0 equiv), and base
(3.00 mmol, 3.0 equiv) were added to a stirring solution of Pd(dba)2 (29 mg, 0.05 mmol, 5
mol %), the phosphine (0.10 mmol, 10 mol%), and the internal standard naphthalene (128
mg, 1.0 mmol, 1.0 equiv) in 4 mL of solvent under an atmosphere of argon.
Triethoxysilane (246 mg, 277 ?L, 1.50 mmol, 1.5 equiv) was added, causing bubbling,
formation of yellow foam, and darkening of the reaction mixture.  The reaction mixture was
allowed to stir at room temperature for 12 h.  Progress was monitored by GC analysis of
aliquots of the quenched reaction mixture.  GC response factors relative to the internal
naphthalene standard were determined, and the observed percentages of products were
normalized accordingly.  The reduced product anisole 119 was identified by comparison of
the GC retention time to that of an authentic sample.
100
Br
OCH3
H Si(OEt)3
Si(OEt)3
OCH3
H
OCH3
+ +
Pd(dba)2
ligand
base
solvent
86 118 119
Conditionsa Yield (%)b,c
Ligand Base Solvent
Entry (10 mol %) (3 mmol) (4 mL) 118 119
1 P(o-tol)3 i-Pr2NEt NMP 21 79
2 P(o-tol)3 i-Pr2NEt DMF 15 70
3 none i-Pr2NEt DMF 14 86
4 PPh3 i-Pr2NEt DMF 0 5
5 dppf i-Pr2NEt NMP 0 8
6 P(t-Bu)3 i-Pr2NEt NMP 59 41
7 P(t-Bu)3 i-Pr2NEt DMF 45 55
8 P[(2,4,6-OMe)Ph]3 i-Pr2NEt NMP 8 92
9 P(cy)2(o-biphenyl) i-Pr2NEt NMP 17 83
10 P(t-Bu)2(o-biphenyl) i-Pr2NEt NMP 75 25
11 P(t-Bu)2(o-biphenyl) i-Pr2NEt DMF 36 64
12 P(t-Bu)2(o-biphenyl) i-Pr2NEt THF 6 54
13 P(t-Bu)2(o-biphenyl) i-Pr2NEt CH3CN 6 93
14 P(t-Bu)2(o-biphenyl) i-Pr2NEt toluene 3 19
15 P(t-Bu)2(o-biphenyl) none NMP 0 4
16 P(t-Bu)2(o-biphenyl) Et3N NMP 55 45
17 P(t-Bu)2(o-biphenyl) pyridine NMP 0 5
18 P(t-Bu)2(o-biphenyl) 2,6-lutidine NMP 32 26
19 P(t-Bu)2(o-biphenyl) DBU NMP 0 57
20 P(t-Bu)2(o-biphenyl) KOAc NMP 22 78
21 P(t-Bu)2(o-biphenyl) Cs2CO3 NMP 3 97
a Reactions of 4-bromoanisole (86) (1.0 equiv) with H-Si(OEt)
3 (1.5 equiv) wereallowed to stir at room temperature for 12 h in 4 mL of solvent by using Pd(dba)
2 (5 mol%), phosphine (10 mol %), and base (3.0 equiv).  b GC yields are based on amount of
4-bromoanisole.  c Remaining percentage was unreacted starting material.
Table 6.  Optimization of the Silylation of 4-Bromoanisole.
General Procedure for the Silylation of Aryl Halides (Tables 7-10)  All siloxanes
were synthesized using a modification of the procedure reported by Masuda.221  The
indicated aryl halide (5.00 mmol, 1.0 equiv), and i-Pr2NEt (1.94 g, 2.61 mL, 15.0 mmol, 3.0
equiv) were added to a stirring solution of Pd(dba)2 (86 mg, 0.15 mmol, 3 mol %), and
101
P(t-Bu)2(o-biphenyl) (120) (90 mg, 0.30 mmol, 6 mol%) in 20 mL of NMP under an
atmosphere of argon.  Triethoxysilane (1.23 g, 1.38 mL, 7.50 mmol, 1.5 equiv) was added,
causing bubbling, formation of yellow foam, and darkening of the reaction mixture.  Unless
otherwise noted, the reaction was performed at the given temperature until GC analysis
indicated that the starting material had been consumed.  The reaction mixture was
extracted with 5 x 100 mL pentane, without the addition of water or aqueous solutions,
which led to intractable emulsions and potential polymerization; note that NMP and
pentane are immiscible.  The combined pentane extracts were washed with 3 x 100 mL
water to remove NMP, dried over MgSO4, filtered, and concentrated in vacuo.  Purification
of the residue by bulb-to-bulb distillation yielded the siloxane.
4-(Triethoxysilyl)anisole (Table 7, entry 1).  The general
procedure for silylation was followed using 4-bromoanisole
(935 mg, 626 ?L, 5.00 mmol), i-Pr2NEt (1.94 g, 2.61 mL, 15.0
mmol), Pd(dba)2 (86 mg, 0.15 mmol), P(t-Bu)2(o-biphenyl) (120) (90 mg, 0.30 mmol), and
triethoxysilane (1.23 g, 1.38 mL, 7.50 mmol) in 20 mL of NMP.  The reaction was heated at
60 ?C for 12h.  Bulb-to-bulb distillation (125 ?C, 0.5 torr) afforded 919 mg (68 %) of
4-(triethoxysilyl)anisole as a colorless oil.  Spectral data is reported above.
4-(Triethoxysilyl)toluene (Table 7, entry 2).  The general
procedure for silylation was followed using 4-bromotoluene (855
mg, 638 ?L, 5.00 mmol), i-Pr2NEt (1.94 g, 2.61 mL, 15.0 mmol),
Pd(dba)2 (86 mg, 0.15 mmol), P(t-Bu)2(o-biphenyl) (120) (90 mg, 0.30 mmol), and
triethoxysilane (1.23 g, 1.38 mL, 7.50 mmol) in 20 mL of NMP.  The reaction was heated at
60 ?C for 12 h.  Bulb-to-bulb distillation (125 ?C, 0.5 torr) afforded 547 mg (43%) of
4-(triethoxysilyl)toluene as a colorless oil.  Spectral data is reported above.
(EtO)3Si OCH3
(EtO)3Si CH3
102
Br
H Si(OEt)3
Si(OEt)3 H
R R R
+ +Pd(dba)2
P(t-Bu)2(o-biphenyl)(120)
i-Pr2NEt
NMP
90 92 121
Entry Aryl Bromide
(90)
% Yielda-c
(92)
Entry Aryl Bromide
(90)
% Yielda-c
(92)
1 Br OCH3 68 6 Br OAc 30
2 Br CH3 43 7 Br OH 28d,e
3
O
O
Br
44 8 Br 5
4 Br NHAc 33 9 Br
O
0
5 Br NH2 38d,e 10 Br Cl 0
a Reactions of arylbromide (90) (1.0 equiv) with H-Si(OEt)
3 (1.5 equiv) wereallowed to stir at 60 ?C for 12 h in NMP by using 3 mol % Pd(dba)
2,(t-Bu)
2P(o-biphenyl)(120) (6 mol %), and i-Pr2NEt (3 equiv).  
b Isolated yield of
purified (>95%) product.  c Unless otherwise indicated, remaining percentage
was reduced starting material (121).  d Reaction allowed to stir at room
temperature.  e Reaction stopped at 2 h.
Table 7.  Silylation of Aryl Bromides.
4-(Triethoxysilyl)-1,2-(methylenedioxy)benzene (Table 7,
entry 3).  The general procedure for silylation was followed using
4-(triethoxysilyl)-1,2-(methylenedioxy)benzene (1.01 g, 602 ?L,
5.00 mmol), i-Pr2NEt (1.94 g, 2.61 mL, 15.0 mmol), Pd(dba)2 (86 mg, 0.15 mmol),
P(t-Bu)2(o-biphenyl) (120) (90 mg, 0.30 mmol), and triethoxysilane (1.23 g, 1.38 mL, 7.50
mmol) in 20 mL of NMP.  The reaction was heated at 60 ?C for 12 h.  Bulb-to-bulb
distillation (125 ?C, 0.5 torr) afforded 626 mg (44%) of
O
O
Si(OEt)3
103
4-(triethoxysilyl)-1,2-(methylenedioxy)benzene as a colorless oil.  Spectral data is
reported above.
4-(Triethoxysilyl)acetanilide (Table 7, entry 4).  The
general procedure for silylation was followed using
4-bromoacetanilide (1.07 g, 5.00 mmol), i-Pr2NEt (1.94 g, 2.61
mL, 15.0 mmol), Pd(dba)2 (86 mg, 0.15 mmol), P(t-Bu)2(o-biphenyl) (120) (90 mg, 0.30
mmol), and triethoxysilane (1.23 g, 1.38 mL, 7.50 mmol) in 20 mL of NMP.  The reaction
was heated at 60 ?C for 12 h.  Bulb-to-bulb distillation (125 ?C, 0.5 torr) afforded 491 mg
(33%) 4-(triethoxysilyl)acetanilide as a colorless oil.  IR (neat) 3307 (br), 2975 (s), 1670
(s), 1593 (s), 1524 (s), 1392 (s), 1318 (s), 1291 (s), 1166 (s), 1072 (vs) cm-1; 1H (NMR)
(CDCl3) ? 1.24 (t, J = 6.8, 9 H), 2.18 (s, 3 H), 3.85 (q, J = 6.8, 6 H), 7.52 (d, J = 8.3, 2 H),
7.64 (d, J = 8.3, 2 H); 13C (NMR) (CDCl3) ? 18.2, 24.5, 58.7, 119.1, 128.6, 135.7, 140.1,
169.0; MS (m/z) 297 (10), 252 (68), 205 (100), 176 (31), 162 (15), 147 (48); HRMS for
C14H23O4NSi calcd 297.1396, found 297.1399.  The IR, 1H and 13C NMR data were
identical to published spectral data.221
4-(Triethoxysilyl)aniline (Table 7, entry 5).  The general
procedure for silylation was followed using 4-bromoaniline (860
mg, 573 ?L, 5.00 mmol), i-Pr2NEt (1.94 g, 2.61 mL, 15.0 mmol),
Pd(dba)2 (86 mg, 0.15 mmol), P(t-Bu)2(o-biphenyl) (120) (90 mg, 0.30 mmol), and
triethoxysilane (1.23 g, 1.38 mL, 7.50 mmol) in 20 mL of NMP.  The reaction was stirred at
25 ?C for 2 h.  Bulb-to-bulb distillation (125 ?C, 0.5 torr) afforded 485 mg (38%) of
4-(triethoxysilyl)aniline as a colorless oil.  IR (neat) 3469 (m), 3372 (s), 3223 (w), 2974
(s), 2926 (s), 2885 (s), 1624 (s), 1601 (s), 1509 (m), 1390 (m), 1295 (m), 1166 (s), 1074
(vs) cm-1; 1H (NMR) (CDCl3) ? 1.23 (t, J = 7.0, 9H), 3.79 (s, 2H), 3.84 (q, J = 7.0, 6H),
6.67 (d, J = 8.3, 2H), 7.46 (d, J = 8.3, 2H); 13C (NMR) (CDCl3) ? 18.3, 28.6, 114.4, 118.4,
(EtO)3Si NHAc
(EtO)3Si NH2
104
(EtO)3Si OAc
136.3, 148.6; MS (m/z) 255 (100), 210 (48), 153 (11), 147 (34), 136 (9), 135 (3); HRMS
for C12H21O3NSi calcd 255.1291, found 255.1292.
4-Acetoxy(triethoxysilyl)benzene (Table 7, entry 6).  The
general procedure for silylation was followed using
4-acetoxybromobenzene (1.01 g, 5.00 mmol), i-Pr2NEt (1.94 g,
2.61 mL, 15.0 mmol), Pd(dba)2 (86 mg, 0.15 mmol), P(t-Bu)2(o-biphenyl) (120) (90 mg,
0.30 mmol), and triethoxysilane (1.23 g, 1.38 mL, 7.50 mmol) in 20 mL of NMP.  The
reaction was heated at 60 ?C for 12 h.  Bulb-to-bulb distillation (125 ?C, 0.5 torr) afforded
448 mg (30%) of 4-acetoxy(triethoxysilyl)benzene as a colorless oil following purification.
IR (neat) 2976 (s), 2887 (s), 1767 (s), 1593 (m), 1499 (w), 1392 (m) cm-1; 1H (NMR)
(CDCl3) ? 1.22 (t, J = 6.8, 9 H), 2.28 (s, 3 H), 3.84 (q, J = 6.8, 6 H), 7.09 (d, J = 8.3, 2 H),
7.67 (d, J = 8.3, 2 H); 13C (NMR) (CDCl3) ? 18.1, 21.0, 58.7, 121.0, 128.6, 136.1, 152.5,
169.0; MS (m/z) 298 (3), 256 (100), 210 (51), 183 (17), 155 (27), 147 (62); HRMS for
C14H22O5Si calcd 298.1237, found 298.1238.  The IR, 1H and 13C NMR data were identical
to published spectral data.221
4-(Triethoxysilyl)phenol (Table 7, entry 7).  The general
procedure for silylation was followed using 4-bromophenol (865
mg, 5.00 mmol), i-Pr2NEt (1.94 g, 2.61 mL, 15.0 mmol), Pd(dba)2
(86 mg, 0.15 mmol), P(t-Bu)2(o-biphenyl) (120) (90 mg, 0.30 mmol), and triethoxysilane
(1.23 g, 1.38 mL, 7.50 mmol) in 20 mL of NMP.  The reaction was stirred at 25 ?C for 2 h.
Bulb-to-bulb distillation (125 ?C, 0.5 torr) afforded 359 mg (28%) of
4-(triethoxysilyl)phenol as a colorless oil following purification.  IR (CCl4) 3606 (s), 3356
(vs), 2976 (s), 2926 (s), 2885 (s), 1602 (m), 1582 (w), 1506 (m), 1390 (w), 1261 (w),
1167 (m), 1125 (s), 1107 (s), 1080 (s) cm-1; 1H (NMR) (CDCl3) ? 1.24 (t, J = 7.2, 9H),
3.87 (q, J = 7.2, 6H), 6.23 (s, 1H), 6.85 (d, J = 8.3, 2H), 7.55 (d, J = 8.3, 2H); 13C (NMR)
(CDCl3) ? 18.3, 59.0, 115.4, 121.2, 137.0, 158.1; MS (m/z) 256 (100), 241 (13), 220 (12),
(EtO)3Si OH
105
211 (43), 210 (40), 183 (13), 167 (11), 163 (17), 155 (14), 147 (55), 119 (18); HRMS for
C12H20O4Si calcd 256.1131, found 256.1135.
Triethoxyphenylsilane (Table 7, entry 8).  The general procedure
for silylation was followed using bromobenzene (785 mg, 527 ?L, 5.00
mmol), i-Pr2NEt (1.94 g, 2.61 mL, 15.0 mmol), Pd(dba)2 (86 mg, 0.15
mmol), P(t-Bu)2(o-biphenyl) (120) (90 mg, 0.30 mmol), and triethoxysilane (1.23 g, 1.38
mL, 7.50 mmol) in 20 mL of NMP.  The reaction was heated at 60 ?C for 12 h.  Bulb-to-
bulb distillation (125 ?C, 0.5 torr) afforded 60 mg (5%) of triethoxyphenylsilane as a
colorless oil following purification.  Spectral data is reported above.
H Si(OEt)3Ar-Br Ar-Si(OEt)3 Ar-H+
Pd(dba)2
P(t-Bu)2(o-biphenyl)(120)
i-Pr2NEt
NMP122 123 124
+
Entry Heteroaryl Bromide
(122)
% Yielda-c
(123)
Entry Heteroaryl Bromide
(122)
% Yielda-c
(123)
1
S Br
43 4
N Br
0
2
N Br
0d 5
N
Br
0
3
N
Br
0 6
N
Br
MeO
57
a Reactions of heteroarylbromide (122) (1.0 equiv) with H-Si(OEt)
3 (1.5 equiv)
were allowed to stir at 60 ?C for 12 h in NMP by using 3 mol % Pd(dba)2,
(t-Bu)2P(o-biphenyl)(120) (6 mol %), and i-Pr2NEt (3 equiv).  b Isolated yield of
purified (>95%) product.  c Unless otherwise noted, the remaining percentage was
reduced starting material (124).  d Trace amounts of 2,2?-dipyridyl were observed
by G.C. analysis.
Table 8.  Silylation of Heteroaryl Bromides.
(EtO)3Si
106
2-(Triethoxysilyl)thiophene (Table 8, entry 1).  The general
procedure for silylation was followed using 2-bromothiophene (815 mg,
484 ?L, 5.00 mmol), i-Pr2NEt (1.94 g, 2.61 mL, 15.0 mmol), Pd(dba)2 (86
mg, 0.15 mmol), P(t-Bu)2(o-biphenyl) (120) (90 mg, 0.30 mmol), and triethoxysilane (1.23
g, 1.38 mL, 7.50 mmol) in 20 mL of NMP.  The reaction was heated at 60 ?C for 12 h.
Bulb-to-bulb distillation (125 ?C, 0.5 torr) afforded 530 mg (43%) of
2-(triethoxysilyl)thiophene as a colorless oil.  IR (neat) 2976 (s), 2888 (s), 1695 (w), 1501
(w), 1442 (s), 1407 (s), 1391(m), 1296 (m), 1216 (m), 1167 (s) cm-1; 1H (NMR) (CDCl3)
?1.25 (t, J = 7.0, 9 H), 3.90 (q, J = 7.0, 6 H), 7.22 (dd, J = 3.3, 4.5, 1 H), 7.48 (d, J = 3.3,
1 H), 7.66 (d, J = 4.5, 1 H); 13C (NMR) (CDCl3) ? 19.4, 60.3, 129.4, 130.6, 133.2, 138.1;
MS (m/z) 246 (52), 213 (6), 201 (34), 187 (7), 167 (7), 158 (13), 147 (100), 135 (34);
HRMS for C10H18O3SiS calcd 246.0765, found 246.0746.  The IR, 1H and 13C NMR data
were identical to published spectral data.221
5-(Triethoxysilyl)-2-methoxypyridine (102) (Table 8, entry
6).  The general procedure for silylation was followed using
5-bromo-2-methoxypyridine (940 mg, 647 ?L, 5.00 mmol), i-
Pr2NEt (1.94 g, 2.61 mL, 15.0 mmol), Pd(dba)2 (86 mg, 0.15 mmol), P(t-Bu)2(o-biphenyl)
(120) (90 mg, 0.30 mmol), and triethoxysilane (1.23 g, 1.38 mL, 7.50 mmol) in 20 mL of
NMP.  The reaction was heated at 60 ?C for 12 h.  Bulb-to-bulb distillation (125 ?C, 0.5
torr) afforded 773 mg (57%) of 5-(triethoxysilyl)-2-methoxypyridine as a colorless oil
following purification.  Spectral data is reported above.
N
Si(OEt)3
H3CO
S Si(OEt)3
107
Br
H Si(OEt)3
Si(OEt)3 H
R R R
+ +Pd(dba)2
P(t-Bu)2(o-biphenyl)(120)
i-Pr2NEt
NMP
90 92 121
Entry Aryl Bromide (90) % Yield (92)a-c Entry Aryl Bromide (90) % Yield (92)a-c
1 Br OCH3 68 4 Br CH3 43
2 Br
OCH3
25 5 Br
CH3
10
3 Br
H3CO
0 6 Br
H3C
0
a Reactions of arylbromide (90) (1.0 equiv) with H-Si(OEt)
3 (1.5 equiv) were
allowed to stir at 60 ?C for 12 h in NMP using 3 mol % Pd(dba)2,
(t-Bu)2P(o-biphenyl) (120) (6 mol %), and i-Pr2NEt (3 equiv).  b Yields are isolated
yields of purified (>95%) product.  c Remaining yield was of reduced starting
material (121).
Table 9.  Silylation of Aryl Bromides: Effect of Substituent Position.
3-(Triethoxysilyl)anisole (Table 9, entry 2).  The general
procedure for silylation was followed using 3-bromoanisole (935
mg, 633 ?L, 5.00 mmol), i-Pr2NEt (1.94 g, 2.61 mL, 15.0 mmol),
Pd(dba)2 (86 mg, 0.15 mmol), P(t-Bu)2(o-biphenyl) (120) (90 mg, 0.30 mmol), and
triethoxysilane (1.23 g, 1.38 mL, 7.50 mmol) in 20 mL of NMP.  The reaction was heated at
60 ?C for 12 h.  Bulb-to-bulb distillation (125 ?C, 0.5 torr) afforded 338 mg (25%) of
3-(triethoxysilyl)anisole as a colorless oil.  Spectral data is reported above.
3-(Triethoxysilyl)toluene (Table 3, entry 5).  The general
procedure for silylation was followed using 3-bromotoluene (855 mg,
607 ?L, 5.00 mmol), i-Pr2NEt (1.94 g, 2.61 mL, 15.0 mmol), Pd(dba)2
(86 mg, 0.15 mmol), P(t-Bu)2(o-biphenyl) (120) (90 mg, 0.30 mmol), and triethoxysilane
(EtO)3Si
OCH3
(EtO)3Si
CH3
108
(1.23 g, 1.38 mL, 7.50 mmol) in 20 mL of NMP.  The reaction was heated at 60 ?C for 12 h.
Bulb-to-bulb distillation (125 ?C, 0.5 torr) afforded 127 mg (10%) of
3-(triethoxysilyl)toluene as a colorless oil.  Spectral data is reported above.
H Si(OEt)3Ar-I Ar-Si(OEt)3 Ar-H+
Pd(dba)2
P(t-Bu)2(o-biphenyl)(120)
i-Pr2NEt
NMP128 123 124
+
Entry Aryl Iodide (128) % Yield (123)a-c Entry Aryl Iodide (128) % Yield (123)a-c
1 I OCH3 86 10 I NHAc 68e
2
I
OCH3
52 11 I NH2 77e
3 I
H3CO
10 12 I OAc 75e
4 I CH3 80 13 I OH 70d
6
I
CH3
65 14 I
O
24
7
I
H3C
0d 15
N I
0d,g
8 I Br 68e,f 16
N
I
10
9 I Cl 75e 17
S I
92
a Reactions of aryliodide (128) (1.0 equiv) with H-Si(OEt)
3 (1.5 equiv) were allowed to stirat 60 ?C for 12 h in NMP using Pd(dba)
2 (3 mol %), (t-Bu)2P(o-biphenyl) (120) (6 mol %),and i-Pr
2NEt (3 equiv).  
b Yields shown in parentheses are GC yields; all other yields are
isolated yields of purified (>95%) product.  c Unless noted otherwise, the remaining
percentage was of reduced starting material (124).  d Yield confirmed by GCMS.
e Reaction allowed to stir at room temperature.  f Reaction stopped at 2 h.  g Dipyridyl was
isolated in 15% yield.
Table 10.  Palladium-Catalyzed Silylation of Aryl Iodides.
109
4-(Triethoxysilyl)anisole (Table 10, entry 1).  The general
procedure for silylation was followed using 4-iodoanisole (1.17
g, 5.00 mmol), i-Pr2NEt (1.94 g, 2.61 mL, 15.0 mmol), Pd(dba)2 (86 mg, 0.15 mmol),
P(t-Bu)2(o-biphenyl) (120) (90 mg, 0.30 mmol), and triethoxysilane (1.23 g, 1.38 mL, 7.50
mmol) in 20 mL of NMP.  The reaction was heated at 60 ?C for 12 h.  Bulb-to-bulb
distillation (125 ?C, 0.5 torr) afforded 1.16 g (86%) of 4-(triethoxysilyl)anisole as a
colorless oil.  Spectral data is reported above.
3-(Triethoxysilyl)anisole (Table 10, entry 2).  The general
procedure for silylation was followed using 3-iodoanisole (1.17 g,
596 ?L, 5.00 mmol), i-Pr2NEt (1.94 g, 2.61 mL, 15.0 mmol),
Pd(dba)2 (86 mg, 0.15 mmol), P(t-Bu)2(o-biphenyl) (120) (90 mg, 0.30 mmol), and
triethoxysilane (1.23 g, 1.38 mL, 7.50 mmol) in 20 mL of NMP.  The reaction was heated at
60 ?C for 12 h.  Bulb-to-bulb distillation (125 ?C, 0.5 torr) afforded 703 mg (52%) of
3-(triethoxysilyl)anisole as a colorless oil.  Spectral data is reported above.
2-(Triethoxysilyl)anisole (Table 10, entry 3).  The general
procedure for silylation was followed using 2-iodoanisole (1.17 g, 650
?L, 5.00 mmol), i-Pr2NEt (1.94 g, 2.61 mL, 15.0 mmol), Pd(dba)2 (86 mg,
0.15 mmol), P(t-Bu)2(o-biphenyl) (120) (90 mg, 0.30 mmol), and triethoxysilane (1.23 g,
1.38 mL, 7.50 mmol) in 20 mL of NMP.  The reaction was heated at 60 ?C for 12 h.  Bulb-
to-bulb distillation (125 ?C, 0.5 torr) afforded 135 mg (10%) of 2-(triethoxysilyl)anisole as
a colorless oil.  Spectral data is reported above.
4-(Triethoxysilyl)toluene (Table 10, entry 4).  The general
procedure for silylation was followed using 4-iodotoluene (1.09
g, 5.00 mmol), i-Pr2NEt (1.94 g, 2.61 mL, 15.0 mmol), Pd(dba)2
(86 mg, 0.15 mmol), P(t-Bu)2(o-biphenyl) (120) (90 mg, 0.30 mmol), and triethoxysilane
(1.23 g, 1.38 mL, 7.50 mmol) in 20 mL of NMP.  The reaction was heated at 60 ?C for 12 h.
(EtO)3Si
H3CO
(EtO)3Si OCH3
(EtO)3Si
OCH3
(EtO)3Si CH3
110
Bulb-to-bulb distillation (125 ?C, 0.5 torr) afforded 1.02 g (80%) of
4-(triethoxysilyl)toluene as a colorless oil.  Spectral data is reported above.
3-(Triethoxysilyl)toluene (Table 10, entry 6).  The general
procedure for silylation was followed using 3-iodotoluene (1.09 g,
642 ?L, 5.00 mmol), i-Pr2NEt (1.94 g, 2.61 mL, 15.0 mmol),
Pd(dba)2 (86 mg, 0.15 mmol), P(t-Bu)2(o-biphenyl) (120) (90 mg, 0.30 mmol), and
triethoxysilane (1.23 g, 1.38 mL, 7.50 mmol) in 20 mL of NMP.  The reaction was heated at
60 ?C for 12 h.  Bulb-to-bulb distillation (125 ?C, 0.5 torr) afforded 827 mg (65%) of
3-(triethoxysilyl)toluene as a colorless oil.  Spectral data is reported above.
4-Bromo(triethoxysilyl)benzene (Table 10, entry 8).  The
general procedure for silylation was followed using
1-bromo-4-iodobenzene (1.42 g, 5.00 mmol), i-Pr2NEt (1.94 g,
2.61 mL, 15.0 mmol), Pd(dba)2 (86 mg, 0.15 mmol), P(t-Bu)2(o-biphenyl) (120) (90 mg,
0.30 mmol), and triethoxysilane (1.23 g, 1.38 mL, 7.50 mmol) in 20 mL of NMP.  The
reaction was stirred at 25 ?C for 2 h.  Bulb-to-bulb distillation (125 ?C, 0.5 torr) afforded
1.09 g (68%) of 4-bromo(triethoxysilyl)benzene as a colorless oil.  IR (neat) 2975 (s),
2926 (s), 2887 (s), 1575 (m), 1481 (m), 1442 (m), 1390 (m), 1379 (m), 1295 (w), 1165
(s), 1073 (vs) cm-1; 1H (NMR) (CDCl3) ? 1.24 (t, J = 7.2, 9H), 3.86 (q, J = 7.2, 6H), 7.50-
7.55 (m, 4H); 13C (NMR) (CDCl3) ? 18.4, 59.0, 125.5, 130.1, 132.3, 136.6; MS (m/z) 320
(5), 318 (5), 275 (26), 273 (22), 239 (16), 231 (11), 219 (11), 217 (12), 201 (10), 195
(33), 163 (12), 162 (18), 149 (11), 148 (21), 147 (100), 137 (10), 135 (32); HRMS for
C12H19O379BrSi calcd 318.0287, found 318.0295.
4-Chloro(triethoxysilyl)benzene (Table 10, entry 9).  The
general procedure for silylation was followed using
1-chloro-4-iodobenzene (1.19 g, 5.00 mmol), i-Pr2NEt (1.94 g, 2.61
mL, 15.0 mmol), Pd(dba)2 (86 mg, 0.15 mmol), P(t-Bu)2(o-biphenyl) (120) (90 mg, 0.30
(EtO)3Si Br
(EtO)3Si Cl
(EtO)3Si
CH3
111
(EtO)3Si OAc
mmol), and triethoxysilane (1.23 g, 1.38 mL, 7.50 mmol) in 20 mL of NMP.  The reaction
was stirred at 25 ?C for 12 h.  Bulb-to-bulb distillation (125 ?C, 0.5 torr) afforded 1.03 g
(75%) of 4-chloro(triethoxysilyl)benzene as a colorless oil.  IR (neat) 2975, 2888, 2360,
1699, 1583, 1557, 1485, 1443, 1389, 1296, 1261 cm-1; 1H (NMR) (CDCl3) ? 1.17 (t, J =
7.0, 9 H), 3.79 (q, J = 7.0, 6 H), 7.28 (d, J = 8.5, 2 H), 7.54 (d, J = 8.5, 2 H); 13C (NMR)
(CDCl3) ? 18.1, 58.8, 128.1, 129.5, 136.1, 136.7; MS (m/z) 274 (3), 239 (27), 229 (44),
185 (15), 173 (25), 162 (31), 147 (100), 135 (9); HRMS for C12H19O3ClSi calcd 274.0792,
found 274.0792.  The IR, 1H and 13C NMR data were identical to published spectral
data.221
4-(Triethoxysilyl)acetanilide (Table 10, entry 10).  The
general procedure for silylation was followed using
4-iodoacetanilide (1.31 g, 5.00 mmol), i-Pr2NEt (1.94 g, 2.61 mL,
15.0 mmol), Pd(dba)2 (86 mg, 0.15 mmol), P(t-Bu)2(o-biphenyl) (120) (90 mg, 0.30 mmol),
and triethoxysilane (1.23 g, 1.38 mL, 7.50 mmol) in 20 mL of NMP.  The reaction was
stirred at 25 ?C for 12h.  Bulb-to-bulb distillation (125 ?C, 0.5 torr) afforded 1.01 g (68%)
of 4-(triethoxysilyl)acetanilide as a colorless oil.  Spectral data is reported above.
4-(Triethoxysilyl)aniline (Table 10, entry 11).  The general
procedure for silylation was followed using 4-iodoaniline (1.10 g,
5.00 mmol), i-Pr2NEt (1.94 g, 2.61 mL, 15.0 mmol), Pd(dba)2 (86
mg, 0.15 mmol), P(t-Bu)2(o-biphenyl) (120) (90 mg, 0.30 mmol), and triethoxysilane (1.23
g, 1.38 mL, 7.50 mmol) in 20 mL of NMP.  The reaction was stirred at 25 ?C for 12 h.  Bulb-
to-bulb distillation (125 ?C, 0.5 torr) afforded 983 mg (77%) of 4-(triethoxysilyl)aniline as a
colorless oil.  Spectral data is reported above.
4-Acetoxy(triethoxysilyl)benzene (Table 10, entry 12).  The
general procedure for silylation was followed using
(EtO)3Si NHAc
(EtO)3Si NH2
112
4-acetoxyiodobenzene (1.31 g, 5.00 mmol), i-Pr2NEt (1.94 g, 2.61 mL, 15.0 mmol),
Pd(dba)2 (86 mg, 0.15 mmol), P(t-Bu)2(o-biphenyl) (120) (90 mg, 0.30 mmol), and
triethoxysilane (1.23 g, 1.38 mL, 7.50 mmol) in 20 mL of NMP.  The reaction was stirred at
25 ?C for 12 h.  Bulb-to-bulb distillation (125 ?C, 0.5 torr) afforded 1.12 g (75%) of
4-acetoxy(triethoxysilyl) benzene as a colorless oil.  Spectral data is reported above.
4-(Triethoxysilyl)phenol (Table 10, entry 13).  The general
procedure for silylation was followed using 4-iodophenol (1.10 g,
5.00 mmol), i-Pr2NEt (1.94 g, 2.61 mL, 15.0 mmol), Pd(dba)2 (86
mg, 0.15 mmol), P(t-Bu)2(o-biphenyl) (120) (90 mg, 0.30 mmol), and triethoxysilane (1.23
g, 1.38 mL, 7.50 mmol) in 20 mL of NMP.  The reaction was stirred at 25 ?C for 12 h.  Bulb-
to-bulb distillation (125 ?C, 0.5 torr) afforded 897 mg (70%) of 4-(triethoxysilyl)phenol as
a colorless oil.  Spectral data is reported above.
4-(Triethoxysilyl)acetophenone (Table 10, entry 14).  The
general procedure for silylation was followed using
4-iodoacetophenone (1.23 g, 5.00 mmol), i-Pr2NEt (1.94 g, 2.61
mL, 15.0 mmol), Pd(dba)2 (86 mg, 0.15 mmol), P(t-Bu)2(o-biphenyl) (120) (90 mg, 0.30
mmol), and triethoxysilane (1.23 g, 1.38 mL, 7.50 mmol) in 20 mL of NMP.  The reaction
was heated at 60 ?C for 12 h.  Bulb-to-bulb distillation (125 ?C, 0.5 torr) afforded 339 mg
(24%) of 4-(triethoxysilyl)phenol as a colorless oil.  IR (neat) 2975 (s), 2927 (s), 2890
(s), 1728 (m), 1689 (s), 1497 (w), 1443 (m), 1390 (m), 1360 (m), 1263 (s), 1167 (s), 1079
(vs) cm-1; 1H (NMR) (CDCl3) ? 1.26 (t, J = 7.0, 9H), 2.61 (s, 3H), 3.89 (q, J = 7.0, 6H),
7.79 (d, J = 8.0, 2H), 7.95 (d, J = 8.0, 2H); 13C (NMR) (CDCl3) ? 18.3, 26.8, 59.0, 127.4,
135.2, 137.4, 138.4, 198.5; MS (m/z) 282 (8), 268 (22), 267 (100), 239 (15), 238 (67),
237 (57), 223 (16), 209 (18), 193 (13), 181 (20), 165 (19), 163 (24), 147 (16), 138 (12),
135 (9); HRMS for C14H22O4Si calcd 282.1287, found 282.1288.
(EtO)3Si
O
(EtO)3Si OH
113
2-(Triethoxysilyl)pyridine (Table 10, entry 15).  The general
procedure for silylation was followed using 2-iodopyridine (532 ?L, 5.00
mmol), i-Pr2NEt (1.94 g, 2.61 mL, 15.0 mmol), Pd(dba)2 (86 mg, 0.15
mmol), P(t-Bu)2(o-biphenyl) (120) (90 mg, 0.30 mmol), and triethoxysilane (1.23 g, 1.38
mL, 7.50 mmol) in 20 mL of NMP.  The reaction was heated at 60 ?C for 12 h.  By GCMS
of the crude reaction mixture, the reaction yielded pyridine as the major product, and none
of the desired silylated product.  Bulb-to-bulb distillation (125 ?C, 0.5 torr) afforded 50 mg
(15%) of 2,2'-dipyridyl (130) following purification.  For 2,2?-dipyridyl: IR (neat) 3069 (m),
3053 (m), 3011 (w), 1584 (s), 1562 (s), 1467 (s), 1421 (s), 1255 (m), 1147 (m) cm-1; 1H
(NMR) (CDCl3) ? 7.12 (t, J = 7.8, 2 H), 7.66 (t, J = 7.8, 2 H), 8.50 (d, J = 7.8, 2 H), 8.59
(d, J = 7.8, 2 H); 13C (NMR) (CDCl3) ? 121.0, 123.7, 136.8, 149.0, 156.0.  The IR, 1H and
13C NMR data were identical to an authentic sample.
3-(Triethoxysilyl)pyridine (Table 10, entry 16).  The general
procedure for silylation was followed using 3-iodopyridine (1.03 g, 5.00
mmol), i-Pr2NEt (1.94 g, 2.61 mL, 15.0 mmol), Pd(dba)2 (86 mg, 0.15
mmol), P(t-Bu)2(o-biphenyl) (120) (90 mg, 0.30 mmol), and triethoxysilane (1.23 g, 1.38
mL, 7.50 mmol) in 20 mL of NMP.  The reaction was heated at 60 ?C for 12 h.  Bulb-to-
bulb distillation (125 ?C, 0.5 torr) afforded 121 mg (10%) of 3-(triethoxysilyl)pyridine as a
colorless oil.  1H (NMR) (CDCl3) ? 1.26 (t, J = 6.8, 9H), 3.90 (q, J = 6.8, 6H), 7.2-7.3 (m,
1H), 7.95 (d, J = 5.9, 1H), 8.65 (d, J = 4.9, 1H), 8.83 (s, 1H); 13C (NMR) (CDCl3) ? 18.0,
58.8, 123.1, 126.6, 142.4, 151.1, 155.0; MS (m/z) 241 (54), 240 (100), 226 (18), 212 (27),
196 (88), 147 (29), 182 (25); HRMS for C11H19O3NSi calcd 241.1134, found 241.1112.
The IR, 1H and 13C NMR data were identical to published spectral data.221  In our
laboratories, using the conditions given by Masuda,221 we obtained a maximum isolated
yield of 10% (Masuda reported a 56% yield).
N
Si(OEt)3
N Si(OEt)3
114
2-(Triethoxysilyl)thiophene (Table 10, entry 17).  The general
procedure for silylation was followed using 2-iodothiophene (552 ?L,
5.00 mmol), i-Pr2NEt (1.94 g, 2.61 mL, 15.0 mmol), Pd(dba)2 (86 mg,
0.15 mmol), P(t-Bu)2(o-biphenyl) (120) (90 mg, 0.30 mmol), and triethoxysilane (1.23 g,
1.38 mL, 7.50 mmol) in 20 mL of NMP.  The reaction was heated at 60 ?C for 12 h.  Bulb-
to-bulb distillation (125 ?C, 0.5 torr) afforded 1.13 g (92%) of 2-(triethoxysilyl)thiophene
as a colorless oil.  Spectral data is reported above.
4-(Triisopropoxysilyl)anisole.  The general procedure for
silylation was followed using 4-iodoanisole (1.17 g, 5.00
mmol), i-Pr2NEt (1.94 g, 2.61 mL, 15.0 mmol), Pd(dba)2 (86 mg,
0.15 mmol), P(t-Bu)2(o-biphenyl) (120) (90 mg, 0.30 mmol), and triisopropoxysilane (1.55
g, 1.50 mL, 7.50 mmol) in 20 mL of NMP.  The reaction was heated at 80 ?C for 12 h.
Bulb-to-bulb distillation (125 ?C, 0.5 torr) afforded 1.17 g (75%) of
4-(triisoproxysilyl)anisole as a colorless oil.  IR (neat) 2972 (s), 2934 (m), 2896 (m), 1597
(s), 1505 (m), 1381 (m), 1369 (m), 1281 (m), 1252 (m), 1174 (s), 1124 (vs) cm-1; 1H
(NMR) (CDCl3) 1.20 (d, J = 6.1, 18 H), 3.81 (s, 3 H), 4.25 (septet, J = 6.1, 3 H), 6.90 (d,
J = 8.7, 2 H), 7.61 (d, J = 8.7, 2 H) ? ; 13C (NMR) (CDCl3) 25.5, 54.9, 65.3. 113.4, 123.8,
136.6, 161.1 ? ; MS (m/z) 314 (17), 299 (9), 253 (72), 211 (15), 205 (38), 187 (15), 167
(100), 147 (15), 121 (20); HRMS for C16H28O4Si calcd 312.1757, found 312.1772.
General Procedure for the Homocoupling of 2-Halopyridines under Palladium
Catalysis.  The indicated 2-halopyridine (1.00 mmol, 1.0 equiv), and i-Pr2NEt (388 mg,
523 ?L, 3.00 mmol) were added to a stirring solution of Pd(dba)2 (29 mg, 0.05 mmol),
P(t-Bu)2(o-biphenyl) (120) (30 mg, 0.1 mmol), and the internal standard naphthalene (128
mg, 1.0 mmol, 1.0 equiv) in 4 mL of NMP under an atmosphere of argon.  The reaction was
heated at 60 ?C for 12 h.  Progress was monitored by GC analysis of aliquots of the
quenched reaction mixture.  GC response factors relative to the internal naphthalene
S Si(OEt)3
(i-PrO)3Si OCH3
115
standard were determined, and the observed percentages of products were normalized
accordingly.  The homocoupled product 2,2?-dipyridyl was identified by comparison of the
GC retention time to that an authentic sample.
2,2?-Dipyridyl (130).  The general procedure for homocoupling was
followed using 2-iodopyridine (129)(205 mg, 106 ?L, 1.00 mmol),
i-Pr2NEt (388 mg, 523 ?L, 3.00 mmol), Pd(dba)2 (29 mg, 0.05 mmol), and
P(t-Bu)2(o-biphenyl) (120) (30 mg, 0.1 mmol), in 4 mL of NMP at 60 ?C for 12 h gave 99%
130 by G.C. analysis.
2,2?-Dipyridyl (130).  The general procedure for homocoupling was
followed using 2-bromopyridine (42)(158 mg, 95 ?L, 1.00 mmol), i-Pr2NEt
(388 mg, 523 ?L, 3.00 mmol), Pd(dba)2 (29 mg, 0.05 mmol), and
P(t-Bu)2(o-biphenyl) (120) (30 mg, 0.1 mmol), in 4 mL of NMP at 60 ?C for 12 h gave 2%
130 and 25% pyridine by G.C. analysis.  The remaining percentage was unreacted
starting material.
General Procedure for the Optimization of the Silylation of Aryl Triflates (131)
(Table 11).  The indicated aryl triflate (1.00 mmol, 1.0 equiv), and base (3.00 mmol, 3.0
equiv) were added to a stirring solution of Pd(dba)2 (29 mg, 0.05 mmol, 5 mol %), the
phosphine (0.10 mmol, 10 mol%), and the internal standard naphthalene (128 mg, 1.0
mmol, 1.0 equiv) in 4 mL of solvent under an atmosphere of argon.  Triethoxysilane (246
mg, 277 ?L, 1.50 mmol, 1.5 equiv) was added, causing bubbling, formation of yellow
foam, and darkening of the reaction mixture.  The reaction mixture was allowed to stir at
room temperature for 12 h.  Progress was monitored by GC analysis of aliquots of the
quenched reaction mixture.  GC response factors relative to the internal naphthalene
standard were determined, and the observed percentages of products were normalized
N N
N N
116
accordingly.  The reduced product 121 was identified by comparison of the GC retention
time to that of an authentic sample.
OTf
R
H Si(OEt)3
Si(OEt)3
R
H
R
+ +
Pd(dba)2
ligand
base
solvent
131 92 121
Conditionsa Yield (%)b,c
Entry R Ligand Base Solvent 92 121
1 OMe P(t-Bu)2(o-biphenyl) i-Pr2NEt NMP 3 90
2 OMe P(t-Bu)2(o-biphenyl) none NMP 0 5
3 OMe P(t-Bu)2(o-biphenyl) i-Pr2NEt dioxane 2 96
4 OMe P(t-Bu)2(o-biphenyl) none dioxane 0 7
5 OMe PPh3 i-Pr2NEt NMP 0 5
6 OMe PPh3 i-Pr2NEt dioxane 0 24
7 OMe P(cy)2(o-biphenyl) i-Pr2NEt NMP 1 32
8 OMe P(cy)2(o-biphenyl) i-Pr2NEt dioxane 1 99
9 NO2 P(t-Bu)2(o-biphenyl) i-Pr2NEt NMP 0 100
10 NO2 P(t-Bu)2(o-biphenyl) none NMP 0 22
11 NO2 P(t-Bu)2(o-biphenyl) i-Pr2NEt dioxane 0 100
12 NO2 P(t-Bu)2(o-biphenyl) none dioxane 0 15
13 NO2 PPh3 i-Pr2NEt NMP 0 100
14 NO2 PPh3 i-Pr2NEt dioxane 0 100
15 NO2 P(cy)2(o-biphenyl) i-Pr2NEt NMP 0 100
16 NO2 P(cy)2(o-biphenyl) i-Pr2NEt dioxane 0 100
a Reactions of aryltriflate (131) (1.0 mmol) with H-Si(OEt)
3 (1.5 mmol) were performed atroom temperature for 12h in 4 mL of solvent by using Pd(dba)
2 (5 mol %), phosphine (10mol %), and base (3 mmol).  b GC yields are based on amount of aryltriflate (131).
c Remaining percentage was unreacted starting material.
Table 11.  Silylation of Aryltriflate Derivatives.
General Procedure for the Optimization of the Silylation of Aryl Halides or Acyl
Chlorides Using Hexamethoxydisilane (Table 12 and Scheme 71).  The indicated
aryl halide or acyl chloride (1.00 mmol, 1.0 equiv), and base (3.00 mmol, 3.0 equiv) were
added to a stirring solution of palladium catalyst (0.05 mmol, 5 mol %), the phosphine
117
(0.10 mmol, 10 mol%), and the internal standard naphthalene (128 mg, 1.0 mmol, 1.0
equiv) in 4 mL of solvent under an atmosphere of argon.  Hexamethoxydisilane (364 mg,
332 ?L, 1.50 mmol, 1.5 equiv) was added, causing darkening of the reaction mixture.  The
reaction mixture was allowed to stir at the given temperature for 12 to 48 h.  Progress was
monitored by GC analysis of aliquots of the quenched reaction mixture.  GC response
factors relative to the internal naphthalene standard were determined, and the observed
percentages of products were normalized accordingly.  The reduced product 121 and
methylbenzoate were identified by comparison of the GC retention time to that of an
authentic sample.
X
(MeO)3Si Si(OMe)3
Si(OMe)3 H
R R R
+ +
Pd(0)
ligand
base
solvent
139 92 121
Substrate Conditionsa Yield
(%)b,c
Entry X R Ligand Pd catalyst / base solvent T
(?C)
92 121
1 I OMe P(t-Bu)2(o-biphenyl) Pd(dba)2 / i-Pr2NEt NMP 25 0 0
2 I OMe P(o-tol)3 Pd(dba)2?CHCl3/i-Pr2NEt NMP 25 0 2
3 Br OMe P(t-Bu)2(o-biphenyl) Pd(dba)2 / i-Pr2NEt NMP 25 0 0
4 Cl OMe P(t-Bu)2(o-biphenyl) Pd(dba)2 / i-Pr2NEt NMP 25 0 0
5 Br Ac P(t-Bu)2(o-biphenyl) Pd(dba)2 / i-Pr2NEt NMP 100 0 100
6 Br Ac P(t-Bu)2(o-biphenyl) Pd(dba)2 / i-Pr2NEt DMPU 100 0 100
7 I Ac P(t-Bu)2(o-biphenyl) Pd(dba)2 / KF (aq) DMPU 75 0 100
8 Br Ac P(t-Bu)2(o-biphenyl) Pd(dba)2 / KF (aq) DMPU 75 0 100
9 Br OMe P(t-Bu)2(o-biphenyl) Pd(dba)2 / K2CO3 (aq) DMPU 75 0 0
10 I OMe Pd(PPh3)4 / TBAF NMP 25 0 0
11 I Me Pd(PPh3)4 / TBAF DMF 25 0 3
12 I Me Pd(PPh3)4 / TBAF HMPA 25 0 3
13d,e Br H Pd(PPh3)4 toluene 140 27 10
a Reactions of aryl halide 139 (1.0 equiv) with (MeO)
3Si-Si(OMe)3 (2.0 equiv) wereperformed using the indicated temperature and solvent for 12h-48h by using the given
palladium catalyst (5 mol %), phosphine (10 mol %), and base (3 equiv).  b GC yields are
based on amount of aryl halide 139.  c Unless otherwise noted, remaining percentage was
unreacted starting material (139).  d Reaction was performed in a sealed tube for 72h.
e Biphenyl was observed in 7% yield.
Table 12.  Silylation of Arylhalides Using Hexamethoxydisilane.
118
Chapter 2.  Trimethylsilyl Cyanide As A Cyanide Source For Nucleophilic
Substitution
Introduction
Fluoride Ion Activation of Silicon Bonds
The study of pentacoordinate and hexacoordinate organosilicon derivatives is
approximately a century old.  Hypercoordinate organosilicon compounds have been
studied since the early 19th century when Dilthey reported the first known hypercoordinate
organosilicates, six-coordinate silicon diketonates.1-4  To date, a wide variety of penta- and
hexacoordinate organosilicon compounds have been synthesized and characterized;
surprisingly, despite the nonexistence of naturally-occurring organosilicates,5,6 a handful of
silicates which have no carbon analogs are biologically active.7-13  The synthesis and
structure of hypercoordinate silicates most notably have been studied and reviewed by
Voronkov,1,14-19 Frye12,20-33 and Lukevics.34-41  In turn, Corriu42-46 has investigated and
extensively reviewed silicate reactivity and reaction mechanisms.
Hypercoordinate silicates first became an area of active research in the DeShong
laboratories with the synthesis of tetrabutylammonium triphenyldifluorosilicate (TBAT, 1,
Scheme 1).47-51  TBAT was initially developed as a source of nucleophilic fluoride ion for
SN2-type displacements48 and for Si-C bond cleavage.47  Stable, crystalline, non-basic,
and non-hygroscopic, pentacoordinate silicate 1 is an excellent fluoride surrogate when
compared to alkali metal fluorides or tetraalkylammonium fluorides (Scheme 1, eq. a).  More
recently, TBAT has been developed as a highly effective phenylation reagent in
palladium-catalyzed cross coupling reactions, offering a silicon-based alternative to Suzuki
(boron) and Stille (tin) reagents (Scheme 1, eq. b).50
119
Scheme 1
Si
MeO I
MeO Ph
Br
1, TBAT Pd(0)
(a)
(b)
Ph
PhPh
F
F
Ph FPh
Bu4N+
Relative to other fluoride sources, TBAT was shown to yield less alkene
elimination by-products in standard nucleophilic displacements of primary and secondary
alkyl halides and sulfonates.  Most notably, when compared to the popular organic-
soluble reagent tetrabutylammonium fluoride (Bu4N+ F-, TBAF), TBAT is far less basic.  For
example in Scheme 2, whereas TBAT achieved nearly quantitative fluoride displacement
of a secondary alkyl tosylate, TBAF provoked elimination leading to alkene by-products.
Scheme 2
OTs TBAT, 1
MeCN, reflux
F +
OTs TBAF
MeCN, 25 ?C
F +
98% 2%
58% 32%
24 h
1 h
It is also noteworthy that reactions with TBAT proceeded much more slowly than
the corresponding reaction with anhydrous TBAF.  Based on the observed rate difference
as well as NMR spectroscopic studies, it was concluded that TBAT does not operate by
a simple in situ disproportionation to TBAF (Scheme 3) and fluorotriphenylsilane (2).
Instead, the hypercoordinate silicate itself must directly transfer a softer, less basic fluoride
nucleophile to the substrate.
120
Scheme 3
Bu4N+F- + Ph3Si-F
2
Si
1, TBAT
Ph
PhPh
F
F Bu4N+
Given the effectiveness of TBAT as a practical reagent for the delivery of fluoride
anion, extension of this strategy to deliver other nucleophiles by generating the reactive
hypercoordinate silicate in situ was investigated (Scheme 4).  In this chapter, it is reported
that trimethylsilyl cyanide (Me3SiCN, 3) and trimethylsilyl azide (Me3SiN3, 4) underwent
reaction with tetrabutylammonium fluoride (TBAF) to generate the respective
hypercoordinate trimethylfluorosilicate (5 or 6) in situ.  Analogous with the observations
using TBAT, silicates 5 and 6 were extremely reactive alternates of cyanide and azide
anion, respectively, for SN2 displacement (vide infra).52-54
Scheme 4
Si
F
Br
R3Si X TBAF
X
X
Bu4N+
1: R = Ph, X = F (TBAT)
5: R = Me, X = CN
6: R = Me, X= N3
R RR
Ph
Ph
2: R = Ph, X = F
3: R = Me, X = CN
4: R = Me, X= N3
The chemistry described in Scheme 4 is one of the characteristic reactions of
tetracoordinate silanes: the activation of Si-H, Si-O, Si-C, Si-N, or Si-M (M = Si, Ge, Sn)
bonds by addition of a nucleophile, typically fluoride ion.  The Si-X bonds of
tetracoordinate silanes normally are not labile in the absence of nucleophilic activation.
Pentacoordinate silicates such as 5 and 6 are widely accepted as the reactive
intermediates in most reactions at silicon, and many new isolable hypercoordinate silicates
have been synthesized as probes of the mechanism of the reactions of silanes.43 Chap. 1,44
121
In his dissertation on the development of TBAT as a fluorinating reagent, Pilcher
presented the properties, reactivity, and methods of analysis of hypercoordinate
fluorosilicates.55  The aim of this chapter is twofold: to review the literature precedence
which supports the existence of hypercoordinate intermediates such as 5 and 6, and to
present pertinent examples of fluoride-mediated reactions of silanes.  The following
features are discussed:
1. The expansion of coordination at silicon.  Formation of pentacoordinate silicon
has been proposed as the fundamental step of most transformations of silicon
compounds.43 Chap. 1,44  Examples of isolable pentacoordinate silicates are
presented as analogues of the key pentacoordinate reaction intermediates 5
and 6.  In addition, analytical methods for the characterization of
hypercoordinate silicates are discussed.
2. Mechanisms of nucleophilic substitutions at silicon.  The process depicted in
Scheme 4 involves nucleophilic attack on silicon by fluoride ion, and
displacement of the group X (cyanide or azide).  Nucleophilic substitutions at
silicon take place via the hypercoordinate intermediate, such as 5 and 6, and
not through an SN1 or SN2-type process.
3. Pertinent examples of fluoride ion activation of silicon bonds in organic
synthesis, encompassing desilylation (removal of protecting groups),
reduction, and group transfer reactions (allylation, arylation, acylation, etc.).
Particular attention will be paid to experimental evidence for the participation of
hypercoordinate silicate intermediates.
Finally, the results of studies in the DeShong lab on the use of organosilicon compounds
under nucleophile-activated conditions are presented, and discussed.
122
Atomic and Molecular Properties of Tetracoordinate and Hypercoordinate
Organosilicates
Silicon compounds are often compared to their carbon-based analogues: silicon is
in the same period of the periodic table as carbon; intuitively, their chemistries should be
similar.  Silanes, like alkanes, are neutral, tetracoordinate species.  However, beyond
sharing a valence number of four, the properties of carbon and silicon compounds are
surprisingly different.  On the basis of this periodic proximity of silicon to carbon, the first
researchers of silicon chemistry correctly postulated that silicon compounds should
undergo similar chemical transformations, most notably nucleophilic substitution.56
However, fundamental differences in the atomic and molecular natures of silicon and
carbon cause a divergence in their respective mechanistic pathways to nucleophilic
substitution.  The larger atomic size, lower electronegativity, and the availability of low
energy d orbitals endow silicon with enhanced reactivity, and metallic properties.
The most notable contrast between silicon and carbon is that silicon can expand
beyond its normal coordination number of four, becoming what is termed hypercoordinate.
Silicates are a class of anionic compounds featuring a silicon atom with five (7 and 8) or
six (9) ligands as opposed to the normal silane coordination number of four.
N
F
Si
F F
F
NSiN S
N
N
9TAS-F, 8
F
F
MeMeMeSi
7
Ph
PhPh
OMe
OMe K+ 18-crown-6
2-
The ability of silicon to become hypercoordinate is due to a number of steric and
electronic factors (Table 1).  With a significantly larger covalent radius than carbon, silicon
can satisfy the steric demands of penta- and hexacoordination.55,57  Addition of an anion to
tetracoordinate silicon is a lower energy process than for carbon, as indicated by the
higher silicon electron affinity.58  Conversely, silicon has a lower ionization potential than
carbon, allowing ligands to share the negative charge on, and thereby stabilize a penta-
or hexacoordinate complex.59
123
Si Atomic Property C
1.06 ? atomic radius60 0.66 ?
1.17 ? covalent radius61 0.77 ?
3.35 eV for F3Si? electron affinity58 1.85 eV for CF3C?
8.15 eV ionization potential59 11.26 eV
1.74 Allred-Rochow electronegativity56,62 2.50
Table 1.  Comparison of Atomic Properties of Si and C.
The relatively low silicon electronegativity has two major consequences: (1) silicon
is often polarized in the opposite sense to carbon (i.e., Ph3Si?+-H?- vs. Ph3C???H?+); and
(2) the Si-X and Si-O bonds are highly polarized?much more so than C-X and C-O
bonds?rendering silicon more electrophilic and susceptible to nucleophilic attack.56  Using
ab initio methods and experimentally determined heats of reaction to compare the
structures and bond energies of silyl (H3Si-X) and methyl (H3C-X) derivatives (X = Li,
BeH, BH2, CH3, NH2, OH, F, and Na), Schleyer demonstrated that the relative Si-X and
C-X bond energies are directly proportional to the electronegativity of the group X.63  For
reference, Table 2 lists the relative electronegativities of the atoms to which silicon
typically forms bonds.  In addition, Schleyer described the Si-X covalent bond as more
ionic (Si?+-X?-) in nature than the predominantly covalent C-X bond.64
As indicated by the bond dissociation energies (Table 3), silicon forms remarkably
strong bonds to F and O, and somewhat weak bonds to Si, and H.  In contrast, carbon
forms strong C-C and C-H bonds, and relatively weak C-O and C?X bonds.  The weak
Si-H bond explains in part why hydrosilanes are good reducing agents, in stark contrast
to alkanes.56  Also, formation of the strong Si-F bond is often the thermodynamic driving
force of reactions at silicon; fluoride is typically the unrivaled catalyst for the cleavage of
other Si-X bonds.42  Note that, although the Si?Cl and Si-F bond strengths are greater
than the C-Cl and C-F bond strengths, the Si-X bonds are kinetically quite reactive
(readily broken), and more labile than the equivalent C-X bond.  This discrepancy
between kinetic reactivity and thermodynamic bond strength in substitution reactions at
silicon in comparison to carbon is attributed in part to the attraction of nucleophiles to the
larger partial positive charge on Si.43,56,61
124
Atom Electronegativity Atom Electronegativity
F 4.10 S 2.44
CN 3.60 H 2.20
O 3.50 As 2.20
OH 3.50 P 2.06
N 3.07 Ge 2.02
NH2 3.05 B 2.01
OCH3 2.90 BH2 1.90
Cl 2.83 Si 1.74
Br 2.74 BeH 1.50
C 2.50 Al 1.47
Se 2.48 Na 1.01
CH3 2.45 Li 0.97
Table 2.  Atomic and Group Allred-Rochow Electronegativities.56,62
Bond Energy (kJ mol-1)61,65 Bond Length (?)56
Bond to C Si C66 Si67,68
F 485 582 1.39 1.6
Cl 327 391 1.78 2.05
Br 285 310 1.94 2.21
I 213 234 2.14 2.44
O 336 368 1.41 1.63
N 335 400 1.47 1.74
C 356 373 1.53 1.87
Si 250-335 210-250 1.87 2.34
Table 3.  Approximate Average Bond Dissociation Energies and Bond Lengths for
Tetravalent C and Si.
125
X-Ray crystallographic studies of stable, solid silicates show that tetracoordinate,
pentacoordinate and hexacoordinate silicon compounds adopt the tetrahedral, trigonal
bipyramidal (TBP), and octahedral geometries, respectively (Figure 1).1  Most known
silicon compounds are tetrahedral (3sp3 hybridized).56  Tetrahedral silanes exhibit high
configurational stability, albeit lower than carbon,44 and chiral silanes have been
synthesized predominantly for use as stereochemical probes of the mechanism of
nucleophilic displacement at Si.33,44-46,69-71
Si eq Si eqeq
ap
ap
Sieqeq eqeq
ap
ap
tetrahedral
sp3
? =109.5?
octahedral
sp3d2
? (eq-Si-ap) = 90?
? (eq-Si-eq) = 90?
2
trigonal bipyramidal
sp3d
? (eq-Si-ap) = 90?
? (eq-Si-eq) = 120?
Figure 1.  Hybridization of Tetra-, Penta-, and Hexacoordinate Silicon.
Pentacoordinate complexes are trigonal bipyramidal (TBP) (3sp3d hybridized) with
distinct apical (ap) and equatorial (eq) ligands (Figure 1); the apical bonds (pd-like) are
longer and weaker than the equatorial bonds (sp2-like).1,72  ?Bent?s Rule? dictates that
electronegative groups prefer to occupy the apical sites.73-75  Electron-withdrawing groups
(EWG) tend to decrease the apical silicon-ligand bond lengths and thus increase the
overall stability of the complex.  Unless a ligand in the complex bears a neutralizing
positive charge, the complex bears a negative charge.
Octahedral silicates bear a negative two charge, again, unless cationic ligands are
present to neutralize the overall charge (as in compounds 9 and 11).  A large number of
hexacoordinate silicates have been synthesized and isolated, two of which are shown
below.  The triscatecholate silicate 10 was isolated by Corriu, and shown to be a useful
starting material for the preparation of alkylsilanes.76  Stacked arrays of phthalocyanine
derivative 11 are electrically conductive.77-81
126
R
SiOO OO
O
O
2-
2Na+
10
SiN NNN
N
N
N
N
R'
11
The results of calculation and experimentation indicate that the negative charge lies
on the ligands, with the most electronegative ligands bearing the brunt of the charge.82
Remarkably, as a silicon complex goes from neutral (tetracoordinate) to anionic (penta-,
and then hexacoordinate), the silicon center becomes increasingly positive, and
electrophilic.1  In turn, the ligands become more negative, and nucleophilic.  For example,
the CNDO/2 calculated charges on the central Si atom of SiF4 and SiF5- are +1.214 and
+2.028, respectively; in turn, the charges on the fluorine ligands are -0.304 (sp3), and -
0.399(eq)/-0.415(ap), respectively.83  The net effect of hypercoordination on the reactivity
of a silicate is enhanced ligand Lewis basicity, and increased silicon Lewis acidity.1
Corriu illustrated the ?snowball effect? of increasing electrophilicity at silicon with
increasing coordination number by demonstrating that the rate of conversion from tetra-
(12) to pentacoordinate (13) is slower than the analogous conversion from penta- (14) to
hexacoordinate (15) for a series of catecholate derivatives (Figure 2).84  The researchers
attributed the observed kpent<ktet to the increased electrophilicity at silicon, with the caveat
that the rate enhancement may be partially caused by the increased steric accessibility of
nucleophiles to pentacoordinate silicon.
O
Si
O OO Si OO
O
O
R Si OO
O
O
Si OO
O
O
NuNu
2-
Nu-
ktet
Nu-
kpent
1312 14 15
< R
Figure 2.  Comparison of Rates of Expansion of Coordination.
127
Corriu also demonstrated the enhanced ligand nucleophilicity of hypercoordinate
silicates relative to the tetracoordinate analogs by comparing the rates at which they
perform reduction and group transfer reactions.42  For example, as a hydride donor,
H?Si(OMe)3 is significantly weaker than [H-Si(OMe)4]-.  In parallel, (allyl)SiF3 is a weaker
allylating agent than [(allyl)SiF4]-.  This aspect of hypercoordination will be discussed in
detail later.
As alluded to above, bond lengths to silicon increase with increasing coordination
number.1  The Si-F bond lengths in the series SiF4, SiF5-, and SiF62-, are calculated to be (in
?) 1.875, 1.890(eq)/1.900(ax), and 1.930, respectively.83  Even for asymmetrically
substituted silanes, an increase in the coordination number of silicon results in the
lengthening of all bonds.1  In terms of reactivity, the silicon atom of pentacoordinate
silicates is more sterically accessible than tetrahedral silicon; in other words,
pentacoordinate silicates are more sterically vulnerable to nucleophilic attack than
tetracoordinate silanes.56
Synthesis, Stability and Characterization of Hypercoordinate Organosilicates
Methods for the synthesis of silicates can be summarized as follows (Scheme 5):
(a) addition of an anion to a tetracoordinate silane; (b) addition of a neutral electron pair
donor to a tetracoordinate silane, either intra- or intermolecularly; and (c) substitution by a
chelating ligand.42  The synthesis of silicates is extensively reviewed.85
Scheme 5
Me2N SiF3 Me2N SiF3
OLi
OLi
SiOO
O
O
R
RnSiX4-n    +    X-                   [RnSiX5-n]-
RSiX3     +     2
(a)
(b)
(c) Li+     +     3LiX
128
Each of the general synthetic methods presented in Scheme 5 involves attack on
silicon by a nucleophile.  The reaction ordinarily proceeds if (1) the nucleophile is highly
Lewis basic and silaphilic (i.e., F, O, imidazole); and (2) at least two strong EWG (F, O)
or at least one strong and one weak, polarizable EWG (phenyl, vinyl) are attached to
silicon; otherwise, the reaction equilibrium favors the starting materials.55,56  The Lewis
acidity of silicon, and therefore the reactivity toward nucleophiles, generally increases in
the following order, as predicted by the increasing electron-withdrawing effect of the
ligands: R3SiX < R2SiX2 < RSiX3 < SiX4.56
The following observation illustrates the delicate balance of nucleophile Lewis
basicity and silane electrophilicity needed for the formation of a stable hypercoordinate
silicate:56 no product is isolated when SiCl4 is treated with KCl; however, when SiCl4 is
treated with 2 equiv of pyridine, a better Lewis base than Cl-, SiCl4(pyr)2 is readily
formed.  In contrast to SiCl4, MeSiCl3 does not form an isolable pyridine adduct, due to the
reduction of silicon Lewis acidity caused by methyl substitution.
Many of the best-known organosilicates are derivatives of ethylene glycol,
catechol, or triethanolamine.1  The trend for silicate stability as derived from the chelate
effect is illustrated in Scheme 6; Lehn established that each addition of a bridging ligand
increases the stability of the complex by several orders of magnitude.86
Si
Nu
X
Si
Nu
X
< < <Si
Nu
X
Si
Nu
X
Figure 3.  Increase in Silicate Stability Due Chelating Ligands.
The chelate effect has been exploited often: particularly remarkable is the formation
of a stable pentacoordinate silicate (16) from weakly Lewis acidic silica (SiO2) in refluxing
KOH/ethylene glycol.87,88  Finally, silatranes (17) have been extensively studied, due to
the transannular Si-N dative bond, high stability, and unusual lack of reactivity toward
nucleophilic substitution at silicon.8-13,89
129
Si OO
O
O 2K+
Si
O
O O
O
O O
2-
16 17
SiOO
N
X
O
Organosilicates are characterized by a number of standard organic techniques (IR,
MS, X-ray crystallography), however the single most diagnostic method for determining
the solution-phase structure is NMR spectroscopy.  The NMR characterization of
organosilicates is extensively reviewed.90-97  Organosilicates ordinarily bear at least three
detectable nuclei, 1H, 13C, and 29Si; additionally, given the preponderance of
organofluorosilicates, 19F NMR is commonly available as an analytical tool.
29Si NMR is the most diagnostic NMR technique for the determination of
hypercoordination,56 despite the relatively lengthy acquisition times caused by the low
sensitivity (7.84 x 10-3 relative to 1H) and natural abundance (4.70 %) of 29Si, long spin-
lattice relaxation times (T1) and negative gyromagnetic ratio.98  These shortcomings are
upstaged by the very large chemical shift range (-180 to 250 ppm), and extreme
sensitivity of the chemical shift to changes in silicon coordination number.  A dramatic
upfield shift (between 40 and 80 ppm) accompanies coordination expansion from tetra- to
pentacoordinate.  Typically, tetracoordinate silicon occurs in a range from 45 to ?115 ppm.
Five- and six-coordinate silicates are more shielded, occurring in the range from ?70 to
?200 ppm.93  For example (Table 4), the conversion of triphenylsilylfluoride (2, Ph3SiF) to
TBAT (1, [Ph3SiF2]-[Bu4N]+) causes an upfield shift from -4.0 to -106.3 ppm.47-49,55  For
fluorosilanes, Si-F coupling (JSi-F) is reduced by 40 to 80 Hz upon extracoordination as a
result of the change in hybridization at silicon.  Using the same example, the conversion of
triphenylsilylfluoride (2) to TBAT (1) causes a decrease in JSi-F from 282 to 251 Hz.47-49,55
130
Compound 29Si
(ppm)
19F
(ppm)
13Ca
(ppm)
JSi-F
(Hz)
2J
C-F
(Hz)
SiPh3F, 2 -4.0, d -87.5 132.5, d 282 17
[Ph3SiF2]-[Bu4N]+, 1 -106.3, t -17.9 128.2, d 251 163
? = -102.3 +69.6 -4.3 -31 +146
Ph2SiF2 8.7, d -64.3 (b) 281 (b)
[Ph2SiF3]-[Bu4N]+ -108.7,q -74.0 (b) 240 (b)
? = - 73 +9.7 (b) -41 (b)
a Value for the carbon directly attached to silicon.  b No quaternary signal observed.
Table 4.  Comparison of NMR Data for Tetracoordinate and Pentacoordinate Silicates (25
?C, CDCl3).47-49,55
Experience garnered in the DeShong lab has shown that prolonged exposure of
silicates to the NMR solvent CDCl3 can result in decomposition of the silicate.49
Presumably due to traces of acid in commercial grade deuterated chloroform, TBAT (1)
undergoes slow decomposition upon standing in CDCl3 as observed by 1H and 19F-NMR
spectroscopy.  It was shown that freshly made solutions showed no evidence of
decomposition for several hours, allowing for the acquisition of clean spectra.
Mechanisms of Nucleophilic Substitution Reactions at Silicon
The ability of silanes to become hypercoordinate has a profound effect on the
mechanisms of substitution reactions at silicon.  Specifically, where carbon compounds
can undergo SN1 or SN2 substitution, the accepted mechanisms for silicon substitution
typically involve a hypercoordinate silicate intermediate.43 Chap. 1,44  Investigations into the
mechanism of nucleophilic substitution at silicon have employed the same techniques
used to elucidate the mechanism of nucleophilic substitution at carbon.44  The classic
identifiers of carbon or silicon substitution mechanisms (SN1 vs. SN2) are kinetics
(unimolecular or bimolecular), stereochemistry (racemization or inversion) and solvent
effects.99  Three reasonable mechanistic pathways for nucleophilic substitution at silicon
have been investigated: SN1 processes, involving a silylium (R3Si+) intermediate; SN2-
131
type processes; and a free-radical pathway, consisting of a one-electron transfer from the
electron-rich nucleophile to the electrophilic silicon center.44
Highly substituted organic halides undergo nucleophilic substitution, typically
solvolysis, via an achiral carbocation intermediate with concomitant racemization (SN1).100
In contrast, even when substituted by highly stabilizing groups (vinyl, ferrocenyl), chiral
monofunctional triarylsilanes do not undergo SN1 substitution (Scheme 6), as
demonstrated by substitution with a high degree of stereochemical retention or
inversion.101-108  Formation of the silylium intermediate (18) is energetically feasible, but is
kinetically outpaced by bimolecular processes.44,109,110  Eaborn demonstrated the formation
of the silylium intermediate through kinetic and stereochemical studies of the methanolysis
of highly sterically hindered, SN2-supressed silanes.111  Exceptionally hindered substrates
aside, silylium ions are not intermediates in the majority of solution-phase reactions,
including nucleophilic substitution.44,56
Scheme 6
R
SiX
R"R'
R
SiNu
R"
R'
R
Si Nu
"R'R
R
Si
"R R'
- X- + Nu- +
18
Racemization under solvolysis conditions has been observed, with or without the
inclusion of an acid catalyst (Scheme 7).  Racemization is not attributed to the formation of
a silylium intermediate, however, but rather to equilibration and formation of an achiral,
symmetrical pentacoordinate intermediate (19).  In order for equilibration and racemization
to ensue, the leaving group and the nucleophile must either be the same species,56 or be
thermodynamically similar (i.e., the Si-X bond strengths must be approximately equal, to
allow equilibration to occur, i.e., X = Cl, Nu = NR3).112-114
Scheme 7
MeAr Si
OMe
Ph
Me H+ Ar
Si
O
PhMe
H Me
Ar Si
O PhH Me
OMe H
Ar Si
OMe
Ph
Me
H+
Ar Si
O
PhMe
H Me
(S)(R) 19
2-
132
Single-electron transfer (SET) mechanisms similarly have been ruled out.44  In
analogy to SET substitution reactions of carbon compounds, it is feasible that silicates
could undergo nucleophilic substitution through a single-electron transfer from the electron-
rich nucleophile to electrophilic silicon (Scheme 8).44  However, electrochemical data (half-
wave reduction potentials) indicate that the Si-X bond is loathe to react by a one-electron
transfer process; it is more difficult to add an extra electron to a Si-X bond than a C-X
bond.115  Also, when reagents that are highly reactive toward substitution with alkyl
halides through an exclusively free-radical pathway are employed (i.e.,
Cp(DPPE)FeMgBr), no reaction occurs with halosilanes.116-118
Scheme 8
: Nu     +     X?SiR3               Nu     +     X?SiR3                : X     +     Nu?SiR3
Many studies have been devoted to proving the formation of a pentacoordinate
intermediate in the mechanism of nucleophilic displacement at silicon.44  A true, carbon-like
SN2 mechanism would include backside attack of the nucleophile, a pentacoordinate
transition state, inversion of stereochemistry at the silicon reaction center, and exhibit
bimolecular reaction kinetics (Scheme 9, eq. a).99  What is experimentally observed for
silicon displacements, however, is either effectively complete inversion or retention of
stereochemistry; and, consistent with formation of an intermediate involving both the
nucleophile and the substrate in the rate determining step, bimolecular reaction kinetics are
observed (Scheme 2.10, eq. b).56  The difference is subtle: where carbon compounds
form a pentacoordinate transition state (20), silicon compounds form a discrete
pentacoordinate reaction intermediate (121).  Thermodynamically, reactions at silicon
typically have a very low activation energy (?H ? ? 3 kcal/mol) and a high entropy of
activation (?S ? ? -60 e.u.), indicating an entropy-driven process with a highly organized
transition state, such as that leading to a pentacoordinate intermediate.44
133
Scheme 9
R
CX
R"R'
R
C Nu
"R
'RNu
R
C
"R R'
- XNu?-?-X
R
Si Nu
"R
'R
R
Si
"R R'
- XNuX
?
R
SiNu
R"R'
OR
(a)
(b)
20
21
R
SiX
R"R'
Nu
Kinetic studies consisting of comparison of the rate constants for displacements of
pairs of leaving groups (i.e., X = Cl vs. OMe) leading to either exclusively inversion or
exclusively retention showed the same rate of displacement, irrespective of the leaving
group.119-121  In addition, no rate difference (deuterium isotope effect) was observed for the
displacements of H and D.  This data indicates that the rate determining step does not
involve Si-X bond cleavage; thus, a single step SN2 mechanism (Figure 4, (a)) is not
occurring, but rather a two-step mechanism involving rate-determining formation of a
discrete reaction intermediate (Figure 4, (b)).44
E
RC
E
RC
(a) (b)
Figure 4.  Reaction Coordinates for (a) Single-Step and (b) Two-Step Substitution
Processes.
The intramolecular formation of pentacoordinate silicates by the capture of
tetracoordinate silicon by a Lewis base, especially amines and amides, is an often-used
device for the study of hypercoordinate silicates.42,122-126  Bassindale presented a cogent
134
argument for the formation of a pentacoordinate reaction intermediate by the intramolecular
capture of a silane by a series of pyridones (Scheme 10).56,127-129  In addition to detecting
the hypercoordinate intermediate 22 by 29Si NMR, Bassindale showed that the equilibrium
shifts to the right when (1) the pyridone substituent R becomes more electron-donating,
causing oxygen to become more nucleophilic; and (2) the leaving group ability increases
(OR < Cl < Br < OTf).
Scheme 10
N O
Si
R
N
R
Si
O N
R
Si
O X
22
Me Me
XX
Me MeMeMe
Finally, the stereochemistry of nucleophilic displacement of chiral silanes has been
extensively reviewed.44,56,130  When accompanied by kinetic data, the stereochemical
outcome of nucleophilic displacements of silicon has provided great insight into the
mechanism.  Inversion of stereochemistry (Walden inversion) is a manifestation of SN2
displacement at carbon.  Most nucleophilic displacements at silicon also occur in a
predictable manner; however the reaction takes place with either a high degree of
configurational retention or inversion, as determined by the quality of the leaving group
and the hardness of nucleophile.  A more subtle influence on the stereochemistry of
displacement is exacted by the steric bulk of the nucleophile, the hardness of the counter
ion, and the configurational strain of the silane.
Inversion is believed to occur as a result of 180? backside attack, and generally
occurs with soft nucleophiles; retention occurs as a result of 90? front-side (equatorial)
attack, generally by hard nucleophiles (Figure 5).  Front-side attack is possible with
silanes because the Si-X bonds are significantly longer than the C-X bonds: a small, hard
nucleophile can access the ?*Si-X LUMO on silicon on the same side as the leaving group
without enduring unfavorable orbital interactions with the leaving group.  In contrast, soft
135
nucleophiles have larger, diffuse valence orbitals which cannot safely negotiate the front-
side approach without experiencing a sizeable out-of-phase overlap with the leaving
group.  In all cases, the proposed mechanism includes participation of the hypercoordinate
intermediate.
XSi
Nu
Si
Nu
X
Si X
Nu
Si X
Nu
unfavorable
out-of-phase
overlap
180? backside attack
inversion
soft nucleophiles
90? frontside attack
retention
hard nucleophiles
LUMO (?*Si-X)
HOMO (Nu)
Figure 5.  Angle of Attack by Nucleophiles on Silanes.
Fluoride Ion Activation of Silicon Bonds in Organic Synthesis
Synthetic chemists have exploited the unique reactivity of pentacoordinate
silicates for nearly thirty years:42 the first example of a nucleophile-activated reaction of
silanes was Corey?s use of fluoride ion to remove silicon protecting groups.131,132
Recognition of the heightened reactivity of hypercoordinate silicates has led to the
development of novel chemistry, in particular the use of nucleophiles to activate the Si-O,
Si-C, and Si-H bonds of tetracoordinate silane reagents via the presumed
pentacoordinate reactive intermediate (23, Scheme 11).42  While employed less frequently
for organic synthesis, this approach also has been used to activate Si-N and Si-M (M =
Si, Ge, Sn) bonds.35,42,133
136
Scheme 11
Ph H Ph
OSiMe3
H
O
Ph
H
OSiMe3
Ph
O
Me3Si X
Ph Br Ph
X
X
X
Nu-
activation
23
source of "X-"
Si
Nu
X
R RR
As described in detail above, addition of silaphilic catalysts such as fluoride ion to
tetracoordinate silanes increases the reactivity and lability of Si-X bonds in the following
manner:56 relative to the tetracoordinate species, the pentacoordinate silicon center has an
enhanced affinity for nucleophiles due to the increased positive charge on silicon and the
lengthening of silicon-ligand bonds.  In addition, expansion of coordination causes the
ligands to become more nucleophilic due to the assumption of a significant negative
charge, and the weakening of the bond to silicon.  Both of these factors?the increased
silicon Lewis acidity and ligand nucleophilicity upon extracoordination?have been
exploited in organic synthesis.42
A variety of silaphilic catalysts bearing nucleophilic O or N134 have been employed
for the activation of silanes,56 most notably HMPA, Ph3PO, RCO2-, DMAP,20 imidazole and
N-alkyl imidazole derivatives, DMPU, NMP, DMF,135 and DMSO.112,113,136  However, fluoride
is the most often employed nucleophile for the cleavage of other Si-X bonds, because
formation of the strong Si?F bond (582 kJ mol-1)61,65 provides a powerful thermodynamic
driving force toward reaction completion.42  Sources of fluoride ion include R4N+ F- (such as
TBAF), KF/18-crown-6, KHF2,137 CsF, TAS-F (8),138 and TBAT, (1)47,55 among others.47,48,138-
146  Effective fluoride reagents are sources of ?naked? and therefore highly nucleophilic
fluoride by virtue of being unencumbered by a solvent cage and only weakly associated
with the countercation.147  As illustrated below, selection of the proper fluoride species is
crucial to controlling the outcome of reactions of silicates.
137
Fluoride Activation of the Si-O Bond
Silyl ethers are ubiquitous to organic synthesis, in the form of protecting groups for
alcohols and as silyl enol ethers.35,133,148,149  The development of orthogonally reactive
silicon protecting groups is one of the greatest advances in modern synthetic organic
chemistry; that said, silicon protecting group chemistry is a discipline unto itself, and is
reviewed, elsewhere.35,133,148  Silyl enol ethers are also greatly valued for their synthetic
utility: in the presence of an activator such as fluoride, silyl enol ethers function as enolate
equivalents (Scheme 12), capable of delivering excellent regio- and stereoselectivity with
a low incidence of self-condensation in the kinetically controlled aldol condensation.
Enolates thus generated have been used most often for alkylation,150-153 cross-
aldolization153-156 and Michael addition.157-159
Scheme 12
Me
OTMS
+ PhCHO (1) TBAF/THF
(2) H2O
Me
O
Ph
OH
68%
In the aldol reaction of silyl enol ethers, two general mechanisms are believed to
occur, as dictated by the nucleophilicity of the fluoride source (Scheme 13); both involve
formation of the pentacoordinate silicate 24 as the first step.  The first mechanism occurs
when weakly nucleophilic fluoride species are used, such as KF or CsF (eq. a).  In this
case, the weak fluoride nucleophile faces competition for coordination to the
pentacoordinate silicon electrophile 24 from the Lewis basic oxygen of the substrate,160-162
resulting in formation of hexacoordinate intermediate 25 and a chelation-like control of the
reaction stereochemistry via a chairlike transition state.  This accounts for the high degree
of stereocontrol observed under weakly nucleophilic conditions.159
138
Scheme 13
Me3SiO F OSi
F
24
KFor CsF
TAS-F, 8
-Me3SiF2-
R"CHO
25
O
Si
F
O
H
"R
- F O
"R
M e3SiO
(a)
O- TAS+
26
R"CHO O
"R
O
(b)
2F
Me3SiF2-
The second mechanism constitutes simple deprotection and formation of the free
enolate; silicon does not participate in the critical carbon-carbon bond forming step (eq. b).
In this case, a highly nucleophilic fluoride activator such as TAS-F (8) rapidly saturates
the silicon center, displacing the free enolate 26 and generating Me3SiF2-; because the
process is catalytic in fluoride, this mode of reaction cannot be controlled
stoichiometrically.152-155,158  The free enolate 26 thus generated is nucleophilic enough to
react with primary alkyl halides (Scheme 14, eq. a).150,151  In contrast, the hypercoordinate
silicate 25 generated upon activation by the weakly nucleophilic fluoride species CsF is
not sufficiently reactive to achieve displacement (eq. b).42,152,153
Scheme 14
OSiMe3
Br+
BnNMe3+ F- (BTAF)
THF, 37%
O
CsF no reaction
(a)
(b)
Ph
Ph
Lastly, the aldol reaction of the free enolate has a different stereochemical outcome
from the silicon-centered process.  As illustrated in Scheme 15, a predominantly anti
geometry of the aldol products is observed regardless of the configuration of the starting
silyl enol ether 27; this is in congruence with the aldol reaction of free (non-metal chelated)
enolates generated by other means under kinetically-controlled reaction conditions.  In
139
addition, the diastereoselectivity of the reaction of the free enolate 28 is the same
irrespective of the nature of the silyl group on the starting material.152-156,163,164
Scheme 15
RCHO
O
R
OSiMe3
MAJOR
anti
Et
O
R
OSiMe3
MINOR
syn
Et
Et
O- TAS+
27
E or Z
Et
OSiMe3 +TAS-F, 8
-Me3SiF2-
28
The stereoselectivity afforded by the fluoride-catalyzed aldol reaction of silyl enol
ethers was recently exploited by Hosomi and co-workers in the TBAF-mediated
stereoselective synthesis of 1,3-diols 30 and 31 from the dimethylsilyl enol ether
derivatives of acyclic ketones 29 and aldehydes (Scheme 2.19).165
Scheme 16
R
OSiHMe2
Me R R'
OH
Me
R R'
OH
Me
OH OH
R = alkyl, aryl
R'CHO, TBAF
THF, -78 ?C
+
up to 99 :1
30 3129
43-87%
Ando and co-workers achieved the asymmetric aldol condensation of a series of
alkyl and aryl silyl enol ethers 32 with benzaldehyde in the presence of chiral quaternary
ammonium salts 33 derived from Cinchona alkaloids (Scheme 17).166  Alcohols 34 were
obtained in 46-78% yield with ee?s as high as 62%.
Scheme 17
R
OSiMe3
R = alkyl, aryl
PhCHO, THF, -70 ?C
46-76% R Ph
O OH
ee 35-62%
*
N
R'
"RO NH Bn
F
R' = H, OMe; R" = H, Ph, Bn, 1-naph
32
33
34
140
Fluoride Activation of the Si-H Bond
One of the most synthetically useful fluoride-mediated reactions of silanes is the
reduction (hydrosilation) of carbonyl compounds with organosilicon hydrides (Scheme 18,
eq. a); in addition, hydrosilanes effect the silylation of alcohols (eq. b).42,159  Fluoride ion
was shown to be a particularly efficient catalyst167,168 under homogeneous (i.e., CsF in
MeCN)169 or heterogeneous (i.e., CsF, no solvent)170,171 conditions.
Scheme 18
ROH
Et3SiH
Et3SiOR
CsF, MeCN
R Ar
O
R Ar
OSiEt3
(a)
(b)CsF, MeCN
Like most nucleophile-catalyzed reactions of organosilicates, the reaction outcome
can be rationalized by the initial formation of a pentacoordinate silicate 35 (Scheme
19).42,160  Subsequent coordination of the carbonyl or alcohol oxygen to the
pentacoordinate silicon, followed by intramolecular hydride transfer achieves hydrosilation
or formation of the silyl ether, respectively.42  Studies of isolable anionic silicates provides
evidence for formation of the pentacoordinate intermediate 35.42  Stable pentacoordinate
hydrosilicates were shown to reduce a variety of carbonyl compounds in the absence of
a nucleophilic catalyst, whereas the analogous tetracoordinate hydrosilanes were
unreactive.172
Scheme 19
Et3SiH
R Ar
OSiEt3
F
F
Si
H
Et EtEt
F
Si
H
Et
O
Et
Et
Ar
R
F
Si
H
Et
O
Et
Et
H
R
- F
Et3SiOR
ArCOR
ROH +  H235 - F
141
Generally the reduction process is stereoselective for the product as predicted by
the Felkin-Anh model,173,174 and is independent of the nature of the fluoride ion.42  For
example, chiral ketones 36 were reduced in good yield (83%) to give the anti alcohol 37
with de?s as high as 98% (Scheme 20).175
Scheme 20
Ph
O
R PhMe2SiH Ph
OH
R
R = NMe2 (anti : syn = >99:1)
R = OBz (anti : syn = 96:4)
36 37
TBAF, THF
As with the fluoride-mediated reactions of silyl enol ethers, the stereochemical
outcome of the hydrosilation of aldehydes and ketones supports the proposed
mechanism (Scheme 21).  For instance, the anti-Felkin-Anh stereoselectivity favoring
formation of diol 39 in the intramolecular reduction of ?-dimethylsiloxy ketones 38 can be
explained by the influence of a chair-like intermediate on the facial selectivity of the
reduction.176
Scheme 21
Ph
O TAS-F, 8
Ph
OSiMe2H
H
Si
F
O
O
Me
Me
Ph
H
H
H Ph
F
Si
H
O
O
Me
Me
Ph
H
H
H Ph Ph Ph
OHOH
Ph Ph
OHOH
39
40
38
39:40 = 3:1
THF
68%
Fluoride Activation of the Si-C Bond
The fluoride-promoted desilylation of organosilicates containing the C-SiR3 bond is
a general method for C-C bond formation via the transfer to carbon electrophiles of allyl,177
acyl,178 alkynyl,179,180 propargyl,181,182 benzyl,183,184 oxiranyl,185 and other stabilized
carbanions.35,42,133,159  As described in the first chapter, organosilicates also participate in a
142
variety of interesting fluoride-promoted transition metal catalyzed C-C bond forming
reactions; however, these are beyond the scope of this chapter.42  In particular, fluoride
activation of the Si-allyl bond has been extensively used in organic synthesis for the
allylation of aldehydes, ketones, and ?,?-unsaturated compounds (Michael addition).56
The regioselectivity of the addition reaction of trimethylallylsilanes (42 and 43) to
aldehydes (41) is controlled by steric crowding and the electronic distribution at each allyl
terminus, and mixtures of ?- and ?-alkylated products (44 and 45, respectively) are
observed (Scheme 22).177  Isomeric trialkyl silanes 42 and 43 yield comparable ?- and ?-
alkylated product ratios (44 : 45).
Scheme 22
i-Pr H
O
SiMe3
SiMe3
TBAF
TBAF
i-Pr
OH
i-Pr
OH
+
41
44 45
42
43
44:45 = 1.5:1
The observed regiochemistry is consistent with a mechanism involving generation
of the free allyl anion.177  However, formation of a truly ?free? allyl anion is unlikely: the free
allyl anion is basic enough to abstract a proton from the tetrabutylammonium cation of
TBAF, yet no proton abstraction is observed.42,186  Neither extreme?a free anion or a
silicate-based cyclic transition state?is plausible based on experimental observation.  A
hybrid of these two extremes has been proposed, wherein a non-basic hypercoordinate
silicon complex 46 acts simply as an allyl transfer reagent, and the silicon center exacts no
influence on the regiochemical outcome (Scheme 23).177
Scheme 23
SiMe3 TBAF
Si
F
Me MeMe i-PrCHOSi
F
Me MeMe
- FSiMe3 i-Pr
OH
??
??
46
143
In contrast to the trimethylallylsilane analogs, the more Lewis acidic trifluoro- and
trialkoxyallylsilanes more readily form a hexacoordinate intermediate.42  As with the
reactions of silyl enol ethers, allylation takes place with a high degree of regio- and
stereoselectivity as dictated by the nucleophilicity of the fluoride activator.  Irrespective of
the nature of the fluoride species, the mechanism begins with the formation of the
pentacoordinate fluorosilicate 47 (Scheme 24)  When an extremely nucleophilic fluoride
donor (one that is reactive enough to cleave the relatively strong Si-C bond, such as
phosphazenium fluoride, PZ+F-) is employed, fluoride rapidly attacks the pentacoordinate
intermediate 47, displacing a free allyl anion 49 and generating SiF5- (eq. b); as illustrated
in the mechanism, 2 equiv of PZ+F- are required.187  In agreement with the reactivity of free
allyl anions generated by other means, the allyl anion released from the silicate reacts with
primary alkyl halides.187  When a less reactive fluoride source is employed (in this case
TBAF is sufficiently weak), the substrate coordinates to pentacoordinate intermediate 47
(eq. a).  A hexacoordinate species 48 is formed which ultimately controls the stereo- and
regiochemical (exclusively ?-alkylation) outcome of the allylation by inducing a 6-
membered cyclic transition state.42
Scheme 24
SiF3 Si
F
F FFF
CH2
Si
F
F
F
O
F
H
R
R
OSiF3
PZ+47
(a)
48
49
PZ+F-
RCHO
TBAF
- F
RCHO
R
O (b)
2 F-
SiF5-
- SiF5-
For example, a high degree of stereospecificity was observed for the CsF-induced
addition of (E)- and (Z)-crotyltrifluorosilanes to aldehydes (Scheme 25): erythro isomers
54 were obtained from (E)-crotyltrifluorosilane 50; and threo isomers 55 were obtained
from (Z)-crotyltrifluorosilane 51.188  All yields were moderate to excellent (68-96%).
144
Scheme 25
Si FF
F
F
Me
O
H
R
SiF3 R
OH
R
OHSiF3
Si FF
F
FO
H
RMe
H
H
+ RCHO
54
erythro
55
threo
+ RCHO
R = Ph, 50 (92%):   99/1 erythro/threo
51 (96%):   1/99 erythro/threo
R = octyl, 50 (96%):   99/1 erythro/threo
51 (89%):   2/98 erythro/threo
R = i-Pr, 50 (68%):   99/1 erythro/threo
51 (90%): 10/90 erythro/threo
50
51
52
53
CsF
THF
CsF
THF
?
?
The use of fluoride for the activation of Si-X bonds (especially, X = H, O, and C)
is an effective and well-studied synthetic strategy.  Particularly noteworthy is the
formation of C-C bonds with a high level of regio- and/or stereocontrol.  Notoriously
problematic nucleophiles, such as enolates, or carbon nucleophiles that can not be easily
generated by other means (such as deprotonation) are accessible when delivered as the
silicate.133  To date, this approach has been exploited for the delivery of a wide range of
nucleophiles with a reactivity that is markedly different from the free nucleophile, including
the fluoride ion activation of Si-N and Si-M (M = Si, Ge, Sn) bonds.35,42,133  Ubiquitously,
the experimentally observed difference in reactivity and product distribution between the
silicate-delivered vs. the ?free? nucleophile is rationalized by the formation of a
hypercoordinate silicon reaction intermediate.
145
Results and Discussion
Background
Nucleophilic substitution is one of the most prized and useful transformations in the
chemical arsenal.  At the practical level, however, nucleophilic displacements often require
relatively harsh reaction conditions with high reaction temperatures, polar solvents such
as DMSO, HMPA or DMF, and a large excess of the nucleophile if high yields of product
are to be achieved.  Recently, the DeShong research group reported the use of
tetrabutylammonium triphenyldifluorosilicate (Ph3SiF2- Bu4N+, TBAT, 1) as a source of
nucleophilic fluoride for SN2 displacement of primary and secondary alkyl substrates.47  As
illustrated in Scheme 26, TBAT is an excellent fluoride surrogate when compared to alkali
metal fluorides or tetraalkylammonium fluorides because TBAT is relatively non-basic, as
attested to by the reduced amount of elimination products.  In addition, TBAT is a more
practical reagent to handle, and store: TBAT is crystalline, soluble in a wide range of
organic solvents, and is non-hygroscopic.  The anhydrous nature of TBAT is its greatest
advantage over other fluoride sources: the presence of hydroxide in traditional fluorinating
reagents, from the reaction of fluoride anion and water, causes unwanted side reactions,
most notably elimination or hydroxylation.
The displacement of a secondary tosylate is particularly illustrative (Scheme 26,
eq. b): 98% yield of the desired fluoroalkane was achieved with TBAT (1, 6 equiv) in
refluxing MeCN after 24 h; only 58% yield was obtained with TBAF (2 equiv) in THF at
room temperature after 1 h, with the remaining yield being the alkene elimination
products.48,55
146
Scheme 26
TBAT, 1 (4 equiv)
MeCN, 82 ?C, 24 h
85 %
THF, 25 ?C, 1h
48 %
Br
O O
O
O F
F
TBAF (2 equiv)
OTs F
THF, 25 ?C, 1h
58 %
TBAF (2 equiv)
TBAT, 1 (6 equiv)
MeCN, 82 ?C, 24 h
98 %
O O
O
O OMs
TBAT, 1 (6 equiv)
MeCN, 82 ?C, 24 h
73 %
DMAC, 100 ?C, 2.5h
55 %
KF (saturated)
Admittedly, this technology does have some drawbacks.  The fact that 4 to 6
equivalents of TBAT in MeCN are required to obtain reasonable reaction rates is wasteful
and causes purification problems.  These failings are partly ameliorated by the fact that
unreacted TBAT can be precipitated and filtered from the reaction mixture and recycled.
Also, subsequent optimization showed that excellent results are obtained with just two
equivalents of TBAT in refluxing dioxane.55
In an effort to enhance the reactivity of TBAT, Pilcher and Loezos studied the
performance of a series of TBAT analogues, wherein the phenyl ligands were
systematically replaced by methyl or fluoro substituents.55,189  The new fluorosilicates were
tested in a standard displacement reaction (Table 5).  The observed trend can be
summarized as follows: as a strongly electron-withdrawing fluoride ligand of SiF5- Bu4N+
(59, entry 10) is replaced by a weaker EWG (phenyl), or a weak EDG (methyl), the
147
complex becomes more reactive.  The increase in reactivity parallels the increase in the
length of the Si-F bond, and the concomitant bond weakening.55,189
    4 equiv
fluorosilicate
MeCN, 85 ?C + 9Br9 F9
Entry
#
Fluorosilicate Time
(h)
Fluoro
%
Alkene
%
1 (Me2N)3S+ Me3SiF2- (TAS-F, 8) 0.5 40 60
2 Bu4N+ Me2PhSiF2-, 56 2 84 16
3 Bu4N+ Me2SiF3-, 57 5 85 15
4 Bu4N+ MePh2SiF2-, 58 6 92 8
5 Bu4N+ Ph3SiF2- (TBAT, 1) 24 85 15
6 Bu4N+ MePhSiF3-, 59 24 22 11
7 Bu4N+ Ph2SiF3-, 60 24 22 7
8 Bu4N+ MeSiF4-, 61 24 0 0
9 Bu4N+ PhSiF4-, 62 24 0 0
10 Bu4N+ SiF5-, 63 24 0 0
Table 5.  Reactivity of a Series of Fluorosilicate Complexes in the Fluorination of
1-Bromododecane at 85 ?C.55,189
Although Bu4N+ Me2PhSiF2- (56), Bu4N+ Me2SiF3- (57), and Bu4N+ MePh2SiF2- (58)
(Table 5, entries 2-4), offer a better reactivity profile than TBAT (1, entry 5), with shorter
reaction times and comparable yields, TBAT remains the reagent of choice due a number
of factors: (1) ease of handling and of synthesis from commercially available starting
materials; and (2) the crystalline nature allows for the synthesis of a pure anhydrous
reagent.  TBAT is one of the few isolable solid silicates depicted in Table 5: simple
exchange of methyl for phenyl not only impacts the reactivity of TBAT, but also greatly
destabilizes the complex; even exchange of fluoro for phenyl yields a less stable
silicate.55,189  Conveniently, once the tetracoordinate silane had been synthesized, the
unstable TBAT analogs 56-58 were easily generated in situ by treatment with TBAF
(Scheme 27, eqs. a-c); TBAT itself can be generated without isolation by treatment of
Ph3SiF (2) with TBAF (eq. d).
148
Scheme 27
aq. HF Bu
4N+ [Me2PhSiF2]-, 56TBAF
Bu4N+ [Me2SiF3]-, 57TBAF
aq. HF Bu
4N+ [MePh2SiF2]-, 58TBAFaq. HF
Bu4N+ [Ph3SiF2]-, 1TBAFPh3SiOH Ph3SiF, 2
MePh2SiCl MePh2SiF
Me2PhSiCl Me2PhSiF
Me2SiCl2 Me2SiF2SbF3
(a)
(b)
(c)
(d)
Having demonstrated that hypercoordinate silicate derivatives are practical
reagents for the delivery of fluoride anion,47,48,189 extension of this strategy to deliver other
nucleophiles was investigated.  The goal was to focus on developing a method in which
the hypercoordinate silicon reagent is made in situ from either readily available or easily
synthesized tetracoordinate silane starting materials.  The attention focused on the use of
substituted trimethylsilyl derivatives (Me3SiX), many of which are commercially available
(Scheme 28).
Scheme 28
Me Si MeMe
F
X
Me3Si X TBAF
Bu4N+
5: R = Me, X = CN
6: R = Me, X= N3
3: X = CN
4: X= N3
Ph
Ph XBr
The initial experiments involved Me3SiCN (3) and Me3SiN3 (4), the synthetic utility
of cyanide and azide anion in nucleophilic displacements already being recognized.190
Organonitriles are important synthetic intermediates for the preparation of nitrogen-
containing compounds such as amines and amides, and are readily converted to
carboxylic acids, esters, or aldehydes (Scheme 29).  Because of the polarization of the
carbon-nitrogen triple bond, nitriles undergo a variety of reactions with electrophiles on
nitrogen and nucleophiles on carbon.  In addition, the acidic ?-proton can be removed by
strong base.190  The nitrile moiety itself is present in a number of pharmaceutically useful
natural products, and in industrially important synthetic materials.191
149
Scheme 29
COOHR NCR NCR
R1
NC
R
Cl
NC
R
EtO2C
R
COOH
R
COOR1
R
C
R
O
NH2NH
O
R
CH2NH2
R
CHO
R
C
R
NMgX
R
C
R
O
R1
C
R
NH
R1
R R1
NH2
NCR
base
R1X
CCl4
Cl-CO2Et
1. t-Bu3SnCH2I
2. LiMe
O2
H3O+
or OH-
R1OH
H+
 BF3
 HOAcH2SO4
LiAlH4
LiAlH(OEt)3
R1MgX
H3O+
NH3LiNH
3
150
The DeShong group was interested in synthesizing glycosyl azide derivatives as
precursors to N-linked or N-substituted glycoconjugates.  The chemistry and biology of
N-linked glycosides is a topic of intense interest due to the significant role that these
compounds have in biological processes.192  Synthesis of the 1- or 6-glycosyl azide offers
a facile route to the sugar amide (including glycoproteins), amine, or azanucleoside
(Scheme 30).190
Scheme 30
O
N3
O
NH
O
NH2
O
N
R'
O
R'R' NN
R'
R'
R'-CO2H
PR3
H2/PdRO
RO
RO
RO
O
X
RO N3
-
The most common method of introducing the nitrile or azide moiety is by
nucleophilic displacement.190,193  Nucleophilic displacement is inherently regiospecific and
stereoselective, making this approach particularly valuable to the synthetic chemist.  Alkali
metal cyanide or azide has traditionally been used for this purpose; however, these
reagents require vigorous reaction conditions, a large excess of the reagent, and long
reaction times due in part to their limited solubility in organic solvents.193  To overcome the
poor solubility, phase transfer catalysts are typically employed,194 most notably crown
ethers;147,195,196 however, the high cost and relative toxicity197-200 makes their use less
attractive.  Adsorption of alkali salts onto a solid support has been reported,201-206 however
the addition of water is required which limits the use of these reagents to hydrolytically
stable substrates; in addition, lengthy reaction times were reported, due to poor reaction
kinetics.  Other methods employ toxic reagents or activating agents such as tin(IV)207,208 or
151
HMPA.209-211  Traditional alkali cyanide or azide displacement reactions require polar aprotic
solvents, such as DMSO or DMF, which can be problematic to remove.
The more recently developed tetraalkylammonium salts are advantageous over
their alkali metal salt analogs because they are soluble in THF and acetonitrile, and
reactions are fast at or below room temperature.193,212  Unfortunately, along with displaying
enhanced nucleophilicity relative to alkali metal salts, these reagents are also strongly
basic, promoting elimination from the substrate.  Another problem is that these salts are
hygroscopic, or only available as the hydrate; dehydration often results in decomposition
via attack of the nucleophile on the tetraalkylammonium cation (Scheme 31).144  Water in
the presence of the nucleophile generates hydroxide that may act as a nucleophile,
forming unwanted hydroxy products in addition to the desired cyano- or azido products, or
a base, forming elimination products.
Scheme 31
X Et3N:HX
H2C=CH2
+H NEt3
Initial experiments to determine the viability of using in situ generated silicates
Me3Si(CN)F- Bu4N+ (5) and Me3Si(N3)F- Bu4N+ (6) as sources of nucleophilic cyanide or
azide, respectively, employed benzyl bromide (64) as the substrate, in order to avoid the
possibility of elimination by-products (Scheme 32).  The reaction conditions were
analogous to those used for TBAT displacement reactions.  Benzyl bromide (60) was
treated with 2 equiv Me3SiCN (3) or Me3SiN3 (4), and 2 equiv TBAF in acetonitrile and
brought to reflux to generate the proposed reactive silicate intermediates 5 or 6,
respectively.  In the case of Me3SiCN, phenylacetonitrile (65) was formed quantitatively
in less than 5 min (Scheme 32, eq. a); in the case of Me3SiN3, benzyl azide (66) was
formed quantitatively in 8 h (eq. b).  No reaction occurred in the absence of TBAF.
152
Scheme 32
Br CN
Br N3
Br
Br CN
N3
NaN3c
Me3SiN3 (4), TBAF
MeCN, 25 ?C, 12h
97 %
KCN, 18-crown-6
Me3SiCN (3), TBAF
NaCN, calix[4]areneb
Me3SiCN (3), TBAF
MeCN, 82 ?C, <5 min
95 %
CH3CN, 25 ?C, <5 min
95 %
MeCN, 82 ?C, 24h
100 %
Me3SiN3 (4), TBAF
MeCN, 82 ?C, 8h
95 %
NaN3, hemina
Benzene, 60oC, 6h
92 %
H2O, 60 ?C, 2h
83 %
DMF, 25 ?C, 12h
92 %
(a)
(b)
(c)
(d)
64
64
67
67
65
66
68
69
(a) Ref.212  (b) Ref.194 (c) Ref213
In order to gauge the basicity of the reaction conditions, phenethyl bromide (67),
which is prone to base-catalyzed elimination to afford styrene, was employed as the
substrate (Scheme 32, eqs. c and d).  Under identical reaction conditions, quantitative
yields of the respective cyano-(68) and azido-(69) products were obtained.  Comparison
of the reaction conditions for nucleophilic displacement with those typically employed
demonstrates the effectiveness of the silicate strategy.  Displacements employing alkali
153
metal salts in polar solvents consistently required lengthy reaction times, and afforded
more elimination products than the silicate method (vide supra), attesting to the relative
non-basicity of the silicate methodology.
Concurrent with these studies, Takaya and co-workers published a preliminary
report in which alkyl azide derivatives were prepared using the in situ-generated
hypercoordinate azidosilicate 6.214  Having shown in our laboratories that the simple
substrates depicted in Scheme 32 undergo facile cyanide and azide displacements using
silicates 5 and 6, the goal of the research described below was to determine the
generality, and to optimize the reaction conditions for the use of silicate 5 as a source of
nucleophilic cyanide.  Soli, et al. from the DeShong research group extended the azide
methodology to the synthesis of glycosyl azide derivatives.52,54
Cyanide Displacements Utilizing Hypercoordinate Cyanosilicate 5
The major advantage of the silicate method with the substrates shown in Scheme
32 above was the rate of cyanide displacement in acetonitrile.  The silicate-based
displacements were extremely rapid, whereas the displacements using alkali metal salts of
cyanide were sluggish (typically >12h)(Scheme 32, eqs. a and c).  For example, the
silicate-based displacement of benzyl bromide 64 occurred nearly instantaneously in
refluxing acetonitrile, compared with the crown ether procedure that required 24 hours
under identical conditions (eq. a).  Results for the cyanide displacement with a variety of
primary and secondary substrates bearing halide or sulfonate leaving groups are
summarized in Table 6.
154
Si MeMeMe
CN
F Bu4N+
Me3SiCN TBAF R X R CN
MeCN
53
Entry Substrate
R-X
Product
R-CN
Temp
(?C)
Time
(h)
Yielda.b
(%)
1 (C6H5)CH2Br
64
(C6H5)CH2CN
65
82
25
0.1
1
95
(>95)
2 (C6H5)CH2Cl
70
(C6H5)CH2CN
65
82
25
2
72
(>95)
(>95)
3 CH3(CH2)11I
71
CH3(CH2)11CN
72
82
25
0.1
6
95
(95)
4 CH3(CH2)11Br
73
CH3(CH2)11CN
72
82
25
2
36
95
(>95)
5 CH3(CH2)11Cl
74
CH3(CH2)11CN
72
82
25
3
96
95
(33)c
6 CH3(CH2)11OMs
75
CH3(CH2)11CN
72
82 0.1 95
7 (C6H5)CH2CH2Br
67
(C6H5)CH2CH2CN
68
82
25
0.1
32
95
(>95)
8 CH3(CH2)5CH(I)CH3
76
CH3(CH2)5CH(CN)CH3
77
82
25
1
72
(83)
(68)
9 CH3(CH2)5CH(Br)CH3
78
CH3(CH2)5CH(CN)CH3
77
82
25
2
120
(82)
(79)
10 CH3(CH2)5CH(OTs)CH3
79
CH3(CH2)5CH(CN)CH3
77
82
25
1
48
(76)
(70)
11 (C6H5)CH(Br)CH3
80
(C6H5)CH(CN)CH3
81
82
25
1
5
92
(>95)
12 Br
82 CN
83
7:1
endo : exo 82101e 4896 (0)
d
70
13 Br
84
CN
85
82 48 (<5)f
14
Cl 86
CN
87
82
101e
48
96
(0)d
(0)d
a The indicated substrate, Me
3SiCN (3), and TBAF (1:1.5:1.5 molar ratio) in acetonitrile wereallowed to react at the given temperature, unless otherwise noted.  b Isolated yield after
purification.  The yield determined by G.C. analysis of the crude reaction mixture (vs. an internal
standard) is reported in parentheses.  c Reaction was stopped before completion.  d No reaction
was observed.  e Reaction was performed in dioxane.  f Starting material was consumed; remaining
yield assumed to be cyclohexene.
Table 6.  Reaction of Hypercoordinate Silicate 5 with Alkyl Halides.
155
Several features of the results in Table 6 are noteworthy.  Although displacement
was predictably longer for benzyl chloride (70, entry 2) than for the bromo analog (64,
entry 1), the chloride underwent cyanide displacement in comparable yield.  Previous
methods, while achieving similar yield, required longer reaction times, painstakingly dried
reagents, DMSO as the solvent, or toxic 18-crown-6 as a phase transfer catalyst.147,215,216
Primary alkyl iodide (71, entry 3), bromide (73, entry 4), chloride (74, entry 5), and
mesylate (75, entry 6) were efficiently converted to the corresponding nitrile, where the
relative order of reactivity was as follows: I ? OMs > Br > Cl.  Again, the yield of
displacement product was comparable to traditional methodologies; however, these more
conventional methods employed either high temperatures and lengthy reaction times, or
required DMF as the solvent.203,212  Phenethyl bromide (67, entry 7) which should be more
prone to elimination than the dodecyl substrates, gave no elimination products with silicate
5, again attesting to the non-basic nature of the reagent.  Predictably, secondary halides
and sulfonates reacted slower with competing elimination lowering the yields of nitrile.  For
example, silicate 5 rapidly converted 2-iodooctane (72, entry 8), bromide (74, entry 9),
and tosylate (75, entry 10), to the nitrile 73 in good yield (76-83%), although traces of the
alkene by-product were also observed.
For secondary substrates, the silicate methodology was superior to prior methods
with regard to both yield and ease of use.  Regen and co-workers reported the
displacement of the primary bromide in entry 4 (73, Table 6) in quantitative yield using
NaCN-coated alumina in refluxing toluene for 24 hours.203  However, under the same
conditions, Regen reported that secondary bromide 78 in entry 9 gave only 27% of the
corresponding nitrile after 40 hours.  The Bram group was able to perform the same
transformation in 72% yield, but only under aqueous phase-transfer conditions.217  Finally,
secondary benzylic bromide 80 (entry 11) underwent smooth conversion to the
corresponding nitrile upon treatment with cyanosilicate 5 without the formation of the
elimination product.  Again the yield was superior to that previously reported.201
156
In refluxing acetonitrile, no appreciable amount of nitrile product formed from
norbornyl bromide (82, Table 6, entry 12); however, in refluxing dioxane, displacement of
the exo bromide occurred in good yield to give endo nitrile 83, albeit sluggishly.  This
reaction occurred with predominantly inversion of configuration, supporting our proposed
SN2 mechanism for displacement at the carbon center.  The 1H NMR spectrum as well as
the gas chromatograph of mixtures of endo- and exo-2-norbornane carbonitrile (84) were
unresolved, and therefore could not be used for determining the endo:exo ratio.218-220  Nor
could the two products be separated by physical means.  The 13C NMR spectrum of each
stereoisomer has been reported previously.  Fortunately, the 13C NMR spectrum of the
mixture of stereoisomers is partially resolved at the C1, C6, and Cx (the nitrile carbon)
signals.  The endo/exo ratio was determined by integration of the 13C NMR spectrum: the
relative areas of the carbon signals as shown above were: C6 (6.91:1.00), C1
(6.94:1.00), Cx (6.92:1.00), for an average endo/exo ratio of 6.92:1.00.
1 2
34
7
6
5
CNx
83
As expected, the cyclohexyl halides were poor substrates for the displacement
reaction even with the silicate derivative.  Cyclohexyl bromide (84, Table 6, entry 13)
failed to give the displacement product, and gave the alkene instead, mirroring the results
of previous researchers with more basic reagents.147,196,209  (-)-Menthyl chloride (86, entry
14), was similarly unreactive, presumably due to steric hindrance.  However, it is
noteworthy that the reagent did not induce elimination under these reaction conditions.
Cyanide is an ambident nucleophile and is known to react as a carbon nucleophile
to give nitriles (R-CN), or as a nitrogen nucleophile to yield isocyanides (R-NC).221
Traditionally, NaCN or KCN has been used to form nitriles, and AgCN has been used to
form isocyanides.190  It has been rationalized that alkali metal cyanide dissociates to give
"free" cyanide ion which attacks with its more basic carbon terminus, whereas AgCN does
157
not entirely dissociate, leaving Ag+ complexed to the carbon of the nucleophile, so that
only nitrogen is available for nucleophilic attack.222
We hypothesized that the silicon could function analogously, so that C-
complexation to silicon223 would leave the cyano nitrogen available to act as a nucleophile,
as in Scheme 33.  However, no traces of isonitrile products were detected in the reaction
mixtures by 13C-NMR or IR.  In addition, isonitriles have a characteristic stench even at
low concentration; no foul odor was detected in the crude product.
Scheme 33
Me Si MeMe
F
C
N
Br NCX
:5
Exploration of the Use of Catalytic Amounts of Fluoride
Having shown that a stoichiometric amount of TBAF induces trimethylsilyl cyanide
to transfer cyanide nucleophile to a variety of primary and secondary substrates, studies
were initiated to explore if TBAF could be used catalytically.  As shown in Table 7, it was
found that the displacement of benzyl bromide is not catalytic in fluoride.  More
interestingly, the reaction is not even stoichiometric in TBAF: note that 1.0 equiv of TBAF
relative to the substrate resulted in 89% conversion to the nitrile product.  This is
consistent with observations that when less than 1.2 equiv of TBAF to 1.2 equiv of
Me3SiCN (3) relative to 1.0 equiv of the substrate were employed, the reaction did not
always go to completion.  This is attributable to a number of factors, including: (1)
hydrolysis of Me3SiCN by the water present in commercial grade TBAF (5% H2O),
resulting in formation of Me3SiOH; and (2) the consumption of TBAF by reaction with the
Me3Si-F by-product, resulting in the formation of Me3SiF2- Bu4N+.  As described below,
NMR studies confirm the formation of both R3SiOH and R3SiF2- Bu4N+ in mixtures of
R3SiCN and TBAF.
158
Br CNMe3SiCN (3) / TBAF
MeCN, 1h, 25 ?C
64 65
Entry TBAF
(mol %)
Yielda,b,c
(%)
1 100 89
2 50 42
3 25 15
a Benzyl bromide (64, 1 equiv), Me
3SiCN (3, 1.5 equiv), and thegiven amount of TBAF in MeCN were allowed to react at room
temperature.  b Reactions were complete by 1 h.  c Yield of 65
determined by G.C. analysis of the crude reaction mixture (vs. an
internal standard).
Table 7.  Reaction of Benzyl Bromide (64) with Trimethylsilyl Cyanide (3) and Varying
Amounts of TBAF.
As depicted in Scheme 34, in order for the reaction to be substoichiometric in
TBAF, the leaving group anion Bu4N+Br- must itself become the activating catalyst by
attacking Me3SiCN to form a hypercoordinate bromo cyanosilicate reactive intermediate 88.
In effect, TBAF would act as an initiator, not as a catalyst.  Fluoride catalysis is unlikely,
because regeneration of fluoride would require the cleavage of the strong Si?F bond and
formation of a much weaker Si?Br bond.
Scheme 34
CN
Si
Br
Me MeMeMe3SiCN
Ph BrPh CN
Me3Si-CN
3
CN
Si
F
Me MeMeF
-
Ph Br
Ph CN
Me3Si-F
Me3Si-Br
Bu4N+ Br-
885 +
+
3
159
With the aim of testing the ability of bromide or other typical leaving group anions
to activate Me3SiCN, 1 equiv of benzyl bromide was treated with 1.5 equiv of Me3SiCN
and 1.5 equiv of a series of TBAX salts (X = Br, Cl, I, OTF).  The results are depicted in
Table 8.  As anticipated, bromide, chloride, iodide and triflate ion (Table 8, entries 2-5)
were not sufficiently nucleophilic to activate Me3SiCN.  When a more basic oxygen
nucleophile was employed (tetrabutylammonium acetate, entry 6), phenylacetonitrile was
formed, however the reaction conversion was poor.  These results are explained by the
relative Si?X and Si?O bond strengths, and indicate that there is a strong thermodynamic
driving force behind the formation of the Si?F bond.  The Si?F bond energy (582 kJ?mol-1)
is significantly greater than the Si?O, Si?Cl, Si?Br, or Si?I bond energies (368, 391, 310,
and 234 kJ?mol?1, respectively).
Br CNMe3SiCN (3) / X- Bu4N+
64 65
MeCN
reflux
Entry Nucleophile Time (h) Yield (%)a,b
1 F- Bu4N+ 0.1 >95
2 Br- Bu4N+ 24 0
3 Cl- Bu4N+ 24 0
4 I- Bu4N+ 24 0
5 TfO- Bu4N+ 24 0
6 AcO- Bu4N+ 0.1 45c
a Benzyl bromide (64) (1 equiv), Me
3SiCN (1.5 equiv), and the indicatednucleophile (1.5 equiv) in MeCN were allowed to react at reflux.  b The yield
of 65 was determined by G.C. analysis of the crude reaction mixture (vs. an
internal standard).  c Reaction was allowed to proceed for 24 h, but no
additional progress was detected.
Table 8.  Reaction of Benzyl Bromide (64) and Trimethylsilyl Cyanide (3) with
Tetrabutylammonium Nucleophiles.
160
Investigation of Alternative Fluoride Sources
As illustrated in Table 8, fluoride is the unrivaled species for the activation of
Me3SiCN.  In an effort to fully optimize this methodology, a number of other fluoride
sources were surveyed in a standard displacement reaction.  It was believed that the
hydroxide contaminant in TBAF, and/or the inherent basicity of TBAF could contribute to
the formation of elimination products, and that other less basic fluoride sources could
reduce alkene formation.  In addition, alkali metal salts of fluoride are significantly less
expensive than TBAF.  In order to test the ability of other common fluoride sources to
activate Me3SiCN, 1 equiv of benzyl bromide was treated with 1.5 equiv of Me3SiCN and
1.5 equiv of a series of fluoride salts (KF, CsF, and TBAT, 1).  The order of fluoride
reactivity toward the primary substrate was as follows: TBAF ? TBAT >> KF/18-crown-6
> KF  ? CsF.  Under heterogeneous conditions, the reaction was sluggish, and generally
failed to go to completion (Table 9, entries 2 and 4).  Addition of a phase transfer catalyst
to KF increased the overall yield and shortened the reaction time (entry 3).
Br CNMe3SiCN (3) / F
64 65
MeCN
reflux
Entry Fluoride Salt Time
(h)
Yield
(%)a,b
1 Bu4N+ F- >1 100
2 KF 72 80c
3 KF / 18-crown-6d 48 100
4 CsF 48 75c
5 TBAT, 1 >1 100
a Benzyl bromide (64) (1.0 equiv), Me
3SiCN (3) (1.5 equiv), and the indicated fluoride salt(1.5 equiv) in MeCN were allowed to react at reflux.  b The yield of 65 was determined by
G.C. analysis of the crude reaction mixture (vs. an internal standard).  c Reaction was
allowed to proceed for and additional 24 hours, but no further progress was detected.
d Catalytic in 18-crown-6 (20 mol %).
Table 9.  Reaction of Benzyl Bromide (64) and Trimethylsilyl Cyanide (3) with Alternative
Fluoride Sources.
161
TBAT and TBAF both rapidly induced the reaction (Table 9, entries 1 and 5).
While both reagents performed similarly in the above displacement reaction with benzyl
bromide, TBAT potentially could outperform TBAF in the reaction with secondary
substrates.  As described previously, TBAT is both less basic and more anhydrous than
TBAF, and in theory should suppress elimination.  However, effectively no reactivity
difference was observed in the displacement of secondary alkyl substrates, regardless of
the leaving group (Br, I, or OTs)(Table 10).
X CN
77
Me3SiCN (3) / F
MeCN
reflux
Entry Substrate Fluoride
Source
Time
(h)
Yielda,b,c
(%)
1 CH3(CH2)5CH(I)CH3
76
TBAF
TBAT, 1
1
1
83
85
2 CH3(CH2)5CH(Br)CH3
78
TBAF
TBAT, 1
2
3
82
86
3 CH3(CH2)5CH(OTs)CH3
79
TBAF
TBAT, 1
1
1
76
74
a The yield of 77 was determined by G.C. analysis of the crude reaction
mixture (vs. an internal standard).  b All reactions went to completion; the
remaining yield was 2-octene.  c The remaining yield was 2-octene.
Table 10.  Reaction of Secondary Alkyl Halides with Trimethylsilyl Cyanide (3) and TBAF
or TBAT (1).
Proposed Mechanism
Two feasible mechanistic pathways for the Me3SiCN/TBAF cyanide displacement
reaction are depicted in Scheme 35.  Based on standard silicate chemistry (vide supra),
either path begins with attack of fluoride on silicon to form the hypercoordinate cyano
fluorosilicate 5.  One potential mechanism subsequently involves direct transfer of
cyanide from silicate 5, without formation of a free cyanide nucleophile (route A).  The
second proposed mechanism entails the overall disproportionation of intermediate 5 to
162
tetrabutylammonium cyanide (Bu4N+CN-, 90) and Me3SiF (89); Bu4N+CN- would then act
as the cyanide source (route B).
Scheme 35
Me3SiCN
CN
Si
F
Me MeMeTBAF
53
Bu4N+
- Me3SiF
89
Bu4N+CN-
90
R Br R CN
R Br R CN
route A
route B
The cyanide anion delivered by silicate 5 should have a different reactivity than its
disproportionation product, Bu4N+CN-.  In order to determine a reactivity difference, and to
ultimately determine the reaction mechanism, commercially available Bu4N+CN- was
purchased, and its reactivity compared to the Me3SiCN/TBAF reagent.  The results are
summarized in Table 11.
As seen in Table 11, Bu4N+CN- reacted 1.5 to 9 times faster than the cyanosilicate
reagent 5 with a variety of primary and secondary alkyl halides and sulfonates to form the
corresponding nitrile in good yield.  The product yields were identical for both methods.  As
demonstrated by entries 1 through 4, the order of reactivity for both systems with primary
alkyl halides was I ? OTs > Br > Cl.  In each case, Bu4N+CN- reacted more rapidly than
the silicate system.  Entry 3 is particularly illustrative: where the Me3SiCN/TBAF reaction
only reached 33% conversion after 96 hours, the Bu4N+CN- reaction was complete within
36 hours.  The secondary substrates in entries 5-8 showed a less dramatic difference in
reaction time, and comparable product yields.  Finally, norbornyl bromide (82, entry 9)
was equally as unreactive with Bu4N+CN- as with Me3SiCN/TBAF in refluxing acetonitrile.
In contrast, both the silicate and the Bu4N+CN- methods furnished norbornane carbonitrile
(83) in refluxing dioxane.
163
R X R CN
Me3SiCN (3) / TBAF
or
Bu4N+CN- (90)
MeCN
Entry Substrate Product Reagent Temp
(?C)
Time
(h)
Yielda,b
(%)
1 CH3(CH2)11I
71
CH3(CH2)11CN
72
3/TBAF
Bu4N+CN-
25
25
6
1
95
95
2 CH3(CH2)11Br
73
CH3(CH2)11CN
72
3/TBAF
Bu4N+CN-
25
25
36
3
>95
>95
3 CH3(CH2)11Cl
74
CH3(CH2)11CN
72
3/TBAF
Bu4N+CN-
25
25
96
36
33c
>95
4 (C6H5)CH2CH2Br
67
(C6H5)CH2CH2CN
68
3/TBAF
Bu4N+CN-
25
25
32
2
>95
>95
5 CH3(CH2)5CH(I)CH3
76
CH3(CH2)5CH(CN)CH3
77
3/TBAF
Bu4N+CN-
25
25
72
24
68
71
6 CH3(CH2)5CH(Br)CH3
78
CH3(CH2)5CH(CN)CH3
77
3/TBAF
Bu4N+CN-
25
25
120
96
79
77
7 CH3(CH2)5CH(OTs)CH3
79
CH3(CH2)5CH(CN)CH3
77
3/TBAF
Bu4N+CN-
25
25
48
24
70
74
8 (C6H5)CH(Br)CH3
80
(C6H5)CH(CN)CH3
81
3/TBAF
Bu4N+CN-
25
25
5
3
>95
>95
9 Br
82
CN
83
7:1
endo : exo
3/TBAF
Bu4N+CN-
82
101e
82
101e
48
96
48
72
0d
70
0d
60
a Where 3/TBAF is the reagent, the indicated substrate, Me
3SiCN (3), and TBAF (1:1.5:1.5molar ratio) in acetonitrile were allowed to react at the given temperature, unless otherwise
noted.  Where Bu4N+CN- (90) is the reagent, the indicated substrate, and Bu4N+CN- (1:1.5
molar ratio) in acetonitrile were allowed to react at the given temperature.  b Yield determined
by G.C. analysis of the crude reaction mixture (vs. an internal standard).  c Reaction was
stopped before completion.  d No reaction was observed.  e Reaction was performed in
dioxane.
Table 11. Comparison of Nitrile Synthesis Using Me3SiCN/TBAF or Bu4N+CN-.
164
The observed reactivity difference between the two methods suggests that the
displacement reaction does not involve a simple disproportionation of cyanosilicate 5 to
form Bu4N+CN- (90) in situ (Scheme 36, eq. a).
Scheme 36
Me Si MeMe
CN
F
5
Bu4N+
CN-Bu4N+ + Me3Si-F
Ph Si PhPh
F
F
TBAT, 1
Bu4N+ F
-Bu4N+ + Ph3Si-F
(a)
(b)
89
2
90
Prior research with the analogous fluorosilicate TBAT (1) mirrors these results.
Experimental evidence supported the conclusion that TBAT does not simply
disproportionate to generate TBAF in situ (Scheme 36 above, eq. b), but rather directly
delivers a softer, less basic fluoride nucleophile.  For example, Pilcher demonstrated that
the hypercoordinate fluorosilicate TBAT performed fluoride displacements more slowly,
and gave less elimination than its disproportionation product, TBAF (Scheme 37).48,55
Scheme 37
OTs TBAT, 1
MeCN, reflux
F +
OTs TBAF
MeCN, 25 ?C
F +
98% 2%
58% 32%
24 h
1 h
Having determined that Bu4N+CN- was not the reactive intermediate, investigations
into a mechanism involving hypercoordinate cyanosilicate 5 as the direct source of
cyanide were undertaken.  In addition, the participation of other silicon species such as
dicyano trimethylsilicate (91), or difluoro trimethylsilicate (92) was investigated.
165
CN
Si
CN
Me MeMe
Bu4N+
F
Si
F
Me MeMe
Bu4N+
91 92
F
Si
CN
Me MeMe
Bu4N+
5
Chris Handy of the DeShong group endeavored to obtain spectroscopic evidence
supporting the existence of hypercoordinate cyanosilicate intermediates such as 5, 91 and
92.224  Triphenylsilyl cyanide (Ph3SiCN, 93, Scheme 38) was chosen for study rather than
trimethylsilyl cyanide (3): given that hypercoordinate silicates are inductively stabilized by
aryl substituents (vide supra), it was expected that upon treatment with 1 equiv of TBAF,
a greater amount of the more stable hypercoordinate intermediate 94 would form (Scheme
38).  Also, in contrast to the non-isolable trimethylsilyl silicates 91 and 92, authentic
samples of the triphenylsilyl silicate analogs (95 and 1, respectively) were readily
prepared and characterized.
Scheme 38
Ph3Si TBAF
93
CN Si PhPh
F
F
1, TBAT
Ph
Bu4N+
Si PhPh
CN
CN
95
Ph
Bu4N +
Si PhPh
CN
F
94
Ph
Bu4N +
For reference, Table 12 summarizes the 29Si NMR spectral data for all authentic
samples prepared by Handy.  It was expected that any four- or five-coordinate silicate
species formed in the reaction would be detected the ranges 45 to ?115 ppm or ?70 to
?200 ppm, respectively (vide infra).93
166
Compound 29Si
(ppm)
JSi-F
(Hz)
Ph3SiCN, 93 -28.2, sb -
Ph3SiF, 2 -4.0, d 282
[Ph3SiF2]-[NBu4]+, 1 -106.3, t 251
[Ph3Si(CN)2]-[NBu4]+, 95 -118.0 -
Ph3SiOH, 96 -16.9, s -
Ph3Si-O-SiPh3, 97 -18.2, s -
a Value for the phenyl carbon directly attached to silicon.  b Spectrum in
THF.  c Value for the nitrile carbon.
Table 12.  29Si-NMR Spectral Data for Authentic Samples Used In Mechanistic Studies
(Room Temperature, CDCl3).47-49,55
Treatment of Ph3SiCN (93) with 1 equiv of TBAF led to the immediate
disappearance of the starting material signal and formation of hydrolyzed silane [Ph3SiOH
(96) and its ether Ph3SiOSiPh3 (97)]; at room temperature, no other peaks were observed
in the 29Si NMR spectrum (Figure 6, spectrum b).  The silicon hydrosylates 96 and 97 can
be attributed to the reaction of the water present in TBAF with the starting silane 93 and/or
silicate derivatives 94 and 95.  Handy conclusively demonstrated that the source of these
silicon hydrosylates was likely to be cyano fluorosilicate 94 and/or dicyanosilicate 95.
Treatment of Ph3SiCN (93) with water did not result in formation of either silanol 96 or its
silyl ether 97.  In contrast, an authentic sample of dicyanosilicate 95 underwent immediate
conversion to hydrolyzed silanes 96 and 97.  It was concluded that silicate formation was
a prerequisite for the hydrolysis process.
In order to probe the existence of a rapid equilibrium, Handy performed the same
NMR experiment at -30?C.  As before, treatment of Ph3SiCN (93) with 1 equiv of TBAF
led to the disappearance of the starting material signal and formation of hydrolyzed silane;
however at reduced temperature, a peak corresponding to Ph3SiF2- (TBAT, 1) also was
observed (Figure 6, spectrum c).  In the 13C NMR spectrum, neither Bu4N+CN- (90) nor the
167
starting materials Ph3SiCN (93) and TBAF were observed at any temperature, implying
the rapid and possibly irreversible formation of intermediate 94 at the reaction outset.
29Si spectrum with inverse gated proton decoupling, recorded at 99 MHz on a Bruker AMX 500
spectrometer (D1= 10 sec, P1= 9.00 ?sec, no spinning).  a: Ph3SiCN (93) in THF, 25 ?C, 98 scans; b:
Ph3SiCN (93) + 1 equiv TBAF in THF, 25 ?C, 250 scans; c: Ph3SiCN (93) + 1 equiv TBAF in THF, -30
?C, 400 scans.  The broad peak appearing in the range -90 to -120 ppm in all 29Si spectra is present in
all samples including solvent blanks, and is likely due to the use of silicon-based adhesives in the
assembly of the probe. (Reprinted by permission of C. J. Handy)
Figure 6.  Triphenylsilyl Cyanide (93) and TBAF (1 equiv), 29Si Spectrum.
Formation of TBAT in 1:1 mixtures of Ph3SiCN and TBAF, without the formation of
Bu4N+CN- or Ph3SiF would imply a mechanism involving disproportionation of two
molecules of the hypercoordinate cyano fluorosilicate 94 to dicyanosilicate 95 and TBAT
(1) (Scheme 39).  The absence of signals corresponding to a number of silicates, most
especially the key intermediates cyano fluorosilicate 94 and dicyanosilicate 95, does not
disprove their existence, but rather suggests that these hypercoordinate silicates are
significantly less stable than TBAT, and may exist fleetingly or undergo rapid hydrolysis
168
to the silanol Ph3SiOH (91).  Ultimately, the process is driven at least in part by formation
of the highly stable difluorosilicate 1.  In addition, the fact that dicyanosilicate 90 can be
prepared and observed by IR and NMR spectroscopy, whereas the mixed cyano
fluorosilicate 94 cannot suggests that the equilibrium is further driven by formation of
symmetrical dicyanosilicate 95.
Scheme 39
+2 Si
Ph
Ph
CN
F
94
Ph
Bu4N+
Si PhPh
CN
CN
95
Ph
Bu4N+
Si PhPh
F
F
1, TBAT
Ph
Bu4N+
In summary, no direct evidence of production of hypercoordinate intermediate 94
was provided by the NMR studies performed by Handy, however the spectroscopic
data strongly points away from a simple in situ generation of Bu4N+CN-.  The NMR study
indirectly points to a process involving rapid disproportionation of unstable cyano
fluorosilicate intermediate 94 to the more stable dicyano and difluoro silicates (95 and 1,
respectively, Scheme 39, above).  In theory when this reaction is performed in the
presence of a displacement substrate, either hypercoordinate cyanosilicate 94 or 95 could
function as the source of nucleophilic cyanide (Scheme 40).  However the
disproportionation of 94 to dicyanosilicate 95 and TBAT is very rapid by NMR
spectroscopy, in contrast to the rate of displacement of alkyl halides.  Thus, silicate 95 is
strongly implicated as the reactive intermediate in this process.
Scheme 40
94
TBAT, 1
fast
slowslow slow2 Si Ph
Ph
CN
F
Ph Si PhPh
CN
CN
95
Ph2  R X R X R CNR CN
169
Scheme 41 depicts a plausible mechanism for the Me3SiCN/TBAF displacement
reaction that takes into account the following conclusions based on the NMR data,
experimental observations, and literature precedence: (1) the mechanism involves as its
first step the transient formation of the hypercoordinate cyano fluorosilicate 5 followed by
rapid disproportionation to dicyanosilicate Me3Si(CN)2- Bu4N+ (91) and Me3SiF2- Bu4N+
(92); (2) Bu4N+CN- (90) at no time is generated in significant quantity; (3) TBAF is rapidly
consumed at the reaction outset; (4) the leaving group nucleophile does not participate in
the reaction sequence; and (5) only slightly more than 1 equiv of the Me3SiCN/TBAF
mixture is required for reaction completion, most likely due to water contamination.
Scheme 41
CN
Si
F
Me MeMe
F
Si
CN
Me MeMe
Bu4N+ F-
+
fast
5
5
Me Si MeMe
CN
CN91
Me Si
Me
Me
F
F92
92
Me3SiCN
3
R X R CN
Me3SiCN, 3
Bu4N+Br-
The above proposed mechanism begins with rapid formation and
disproportionation of cyano fluorosilicate intermediate 5 to generate Me3SiF2- (92) and
dicyanosilicate 91.  Hypercoordinate silicate 91 transfers cyanide nucleophile to the
substrate to form alkylnitrile, and to regenerate Me3SiCN (3).  The Me3SiCN thus
produced undergoes rapid fluoride activation by Me3SiF2- (92) to form a second molecule of
cyano fluorosilicate 5, which again disproportionates to Me3SiF2- (92) and a second
molecule of dicyanosilicate 91.  A notable feature of the above proposed mechanism is
Me3SiF2- (92) is required to function as a fluoride source; otherwise 2 equiv of TBAF to 1
equiv of Me3SiCN would be required for reaction completion.  Silicate Me3SiF2- Bu4N+ (92)
should be an excellent fluorinating species in analogy to the powerful fluorinating reagent
Me3SiF2- (Me3N)S+ (TAS-F, 8).
170
F
Si
F
Me
Me Me
N S
N
N
TASF, 8
Bu4N+
92
F
Si
F
Me
Me Me
Conclusions
Treatment of trimethylsilyl cyanide with TBAF resulted in the in situ generation of a
hypercoordinate cyanosilicate.  The reactive silicate has been shown to be highly
effective as a nucleophilic cyanide donor under extremely mild conditions in contrast to
traditional cyanide reagents.  Primary and secondary alkyl halides and sulfonates undergo
rapid and efficient cyanide displacement in the absence of phase transfer catalysts with
the silicate methodology.  The Me3SiCN/TBAF system is significantly less reactive and
less basic than TBA-CN, therefore the mechanism of reaction most like involves the in situ
generation of a hypercoordinate cyanosilicate, rather than disproportionation of Me3SiCN
and TBAF to form TBA-CN in situ.
Epilogue
Since the publication of the above method for azide and cyanide displacements
via hypercoordinate silicate intermediates in 1999,52-54 a number of papers have appeared
in the literature225 which report using our technique, primarily for the stereocontrolled
synthesis of azido sugars,226-233 and for the nucleophilic ring opening of aziridines.227,234  Hou
reported the ring-opening reactions of aziridines 98 with trimethylsilyl compounds triggered
by TBAF to give the corresponding products 99 and 100 regioselectively in excellent yield
(Scheme 42).234  TBAF functions to simply initiate the reaction: the amide leaving group is
itself nucleophilic enough to attack silicon, and cleave the Me3SiX bond.
171
Scheme 42
NHTs
R NHTsR XR
X NHTs
Me3SiX (X = N3, CN)
TBAF (5 mol %)
+
R = H, X = N3, >99% 99
R = H, X = CN, 95% 99
R = CH3, X = N3, 63% (>99 : 1) (99:100)
R = CH3, X = CN, 79% 99
98 99 100THF
Aggarwal demonstrated a potential limitation of the Me3SiX/TBAF strategy:
although this method is relatively mild, highly base-sensitive substrates can react with
TBAF to yield undesired elimination products.227  As illustrated in Scheme 43, eq. a,
attempts by Aggarwal to isolate the ring-opened nitrile 102 were thwarted by formation of
alkene 103.  Control experiments by Aggarwal implicated TBAF as the cause of
elimination (Scheme 43, eq. b): exposure of an authentic sample of the ring-opened
product 104 to TBAF promoted elimination.  Regrettably, Aggarwal did not try substituting
the less basic TBAT for TBAF as the fluoride source, to preempt unwanted elimination.
Scheme 43
N
Ph SiMe3
Ts
TsHN Nu
SiMe3
Ph
Nu101
104
TBAF
Ph Nu
105
(a)
(b)
TsHN CN
SiMe3
Ph
Ph CNTBAF (5 mol %)
THF
102
103
Me3SiCN, 3
Preliminary reports indicate that mannose and glucose derivatives are poor
substrates for cyanide displacement by hypercoordinate cyanosilicate 5 (Scheme 44, eq.
a).  This is in stark contrast to azide displacements by hypercoordinate azidosilicate 6:
Soli demonstrated the synthesis of glycosyl azides from various glycosyl donors in high
yields with excellent regio- and stereocontrol (Scheme 44, eq. b).
172
Scheme 44
O
X
RO
F
Si
CN
Me MeMe
Bu4N+5
X O CNRO
O
N3
ROF
Si
N3
Me MeMe
Bu4N+6
(a)
(b)
Prompted by the interest of the DeShong research group in methods for the
synthesis of mannosyl glycoconjugates, the author and Handy performed investigative
experiments which indicated that 6-O-tosyl and 1-?-bromo per-O-acetylated mannose
derivatives (106 and 107, respectively) were poor substrates for cyanide displacement.
Deacetylation and eventual decomposition of the starting material were observed, even
for the primary tosyl sugar (106).
O
AcO
AcO
AcO
OAc
Br
107
O
TsO
AcO
AcO
OAc
OAc
106
The sensitivity of sugar substrates has been confirmed by Gervay-Hague, using
1-?-iodo per-O-benzylated mannose derivative 108 (Scheme 45).235  When subjected to
standard Me3SiCN/TBAF conditions, the more robust benzyl protecting groups of sugar
108 remained intact, however none of the desired cyano sugar 109 was obtained
(Scheme 45, eq. a).  Instead, the 1,2-elimination compound 110 was formed quantitatively
(Scheme 45, eq. b).
173
Scheme 45
(a)
(b)
O
BnO
BnO
BnO
OBn
I Me3SiCN
Me3SiCN
X O
BnO
BnO
BnO
OBn
CN
O
BnO
BnO
BnO
BnO
108
109
110
TBAF
THF
TBAF
THF
The method described herein for the in situ formation of reactive hypercoordinate
fluorosilicates is potentially quite general; the Me3SiCN/TBAF methodology is a prototype
for the delivery of other anions.  For example, trimethylsilyl isocyanate (Me3Si(NCO)) is
commercially available, and upon activation with TBAF has the potential of delivering the
synthetically valuable190 isocyanate nucleophile via hypercoordinate silicate 111.
Me Si
Me
Me
OCN
F Bu4N+
111
Me Si
Me
Me
F3C
F Bu4N+
113
Me Si
Me
Me
F Bu4N+
112
Preliminary studies by Poli indicate that cyclopentadienyl fluorosilicate 112 is a
useful source of cyclopentadienyl anion for the synthesis of organomolybdenum
complexes where other reagents fail; compound 112 is generated in situ by treatment of
5-(trimethylsilyl)-1,3-cyclopentadiene with TBAF. 236  Lastly, the utilization of
Me3SiCF3/TBAF for the transfer of trifluoromethyl anion has recently been reported; the
researchers attributed the relative mildness and low basicity of this method to the
formation of hypercoordinate silicate intermediate 113.237-241
The scope of this methodology continues to be more precisely defined outside of
the DeShong laboratories, as new reports of its application to complex natural product
174
synthesis appear in the literature.225,229,242  Although no further optimization of this technique
is planned, the DeShong group does continue to employ this reaction for the synthesis of
glycosyl azide derivatives.243
175
Experimental
General.  Thin layer chromatography (TLC) was performed on 0.25 mm Merck silica-
coated glass plates treated with a UV-active binder, with the compounds being visualized
in one or more of the following manners: UV (254 nm), iodine, or vanillin/sulfuric acid
charring.  Flash chromatography was performed using thick-walled glass columns and
medium-pressure silica gel (Davisil? 200-425 mesh) as described by Still.244  Flash
chromatography data is reported as: (column diameter in mm, column height in cm,
solvent).
Infrared spectra were recorded on a Nicolet 5DXC FT-IR spectrophotometer with
the samples prepared as stated.  Band positions are given in reciprocal centimeters (cm-1)
and relative intensities are listed as br (broad), vs (very strong), s (strong), m (medium),
or w (weak).
Melting points were taken in Kimax soft glass capillary tubes using a Thomas-
Hoover Uni-Melt capillary melting point apparatus (Model 6406K) equipped with a
calibrated thermometer.  Melting points are corrected.
Nuclear magnetic resonance (1H, 13C) spectra were recorded on a Bruker DRX-400
spectrometer.  Chemical shifts are reported in parts per million (?) downfield from
tetramethylsilane (TMS).  Coupling constants (J values) are reported in Hertz (Hz), and
spin multiplicities are indicated by the following symbols: s (singlet), d (doublet), t (triplet),
q (quartet), m (multiplet), br s (broad singlet).
Low resolution (MS) and high resolution mass spectra (HRMS) were obtained on
a VG-7070E magnetic sector instrument equipped with a 486 PC-based data system.
GCMS was performed on a Shimadzu QP5000MS coupled with a GC17A gas
chromatograph.
Gas chromatography was performed on a Hewlett Packard 5890 GC equipped
with a flame ionization detector using a 25 m methyl silicon column.
176
Methyl sulfoxide (DMSO), and acetonitrile (MeCN) were each distilled from calcium
hydride.  Dioxane was distilled from sodium-benzophenone ketyl.
All reagents and alkyl halides were purchased from Acros or Aldrich and purified
using the method of Perrin245 prior to use, or prepared by literature procedure as noted.
The substrate 2-iodooctane246 was prepared according to the literature procedure.  In the
case of alkyl sulfonates 75 and 79, the appropriate sulfonate was synthesized from the
alcohol immediately before use using the literature method247,248 and the crude isolated
sulfonate was used without further purification.  Tetrabutylammonium fluoride (TBAF) was
purchased from Acros as a 1.0 M solution in THF and used as received.
Tetrabutylammonium triphenyldifluorosilicate (TBAT) was prepared according to the
literature procedure.48
Glassware used in the reactions described below was dried for a minimum of 12 h
in an oven at 120 ?C.  All reactions were run under an atmosphere of nitrogen or argon at
room temperature unless otherwise noted.
All compounds were determined to be >95% pure by 1H NMR unless otherwise
noted.
General Procedure for Synthesis of Nitriles Using Trimethylsilyl Cyanide
(Me3SiCN, 3) and Tetrabutylammonium Fluoride (TBAF) (Table 6).  Trimethylsilyl
cyanide (149 mg, 200 ?L, 1.50 mmol) and TBAF (1 M in THF, 1.5 mL, 1.5 mmol) were
added to a stirring solution of the alkyl halide (1.00 mmol, 1 equiv) in 10 mL solvent
(MeCN or dioxane) under an atmosphere of nitrogen.  Unless otherwise noted, the
reaction was performed at the given temperature until GC analysis indicated that the
starting material had been consumed.  The reaction mixture was concentrated in vacuo,
and the resulting syrup was purified by flash chromatography.
177
Si MeMeMe
CN
F Bu4N+
Me3SiCN TBAF R X R CN
MeCN
53
Entry Substrate
R-X
Product
R-CN
Temp
(?C)
Time
(h)
Yielda.b
(%)
1 (C6H5)CH2Br
64
(C6H5)CH2CN
65
82
25
0.1
1
95
(>95)
2 (C6H5)CH2Cl
70
(C6H5)CH2CN
65
82
25
2
72
(>95)
(>95)
3 CH3(CH2)11I
71
CH3(CH2)11CN
72
82
25
0.1
6
95
(95)
4 CH3(CH2)11Br
73
CH3(CH2)11CN
72
82
25
2
36
95
(>95)
5 CH3(CH2)11Cl
74
CH3(CH2)11CN
72
82
25
3
96
95
(33)c
6 CH3(CH2)11OMs
75
CH3(CH2)11CN
72
82 0.1 95
7 (C6H5)CH2CH2Br
67
(C6H5)CH2CH2CN
68
82
25
0.1
32
95
(>95)
8 CH3(CH2)5CH(I)CH3
76
CH3(CH2)5CH(CN)CH3
77
82
25
1
72
(83)
(68)
9 CH3(CH2)5CH(Br)CH3
78
CH3(CH2)5CH(CN)CH3
77
82
25
2
120
(82)
(79)
10 CH3(CH2)5CH(OTs)CH3
79
CH3(CH2)5CH(CN)CH3
77
82
25
1
48
(76)
(70)
11 (C6H5)CH(Br)CH3
80
(C6H5)CH(CN)CH3
81
82
25
1
5
92
(>95)
12 Br
82 CN
83
7:1
endo : exo 82101e 4896 (0)
d
70
13 Br
84
CN
85
82 48 (<5)f
14
Cl 86
CN
87
82
101e
48
96
(0)d
(0)d
a The indicated substrate, Me
3SiCN (3), and TBAF (1:1.5:1.5 molar ratio) in acetonitrile wereallowed to react at the given temperature, unless otherwise noted.  b Isolated yield after
purification.  The yield determined by G.C. analysis of the crude reaction mixture (vs. an internal
standard) is reported in parentheses.  c Reaction was stopped before completion.  d No reaction
was observed.  e Reaction was performed in dioxane.  f Starting material was consumed; remaining
yield assumed to be cyclohexene.
Table 6.  Reaction of Hypercoordinate Silicate 5 with Alkyl Halides.
178
CN
Phenylacetonitrile (65) (Table 6, entry 1).  The above general
procedure for the synthesis of nitriles using trimethylsilyl cyanide and
TBAF was followed using benzyl bromide (64) (171 mg, 119?L, 1.00
mmol), trimethylsilyl cyanide (149 mg, 200 ?L, 1.50 mmol) and TBAF (1.5 mL, 1.5 mmol) in
10 mL of MeCN.  The reaction was heated at reflux for 5 min.  Flash chromatography (25
mm, 16 cm, 10% CH2Cl2/pentane) afforded 111 mg (95%) of 65 as a colorless oil.  TLC Rf
= 0.40 (30% CH2Cl2/pentane).  IR (thin film) 3092 (s), 3069 (s), 3035 (s), 2912 (w), 2254
(m), 1604 (m), 1549 (m), 1497 (vs), 1416 (vs) cm-1; 1H NMR (CDCl3) ? 3.65 (s, 2H), 7.23-
7.35 (m, 5H); 13C NMR (CDCl3) ? 23.4, 118.0, 127.8, 127.9, 129.0, 130.0.  The IR, 1H and
13C NMR data were identical to an authentic sample purchased from Aldrich, as well as
published spectral data.218,249
Phenylacetonitrile (65) (Table 6, entry 2).  The above general
procedure for the synthesis of nitriles using trimethylsilyl cyanide and
TBAF was followed using benzyl chloride (70) (127 mg, 115?L, 1.00 mmol), trimethylsilyl
cyanide (149 mg, 200 ?L, 1.50 mmol) and TBAF (1.5 mL, 1.5 mmol) in 10 mL of MeCN.
The reaction was heated at reflux for 2 h.   Flash chromatography (25 mm, 16 cm, 10%
CH2Cl2/pentane) afforded 114 mg (97%) of 65 as a colorless oil.  Spectral data is reported
above.
Tridecanenitrile (72) (Table 6, entry 5).  The
above general procedure for the synthesis of nitriles
using trimethylsilyl cyanide and TBAF was followed using 1-chlorododecane (74) (205
mg, 236 ?L, 1.00 mmol), trimethylsilyl cyanide (149 mg, 200 ?L, 1.50 mmol) and TBAF (1.5
mL, 1.5 mmol) in 10 mL of MeCN.  The reaction was heated at reflux for 2 h.  Flash
chromatography (25 mm, 16 cm, 5% CH2Cl2/pentane) afforded 186 mg (95%) of 72.
Spectral data is reported above.
CN
CN
179
CN
Tridecanenitrile (72) (Table 6, entry 6).  The
above general procedure for the synthesis of nitriles
using trimethylsilyl cyanide and TBAF was followed using methanesulfonic acid dodecyl
ester (75) (264 mg, 1.00 mmol), trimethylsilyl cyanide (149 mg, 200 ?L, 1.50 mmol)  and
TBAF (1.5 mL, 1.5 mmol) in 10 mL of MeCN.  The reaction was heated at reflux for 5 min.
Flash chromatography (25 mm, 16 cm, 5% CH2Cl2/pentane) afforded 186 mg (95%) of 72.
Spectral data is reported above.
Hydrocinnamonitrile (68) (Table 6, entry 7).  The above general
procedure for the synthesis of nitriles using trimethylsilyl cyanide and
TBAF was followed using phenethyl bromide (67) (185 mg, 137 ?L,
1.00 mmol), trimethylsilyl cyanide (149 mg, 200 ?L, 1.50 mmol) and TBAF (1.5 mL, 1.5
mmol) in 10 mL of MeCN.  The reaction was heated at reflux for 5 min.  Flash
chromatography (25 mm, 16 cm, 10% CH2Cl2/pentane) afforded 125 mg (95%) of 68 as a
colorless oil.  TLC Rf = 0.35 (30% CH2Cl2/pentane).  IR (thin film) 3090 (w), 3067 (m),
3032 (s), 2935 (m), 2869 (w), 2250 (w), 1606 (w), 1497 (s), 1455 (s), 1426 (s) cm-1; 1H
NMR (CDCl3) ? 2.50 (t, J = 7.4, 2H), 2.85 (t, J = 7.4, 2H), 7.17-7.31 (m, 5H); 13C NMR
(CDCl3) ? 19.1, 31.3, 119.2, 127.0, 128.2, 128.7, 138.1.  The IR, 1H and 13C NMR data
were identical to an authentic sample, as well as published spectral data.218,250
2-Methyloctanenitrile (77) (Table 6, entry 8).  The above
general procedure for the synthesis of nitriles using trimethylsilyl
cyanide and TBAF was followed using 2-iodooctane (76) (240 mg, 1.00 mmol),
trimethylsilyl cyanide (149 mg, 200 ?L, 1.50 mmol) and TBAF (1.5 mL, 1.5 mmol) in 10 mL
of MeCN.  The reaction was heated at reflux for 1 h.  Flash chromatography (25 mm, 16
cm, 10% CH2Cl2/pentane) afforded 116 mg (83%) of 77 as a colorless oil.  TLC Rf = 0.65
(30% CH2Cl2/pentane).  IR (thin film) 2949 (vs), 2855 (vs), 2240 (w), 1461 (m), 1451
(m), 1390 (m) cm-1; 1H NMR (CDCl3) ? 0.89 (t, J = 6.8, 3H), 1.22-1.40 (m, 8H), 1.31 (d, J =
7.0, 3H), 1.44-1.67 (m, 2H), 2.52-2.67 (m, 1H); 13C NMR (CDCl3) ? 13.8, 17.9, 22.4, 25.3,
26.8, 28.6, 31.4, 33.9, 122.9.  The IR, 1H and 13C NMR data were identical to published
spectral data.220,251,252
CN
CN
180
CN
CN
CN
2-Methyloctanenitrile (77) (Table 6, entry 9).  The above
general procedure for the synthesis of nitriles using trimethylsilyl
cyanide and TBAF was followed using 2-bromooctane (78) (193 mg, 1.00 mmol),
trimethylsilyl cyanide (149 mg, 200 ?L, 1.50 mmol) and TBAF (1.5 mL, 1.5 mmol) in 10 mL
of MeCN.  The reaction was heated at reflux for 1 h.  Flash chromatography (25 mm, 16
cm, 10% CH2Cl2/pentane) afforded 114 mg (82%) of 77 as a colorless oil.  Spectral data
is reported above.
2-Methyloctanenitrile (77) (Table 6, entry 10).  The above
general procedure for the synthesis of nitriles using trimethylsilyl
cyanide and TBAF was followed using p-toluenesulfonic acid 1-methyl-heptyl ester (79)
(284 mg, 1.00 mmol), trimethylsilyl cyanide (149 mg, 200 ?L, 1.50 mmol) and TBAF (1.5
mL, 1.5 mmol) in 10 mL of MeCN.  The reaction was heated at reflux for 1 h.  Flash
chromatography (25 mm, 16 cm, 10% CH2Cl2/pentane) afforded 114 mg (82%) of 77 as a
colorless oil.  Spectral data is reported above.
2-Phenylpropionitrile (81) (Table 6, entry 11).  The above general
procedure for the synthesis of nitriles using trimethylsilyl cyanide and
TBAF was followed using 1-(bromoethyl)benzene (70) (185 mg, 136 ?L,
1.00 mmol), trimethylsilyl cyanide (149 mg, 200 ?L, 1.50 mmol) and TBAF (1.5 mL, 1.5
mmol) in 10 mL of MeCN.  The reaction was heated at reflux for 5 min.  Flash
chromatography (25 mm, 16 cm, 10% CH2Cl2/pentane) afforded 121 mg (92%) of 81 as a
colorless oil.  TLC Rf = 0.45 (30% CH2Cl2/pentane).  IR (thin film) 3091 (m), 3068 (m),
3033 (s), 2987 (s), 2939 (m), 2878 (m), 2244 (m), 1453 (s) cm-1; 1H NMR (CDCl3) ? 1.56
(d, J = 7.3, 3H), 3.84 (q, J = 7.3, 1H), 7.28-7.34 (m, 5H); 13C NMR (CDCl3) ? 21.4, 31.1,
121.6, 126.7, 128.0, 129.1, 137.1.  The IR, 1H and 13C NMR data were identical to an
authentic sample, as well as published spectral data.218,250
181
endo/exo-2-Norbornane Carbonitrile (83) (Table 6, entry 12).  The
above general procedure for the synthesis of nitriles using trimethylsilyl
cyanide and TBAF was followed using exo-2-bromonorbornane (82) (175
mg, 128 ?L, 1.00 mmol), trimethylsilyl cyanide (149 mg, 200 ?L, 1.50 mmol) and TBAF (1.5
mL, 1.5 mmol) in 10 mL of dioxane.  The reaction was heated at reflux for 96 h.  Flash
chromatography (25 mm, 16 cm, 10% CH2Cl2/pentane) afforded 85 mg (70%) of
endo/exo-83 as a colorless oil.  TLC Rf = 0.50 (30% CH2Cl2/pentane).  IR (CCl4) 2970
(b), 2876 (s), 2238 (m), 1456 (m) cm-1; 1H NMR (CDCl3) ? 1.1-1.9 (m, 7.4H), 1.9-2.1 (m,
0.9H), 2.3-2.4 (m, 1.2H), 2.5 (s, 0.7H), 2.6 (s, 0.2H), 2.6-2.7 (m, 0.6H); 13C NMR (CDCl3)
assigned as endo: ? 25.1 (C6), 29.2 (C5), 30.2 (C2), 35.5 (C3), 36.6 (C4), 38.9 (C7),
40.0 (C1), 123.0 (Cx); assigned as exo: ? 28.5, (C6), 28.6 (C5), 31.2 (C2), 36.1 (C3),
36.2 (C4), 37.3 (C7), 41.9 (C1), 123.7 (Cx).  The IR, 1H and 13C NMR data were
identical, except for the endo/exo ratio, to an authentic sample, as well as published
spectral data.218,219,249  The endo/exo ratio was determined by integration of the 13C NMR
spectrum: the relative areas of the carbon signals as shown above were: C6 (6.91:1.00),
C1 (6.94:100), Cx (6.92:1.00), for an average endo/exo ratio of 6.92:1.0.
Cyclohexanecarbonitrile (85) (Table 6, entry 13).  The above general
procedure for the synthesis of nitriles using trimethylsilyl cyanide and TBAF
was followed using cyclohexyl bromide (84) (163 mg, 124 ?L, 1.00 mmol), trimethylsilyl
cyanide (149 mg, 200 ?L, 1.50 mmol) and TBAF (1.5 mL, 1.5 mmol) in 10 mL of MeCN.
The reaction was heated at reflux for 48 h.  GC analysis indicated complete consumption
of the starting material, and formation of a trace amount (<5%) of cyclohexanecarbonitrile
(85).  Cyclohexanecarbonitrile (85) was identified by comparison of the GC retention time
of an authentic sample.  The remaining yield was assumed to be cyclohexene, which was
neither observed by GC nor isolated, due to volatility.
1 2
34
7
6
5
CNx
CN
182
General Procedure For the Reaction of Benzyl Bromide (64) with Trimethylsilyl
Cyanide (3) and Varying Amounts of Tetrabutylammonium Fluoride (TBAF) (Table
7).  All reactions were performed on a 1.0 mmol scale.  Trimethylsilyl cyanide (149 mg, 200
?L, 1.50 mmol), and the indicated amount of TBAF were added to a stirring solution of
benzyl bromide (64) (171 mg, 119?L, 1.00 mmol) and the internal standard naphthalene
(128 mg, 1.0 mmol, 1.0 equiv) in 10 mL MeCN under an atmosphere of nitrogen.  The
reaction was stirred at room temperature for 1 h, when GC analysis indicated that all
reactions had ceased to progress.  Reaction progress was monitored by GC analysis of
aliquots of the quenched reaction mixture.  GC response factors relative to the internal
naphthalene standard were determined, and the observed percentages of products were
normalized accordingly.
Br CNMe3SiCN (3) / TBAF
MeCN, 1h, 25 ?C
64 65
Entry TBAF
(mol %)
Yielda,b,c
(%)
1 100 89
2 50 42
3 25 15
a Benzyl bromide (64, 1 equiv), Me
3SiCN (3, 1.5 equiv), and thegiven amount of TBAF in MeCN were allowed to react at room
temperature.  b Reactions were complete by 1 h.  c Yield of 65
determined by G.C. analysis of the crude reaction mixture (vs. an
internal standard).
Table 7.  Reaction of Benzyl Bromide (64) with Me3SiCN (3) and Varying Amounts of
TBAF.
183
General Procedure for the Reaction of Benzyl Bromide (64) and Trimethylsilyl
Cyanide (3) with Tetrabutylammonium Nucleophiles (Table 8).  All reactions were
performed on a 1.0 mmol scale.  Trimethylsilyl cyanide (149 mg, 200 ?L, 1.50 mmol), and
the indicated tetrabutylammonium salt (1.5 mmol, 1.5 equiv) were added to a stirring
solution of benzyl bromide (64) (119?L, 1.00 mmol) and the internal standard naphthalene
(128 mg, 1.0 mmol, 1.0 equiv) in 10 mL MeCN under an atmosphere of nitrogen.  The
reaction was stirred at reflux until GC analysis indicated that the reaction had ceased to
progress.  Reaction progress was monitored by GC analysis of aliquots of the quenched
reaction mixture.  GC response factors relative to the internal naphthalene standard were
determined, and the observed percentages of products were normalized accordingly.
Br CNMe3SiCN (3) / X- Bu4N+
64 65
MeCN
reflux
Entry Nucleophile Time (h) Yield (%)a,b
1 F- Bu4N+ 0.1 >95
2 Br- Bu4N+ 24 0
3 Cl- Bu4N+ 24 0
4 I- Bu4N+ 24 0
5 TfO- Bu4N+ 24 0
6 AcO- Bu4N+ 0.1 45c
a Benzyl bromide (64) (1 equiv), Me
3SiCN (1.5 equiv), and the indicatednucleophile (1.5 equiv) in MeCN were allowed to react at reflux.  b The yield
of 65 was determined by G.C. analysis of the crude reaction mixture (vs. an
internal standard).  c Reaction was allowed to proceed for 24 h, but no
additional progress was detected.
Table 8.  Reaction of Benzyl Bromide (64) and Trimethylsilyl Cyanide (3) with
Tetrabutylammonium Nucleophiles.
184
General Procedure for the Reaction of Benzyl Bromide (64) and Trimethylsilyl
Cyanide (3) with Alternative Fluoride Sources (Table 9).  All reactions were
performed on a 1.0 mmol scale.  Trimethylsilyl cyanide (149 mg, 200 ?L, 1.50 mmol), and
the indicated fluoride salt (1.5 mmol, 1.5 equiv) were added to a stirring solution of benzyl
bromide (64) (119?L, 1.00 mmol) and the internal standard naphthalene (128 mg, 1.0
mmol, 1.0 equiv) in 10 mL MeCN under an atmosphere of nitrogen.  The reaction was
stirred at reflux until GC analysis indicated that the reaction had ceased to progress.
Reaction progress was monitored by GC analysis of aliquots of the quenched reaction
mixture.  GC response factors relative to the internal naphthalene standard were
determined, and the observed percentages of products were normalized accordingly.
Br CNMe3SiCN (3) / F
64 65
MeCN
reflux
Entry Fluoride Salt Time
(h)
Yield
(%)a,b
1 Bu4N+ F- >1 100
2 KF 72 80c
3 KF / 18-crown-6d 48 100
4 CsF 48 75c
5 TBAT, 1 >1 100
a Benzyl bromide (64) (1.0 equiv), Me
3SiCN (3) (1.5 equiv), and the indicated fluoride salt(1.5 equiv) in MeCN were allowed to react at reflux.  b The yield of 65 was determined by
G.C. analysis of the crude reaction mixture (vs. an internal standard).  c Reaction was
allowed to proceed for and additional 24 hours, but no further progress was detected.
d Catalytic in 18-crown-6 (20 mol %).
Table 9.  Reaction of Benzyl Bromide (64) and Trimethylsilyl Cyanide (3) with Alternative
Fluoride Sources.
185
General Procedure for the Reaction of Secondary Alkyl Halides with
Trimethylsilyl Cyanide (3) and TBAT (1) (Table 10).  All reactions were performed on a
1.0 mmol scale.  Trimethylsilyl cyanide (149 mg, 200 ?L, 1.50 mmol), and TBAT (1) (874
mg, 1.5 mmol) were added to a stirring solution of alkyl halide (1.00 mmol, 1 equiv) and the
internal standard naphthalene (128 mg, 1.0 mmol, 1.0 equiv) in 10 mL MeCN under an
atmosphere of nitrogen.  The reaction was performed at 82 ?C until GC analysis indicated
that the reaction had ceased to progress.  Reaction progress was monitored by GC
analysis of aliquots of the quenched reaction mixture.  GC response factors relative to the
internal naphthalene standard were determined, and the observed percentages of
products were normalized accordingly.  The elimination product 2-octene was identified by
comparison of the GC retention time to the value of that of an authentic sample
X CN
77
Me3SiCN (3) / F
MeCN
reflux
Entry Substrate Fluoride
Source
Time
(h)
Yielda,b,c
(%)
1 CH3(CH2)5CH(I)CH3
76
TBAF
TBAT, 1
1
1
83
85
2 CH3(CH2)5CH(Br)CH3
78
TBAF
TBAT, 1
2
3
82
86
3 CH3(CH2)5CH(OTs)CH3
79
TBAF
TBAT, 1
1
1
76
74
a The yield of 77 was determined by G.C. analysis of the crude reaction
mixture (vs. an internal standard).  b All reactions went to completion; the
remaining yield was 2-octene.  c The remaining yield was 2-octene.
Table 10.  Reaction of Secondary Alkyl Halides with Trimethylsilyl Cyanide (3) and TBAF
or TBAT (1).
186
2-Methyloctanenitrile (77) (Table 10, entry 1).  The above
general procedure for the reaction of secondary alkyl halides with
trimethylsilyl cyanide and TBAT was followed using 2-iodooctane (76) (240 mg, 1.00
mmol), trimethylsilyl cyanide (149 mg, 200 ?L, 1.50 mmol) and TBAT (874 mg, 1.50 mmol)
in 10 mL of MeCN.  The reaction was heated at reflux for 1 h to yield 85% of 77 by GC
analysis.
2-Methyloctanenitrile (77) (Table 10, entry 2).  The above
general procedure for the reaction of secondary alkyl halides with
trimethylsilyl cyanide and TBAT was followed using 2-bromooctane (78) (193 mg, 1.00
mmol), trimethylsilyl cyanide (149 mg, 200 ?L, 1.50 mmol) and TBAT (874 mg, 1.50 mmol)
in 10 mL of MeCN.  The reaction was heated at reflux for 3 h to yield 86% of 77 by GC
analysis.
2-Methyloctanenitrile (77) (Table 10, entry 3).  The above
general procedure for the reaction of secondary alkyl halides with
trimethylsilyl cyanide and TBAT was followed using toluene-4-sulfonic acid
1-methyl-heptyl ester (79) (284 mg, 1.00 mmol), trimethylsilyl cyanide (149 mg, 200 ?L,
1.50 mmol) and TBAT (874 mg, 1.50 mmol) in 10 mL of MeCN.  The reaction was heated
at reflux for 1 h to yield 74% of 77 by GC analysis.
General Procedure for Synthesis of Nitriles Using Tetrabutylammonium Cyanide
(90) (Table 11).  All reactions were performed on a 1.0 mmol scale.  The indicated alkyl
halide (1.00 mmol, 1 equiv) was added to a stirring solution of tetrabutylammonium
cyanide (90) (403 mg, 1.50 mmol) and the internal standard naphthalene (128 mg, 1.0
mmol, 1.0 equiv) in 10 mL MeCN under an atmosphere of nitrogen.  The reaction was
stirred at the given temperature until GC analysis indicated that the reaction had ceased to
progress.  Reaction progress was monitored by GC analysis of aliquots of the quenched
reaction mixture.  GC response factors relative to the internal naphthalene standard were
determined, and the observed percentages of products were normalized accordingly.
CN
CN
CN
187
R X R CN
Me3SiCN (3) / TBAF
or
Bu4N+CN- (90)
MeCN
Entry Substrate Product Reagent Temp
(?C)
Time
(h)
Yielda,b
(%)
1 CH3(CH2)11I
71
CH3(CH2)11CN
72
3/TBAF
Bu4N+CN-
25
25
6
1
95
95
2 CH3(CH2)11Br
73
CH3(CH2)11CN
72
3/TBAF
Bu4N+CN-
25
25
36
3
>95
>95
3 CH3(CH2)11Cl
74
CH3(CH2)11CN
72
3/TBAF
Bu4N+CN-
25
25
96
36
33c
>95
4 (C6H5)CH2CH2Br
67
(C6H5)CH2CH2CN
68
3/TBAF
Bu4N+CN-
25
25
32
2
>95
>95
5 CH3(CH2)5CH(I)CH3
76
CH3(CH2)5CH(CN)CH3
77
3/TBAF
Bu4N+CN-
25
25
72
24
68
71
6 CH3(CH2)5CH(Br)CH3
78
CH3(CH2)5CH(CN)CH3
77
3/TBAF
Bu4N+CN-
25
25
120
96
79
77
7 CH3(CH2)5CH(OTs)CH3
79
CH3(CH2)5CH(CN)CH3
77
3/TBAF
Bu4N+CN-
25
25
48
24
70
74
8 (C6H5)CH(Br)CH3
80
(C6H5)CH(CN)CH3
81
3/TBAF
Bu4N+CN-
25
25
5
3
>95
>95
9 Br
82
CN
83
7:1
endo : exo
3/TBAF
Bu4N+CN-
82
101e
82
101e
48
96
48
72
0d
70
0d
60
a Where 3/TBAF is the reagent, the indicated substrate, Me
3SiCN (3), and TBAF(1:1.5:1.5 molar ratio) in acetonitrile were allowed to react at the given temperature, unless
otherwise noted.  Where Bu4N+CN- (90) is the reagent, the indicated substrate, and
Bu4N+CN- (1:1.5 molar ratio) in acetonitrile were allowed to react at the given temperature.
b Yield determined by G.C. analysis of the crude reaction mixture (vs. an internal
standard).  c Reaction was stopped before completion.  d No reaction was observed.  e
Reaction was performed in dioxane.
Table 11. Comparison of Nitrile Synthesis Using Me3SiCN/TBAF or Bu4N+CN-.
188
CN
CN
CN
Tridecanenitrile (72) (Table 11, entry 1).  The
above general procedure for the synthesis of nitriles
using tetrabutylammonium cyanide was followed using 1-iodododecane (71) (296 mg, 247
?L, 1.00 mmol), and tetrabutylammonium cyanide (404 mg, 1.50 mmol) in 10 mL of MeCN.
The reaction was stirred at room temperature for 1 h to yield 95% of 72 by GC analysis.
Tridecanenitrile (72) (Table 11, entry 2).  The above general procedure for the
synthesis of nitriles using tetrabutylammonium
cyanide was followed using 1-bromododecane (73)
(249 mg, 240 ?L, 1.00 mmol), and tetrabutylammonium cyanide (404 mg, 1.50 mmol) in 10
mL of MeCN.  The reaction was stirred at room temperature for 3 h to yield 97% of 72 by
GC analysis.
Tridecanenitrile (72) (Table 11, entry 3).  The
above general procedure for the synthesis of nitriles
using tetrabutylammonium cyanide was followed using 1-chlorododecane (74) (205 mg,
236 ?L, 1.00 mmol), and tetrabutylammonium cyanide (404 mg, 1.50 mmol) in 10 mL of
MeCN.  The reaction was stirred at room temperature for 36 h to yield 97% of 72 by GC
analysis.
Hydrocinnamonitrile (68) (Table 11, entry 4).  The above general
procedure for the synthesis of nitriles using tetrabutylammonium
cyanide was followed using phenethylbromide (67) (185 mg, 137 ?L, 1.00 mmol), and
tetrabutylammonium cyanide (404 mg, 1.50 mmol) in 10 mL of MeCN.  The reaction was
stirred at room temperature for 2 h to yield 100% of 68 by GC analysis.
CN
189
CN
CN
CN
CN 2-Methyloctanenitrile (77) (Table 11, entry 5).  The above
general procedure for the synthesis of nitriles using
tetrabutylammonium cyanide was followed using 2-iodooctane (76) (240 mg, 1.00 mmol),
and tetrabutylammonium cyanide (404 mg, 1.50 mmol) in 10 mL of MeCN.  The reaction
was stirred at room temperature for 24 h to yield 71% of 77 by GC analysis.
2-Methyloctanenitrile (77) (Table 11, entry 6).  The above
general procedure for the synthesis of nitriles using
tetrabutylammonium cyanide was followed using 2-bromooctane (78) (193 mg, 1.00
mmol), and tetrabutylammonium cyanide (404 mg, 1.50 mmol) in 10 mL of MeCN.  The
reaction was stirred at room temperature for 96 h to yield 77% of 77 by GC analysis.
2-Methyloctanenitrile (77) (Table 11, entry 7).  The above
general procedure for the synthesis of nitriles using
tetrabutylammonium cyanide was followed using toluene-4-sulfonic acid 1-methyl-heptyl
ester (79) (284 mg, 1.00 mmol), and tetrabutylammonium cyanide (404 mg, 1.50 mmol) in
10 mL of MeCN.  The reaction was stirred at room temperature for 24 h to yield 74% of 77
by GC analysis.
2-Phenylpropionitrile (81) (Table 11, entry 8).  The above general
procedure for the synthesis of nitriles using tetrabutylammonium cyanide
was followed using (1-bromoethyl)benzene (80) (185 mg, 136 ?L, 1.00
mmol), and tetrabutylammonium cyanide (404 mg, 1.50 mmol) in 10 mL of MeCN.  The
reaction was stirred at room temperature for 3 h to yield 99% of 81 by GC analysis.
190
1 2
34
7
6
5
CNx
endo/exo-2-Norbornanecarbonitrile (83) (Table 11, entry 9).  The
above general procedure for the synthesis of nitriles using
tetrabutylammonium cyanide was followed using exo-2-bromonorbornane
(82) (175 mg, 128 ?L, 1.00 mmol), and tetrabutylammonium cyanide (404 mg, 1.50 mmol)
in 10 mL of dioxane.  The reaction was stirred at reflux for 72 h to yield 60% of endo/exo-
83 by GC analysis.
191
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