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IRIDIUM CATALYZED AROMATIC BORYLATION
AND ITS APPLICATIONS IN
ONE—POT PREPARATIONS OF SUBSTITUTED
AROMATIC BUILDING BLOCKS

presented by

Ghayoor Abbas Chotana

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IRIDIUM CATALYZED AROMATIC BORYLATION AND ITS APPLICATIONS IN
ONE—POT PREPARATIONS OF SUBSTITUTED AROMATIC BUILDING BLOCKS

BY

Ghayoor Abbas Chotana

A DISSERTATION

Submitted to
Michigan State University
in partial fulfillment of the requirements
for the degree of

DOCTOR OF PHILOSOPHY
Chemistry

2009

ABSTRACT

IRIDIUM CATALYZED AROMATIC BORYLATION AND ITS APPLICATIONS IN
ONE—POT PREPARATIONS OF SUBSTITUTED AROMATIC BUILDING BLOCKS

By
Ghayoor Abbas Chotana

Selective functionalization of hydrocarbons represents one of the most
challenging problems in homogeneous and heterogeneous catalysis. During the last
decade, iridium catalyzed aromatic borylation has emerged as one of the most convenient
methodologies for the regioselective functionalization of aromatic as well as
heteroaromatic hydrocarbons. The most striking feature of this new tool available to the
synthetic chemist is that the regioselectivities are governed by sterics, and hence, are
complementary to those found in electrophillic aromatic substitution or directed ortho
metalation. This unique feature allows for the synthesis of new aromatic building blocks,
which were previously either unknown or difficult to synthesize. Another useful feature
of this new methodology is the tolerance to several common functional groups such as
halogens, esters, amides etc.

Iridium catalyzed borylation ortho to substituents other than H is typically
hindered. Evaluation of steric effects of several substituents showed that CN is one of the
smallest substituents. Since regioselectivities in Ir catalyzed borylation are controlled by
sterics, we reasoned that borylations orlho to CN, an electronic meta director, should be
possible. As a test, we examined several 4-substituted benzonitriles and found good ortho
selectivity for several substrates. Regioselectivities greater than 99% were obtained for
bulkier substituents such as ester, amine, acetanilide and trifluoromethyl. These

borylations were the first general examples of ortho-functionalization of 4-benzonitriles.

 

This contrasts with meta—functionalizations, which have been known for more than a
century.

Good to high regioselectivities were observed in mono- and di—borylation of a
variety of substituted thiophenes. The BPin group was found to survive during
electrophillic aromatic bromination reactions. Poor regioselectivities observed with d’bpy
ligand were improved by using bis-oxazoline derived ligands.

Since Ir catalyzed borylations leave aryl halogen (Cl, Br, and 1) bonds intact, it
might be useful if chemo—selective cross couplings can be accomplished at the halide
positions while retaining the boronate functionality. We have found that under anhydrous
basic conditions, cross coupling reactions such as amination, Sonogashira coupling, and
C—S coupling can be carried out on the C—halogen bond, while keeping the C—B bond
completely intact. The resulting amino boronate esters, aryl alkynyl boronate esters, and
aromatic thio ether boronate esters are all new compounds and are difficult to synthesize
by any other rout.

S-Coordinate, l6-electron, bi-dentate ligated iridium tris-boryl complexes have
been proposed to be the active catalysts in the iridium catalyzed aromatic borylation. Our
attempts to synthesize the proposed active catalysts using various bidentate ligands is
presented, ultimately culminating in the successful synthesis of couple of
(bis-phosphine)lr(BPin)3 complexes, which are the first examples of stable, l6-electron,
iridium tris-boryl complexes. The complex (d’ppe)lr(BPin)3 borylates aromatic

compounds at room temperature.

To my beloved mother

iv

ACKNOWLEDGMENTS

I am very thankful to Prof. Milton Rudolph Smith III for his guidance during my
PhD and for giving me an opportunity to work on one of the most exciting chemistry of
present time. I have learned so many things from him, all of which are not possible to list
here. The most important one is to accept challenges and complete targets on time with
unmatched levels of excellence. He can convert any raw grad student, like me, into gold
with his hard work. I am also very thankful to him for his patience on my mistakes.

I am very thankful to Prof. Robert E. Maleczka Jr. for his valuable suggestions
during boron group meetings. I am thankful to Prof. James K. McCusker, Prof. Babak
Borhan, and Prof. William D. Wulff for serving on my guidance committee.

Thanks to Prof. Aaron L. Odom for his guidance during organometallic group
meetings. I am also thankful to my other teachers at MSU, Prof. Mercouri G. Kanatzidis,
Prof. Joan Broderick, and Prof. Greg Baker, for teaching me advanced chemistry courses.

I am very thankful to Dr. F eng Shi for helping me learn several research
techniques during my PhD. It is always good to work with such a competent person who
not only is hardworking but also has excellent knowledge of chemistry. I am also
thankful to my seniors Dr. Christopher Radano, Dr. Jiang-Yang Cho, and Dr. Daniel
Holmes for their guidance during my first year of research work.

Lastly I am thankful to my family for their kind support and patience while I am

away from them.

 

TABLE OF CONTENTS

LIST OF TABLES

LIST OF FIGURES

 

' LIST OF SYMBOLS AND ABBREVIATIONS.

 

CHAPTER 1
Introduction

 

C-H bond Activation and Functionalization of Hydrocarbons

 

Organoboron Compounds
Synthesis of Alkyl and Alkenyl Boranes

 

 

Synthesis of Aromatic Boronates
Transition Metal Catalyzed Aromatic C—B Bond Formation

 

Uncatalyzed C—H Bond Borylation Reactions

 

Transition Metal Mediated Aromatic C—H Activation/Borylation
Transition Metal Catalyzed Aromatic C—H Activation/Borylation

 

Cross-Coupling Reactions

 

Bibliography

 

CHAPTER 2

Sterically Directed Functionalization of Aromatic C—H Bonds: Selective Borylation ortho

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

to Cyano Groups in Arencs and Heterocycles 34
Introduction 34
Results 37
Conclusions 50
Experimental Details and Spectroscopic Data 51
Bibliography 86

CHAPTER 3

Iridium Catalyzed Borylation of Substituted Thiophenes 92
Introduction 92
Results and Discussion 94
Conclusions 108
Experimental Details and Spectroscopic Data 109
Bibliography 144

CHAPTER 4

Bisoxazoline Ligands in Iridium Catalyzed Aromatic C—H Activation/Borylation _________ 148
Introduction 148
Results and Discussion 150
Conclusions 164
Experimental Details and Spectroscopic Data 165

 

vi

Bibliography _____ l 87

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CHAPTER 5
One-Pot Borylation/Amination Reactions: Synthesis of Arylamine Boronate Esters from
Halogenated Arencs 190
Introduction 190
Results and Discussion _ 192
Conclusions 199
Experimental Details and Spectroscopic Data 200
Bibliography _________ 2 1 5
CHAPTER 6
Part A: Synthesis of Borylated Aromatic Alkynes by One-Pot Borylation/Sonogashira
Coupling 218
Introduction 21 8
Results and Discussion 219
Part B: Synthesis of Borylated Aromatic Thioethers by One-Pot Borylation/C—S
Coupling 226
Introduction 226
Results and Discussion 227
Attempted C—O Coupling of Halo Aryl Boronate Ester 230
Experimental Details and Spectroscopic Data 231
Bibliography 252
CHAPTER 7
Getting the Sterics Just Right: A Five-Coordinate Iridium Complex That Reacts with C—
H Bonds at Room Temperature 256
Introduction 256
Results and Discussion 257
Conclusions 269
Experimental Details and Spectroscopic Data ____________________________ 270
Bibliography 275
Appendices 276
Spectroscopic data of compounds 281

 

vii

ll

LIST OF TABLES

Table 1.1. Ratio of product isomers from reaction of CpFe(CO)2(BCat) with C6H5X ..... 12

Table 2.1. Regioselectivities for borylation of 4-substituted benzonitriles according to

Scheme 2.2 ______________________________________________________________________________________________________________________________ 38
Table 2.2. Calculated steric enthalpies (AAHS) for o-benzene substituents Z and isomer
ratios for borylation ________________________________________________________________________________________________________________ 41
Table 2.3. Diborylation of 4—substituted benzonitriles _________________________________________________________ 47
Table 3.1. Monoborylation of 2-substituted thiophenes according to scheme 3.] _____________ 95
Table 3.2. Monoborylation of 3-substituted thiophenes according to scheme 3.2 _____________ 96

Table 3.3. Monoborylation of 2,5-di-substituted thiophenes according to scheme 3.3 ..... 99

Table 3.4. Diborylation of 2—substituted thiophenes according to scheme 3.4 _________________ 101
Table 3.5. Diborylation of 3-substituted thiophenes according to scheme 3.5 _________________ 104
Table 4.1. Borylation regioselectivities for 4.5 vs. d’bpy (1.23) ________________________________________ 154
Table 4.2. Comparison of regioselectivities for monoborylation of 3-substituted
thiophenes with 4.5 and 1.23 according to scheme 4.3 ______________________________________________________ 158
Table 4.3. Borylation of 2,5—di-substituted thiophenes according to scheme 4.4 _____________ 160

Table 4.4. GC-FID ratios of monoborylated products of 1,3-di-fluorobenzene according
to scheme 4.5 _________________________________________________________________________________________________________________________ 162
Table 4.5. GC-F ID ratios of monoborylated products of 1,2-di-fluorobenzene according
to scheme 4.6 _________________________________________________________________________________________________________________________ 163
Table 5.1. Effects of Ir and Pd precatalyst, base, and solvent on one-pot borylation/
amination of 3-chlorotoluene according to scheme 5.2 ______________________________________________________ 193

Table 5.2. Preparation of 1,3,5-arylamino boronate esters according to scheme 5.3 _______ l95

Table 5.3. One-pot borylation/amination of ortho and para-substituted chlorobenzenes _____
197

------------------------------------------------------------------------------------------------------------------------------------------------

viii

Table 6.1. Preparation of borylated aromatic alkynes by One-pot aromatic borylation/
Sonogashira coupling of aryl bromides according to scheme 6.5 _____________________________________ 223

Table 6.2. Preparation of aromatic thioethers boronate esters by One-pot aromatic
borylation/C—S coupling of aryliodides according to scheme 6.7 _____________________________________ 228

ix

LIST OF FIGURES

Figure 1.1. Synthesis of a meta-substituted phenol by electrophillic aromatic substitution

____________________________________________________________________________________________________________________________________________________ 5
Figure 1.2. Aromatic functionalization via directed ortho metalation __________________________________ 5
Figure 1.3. Oxygenated organoboron compounds __________________________________________________________________ 6
Figure 1.4. Preparation of the first organoboron compound, 1.2 ___________________________________________ 6
Figure 1.5. Hydroboration of alkenes and alkynes _________________________________________________________________ 7
Figure 1.6. Traditional route for the synthesis of aryl boronic acids _____________________________________ 8
Figure 1.7. Synthesis of aryl boronic esters via directed ortho metalation ___________________________ 8
Figure 1.8. Synthesis of aryl boronic acids from trialkyl aryl silanes ___________________________________ 9
Figure 1.9. Palladium catalyzed borylation of aryl halides ____________________________________________________ 9

Figure 1.10. Palladium catalyzed borylation of aryl diazonium tetrafluoroborate salts _______ 9

Figure 1.11. Synthesis of aryl boronic esters via cycloaddition of alkynyl boronate esters

with diynes _______________________________________________________________________________________________________________________________ 10
Figure 1.12. Different routes for the preparation of aryl boronic esters ______________________________ 10
Figure 1.13. Pyrolysis of tri-n-octylborane ___________________________________________________________________________ 11
Figure 1.14. Transition metal mediated photochemical aromatic borylation _____________________ 12
Figure 1.15. First transition metal catalyzed aromatic C—H activation/borylation _____________ 13
Figure 1.16. Thermal, catalytic, regiospecific functionalization of n-octane _____________________ 13

Figure 1.17. Statistical product distribution in sterically directed catalytic borylation of

mono substituted arene ___________________________________________________________________________________________________________ 14
Figure 1.18. Regioselective borylation of 1,3-substituted arene __________________________________________ 15
Figure 1.19. Improved catalysts for aromatic C—H activation/borylation ___________________________ 16

Figure 1.20. Catalytic cycle for iridium catalyzed aromatic C—H activation/borylation” 16

Figure 1.21. Ir/bpy catalyzed aromatic C—H activation/borylation _____________________________________ 17

Figure 1.22. Regioselective borylation in some complex aromatic systems ______________________ 21
Figure 1.23. Diverse functional groups introduced via boronate ester ________________________________ 22
Figure 1.24. Metal catalyzed cross-coupling reactions ________________________________________________________ 23
Figure 1.25. General catalytic cycle for cross-coupling reactions _______________________________________ 24
Figure 1.26. One-pot borylation/cross-coupling reactions ___________________________________________________ 25
Figure 2.1. Product distribution in catalytic borylation of benzonitrile ______________________________ 43
Figure 2.2. Product distribution in catalytic borylation of anisole ______________________________________ 43

Figure 2.3. Directed ortho metlation for the preparation of 2-borylated benzonitriles 45

Figure 3.1. Attempted borylation of 3-bromo-2,5-di-chloro thiophene ____________________________ 105
Figure 3.2. Bromination of thiophene boronic ester ___________________________________________________________ 106
Figure 3.3. Substitution of trimethylsilyl group with bromine __________________________________________ 107
Figure 3.4. One—pot borylation Suzuki coupling of thiophenes _________________________________________ 108
Figure 4.1. Proposed iridium catalysts for aromatic borylation _________________________________________ 151
Figure 4.2. Bidentate di-imine based ligands used for aromatic borylation ______________________ 152
Figure 4.3. Aromatic borylation with bisoxazoline ligands _______________________________________________ 152
Figure 4.4. Regioselectivities for monoborylation of l-methylpyrazole __________________________ 157

Figure 7.1. 31P NMR of 7.6, a small amount of an unknown comound 7.7 is also present

------------------------------------------------------------------------------------------------------------------------------------------------

Figure 7.2. Borylation results of l,3-bis-trifluoromethylbenzene _____________________________________ 259
Figure 7.3. X-ray structures of compounds 7.5 and 7.6 with BPin methyl groups omitted.
The black carbons are those with the closest Ir contacts. In both cases, the Ir—C distances

are significantly longer than those in compounds with Ir C—H agostic interactions ________ 261

Figure 7.4. A comparison of the orientation for the B3 boryl ligands in structures 7.5 and
7.6 with the qualitative transition state 7.7. For compound 7.5, rotation about the Ir—B

xi

 

bond is required to reach the transition state, whereas the boryl orientation in 7.6 is ideal

for cleaving the arene C-H bond _________________________________________________________________________________________ 261
Figure 7.5. Catalytic aromatic borylation with 7.10 and 7.11 at 150 °C ___________________________ 263
Figure 7.6. 3 IP NMR of crude reaction of dppe with 7.5 ___________________________________________________ 266
Figure 7.7. 3 ‘P NMR of crude reaction of 7.18 with 7.5 _________________________ __________________________ 267

Figure 7.8. Proposed formulation of 7.15, 7.17, and 7.19 based on 3 IP NMR data _________ 268

Figure 7.9. Room temperature catalytic borylation with 7.19 ___________________________________________ 269

xii

LIST OF SYMBOLS AND ABBREVIATIONS

Ar
BCat
BPin
BzPinz
bpy
COD
COE

CODC

d’bpy
dd
DFT
DMG
dmpe
DOM
dppe
EAS

equiv

aryl

catecholatoboryl (——BOZC6H4)
pinacolatoboryl (—B02C6H .2)
bis-pinacolato—di-boron (Cle24B204)
bi—pyridyl

1,5-cyclooctadiene

cyclooctene

concentrated
pentamethylcyclopentadienyl, nS-C5(CH3)5
degree Celcius

doublet

di-tert-butyl-bi-pyridyl

doublet of doublet

density functional theory

directed metalation group

1 ,2-bis-(dimethylphosphino)—ethane
directed ortho metalation

1 ,2-bis-(diphenylphosphino)-ethane
electrophilic aromatic substitution
equation

equivalent

xiii

GC

GC-FID

GC-MS

HBPin

Hz

Ind

IR

kcal

LDA

MesH

min

mL

mmol

mol

NMR

OMe

gas chromatography

gas chromatography-flame ionization detector
gas chromatography-mass spectroscopy
hour

pinacolborane

Hertz

indenyl (C9H7)

infrared

coupling constant

kilocalorie
lithium-di-isopropylamide

multiplet

meta

normal (straight chain hydrocarbon)
methyl

mesitylenyl

minutes

milliliters

millimole

mole

nuclear magnetic resonance

ortho

methoxy (OCH3)

xiv

THF

TIPS

TONS

TPy

uL

para
palladium catalyst

phenyl

trimethyl phosphine

iso-propyl

quartet

singlet

triplet

tetrahydrofuran

tri-isopropylsilyl

trinitrotoluene

turn over numbers
tetra—2-pyridinylpyrazine

delta, ppm for NMR spectroscopy
hepticity of ligand

microlitres

XV

CHAPTER 1
Introduction
C—H Bond Activation and Functionalization of Hydrocarbons
Selective C—H bond activation of unreactive hydrocarbons, and subsequent
functionalization to useful products, represents one of the most challenging problems in
homogeneous and heterogeneous catalysis. Such transformations will assist the synthetic
organic chemist to design new retrosynthetic approaches towards complex molecule
synthesis. They could also result in synthesis of new and interesting compounds with
potential applications in wide areas of research ranging from pharmaceutical to material
sciences.
C—H activation refers to the binding of a hydrocarbon C—H bond to the metal

center, normally by cleavage of the bond by oxidative addition (Eq 1.1).

l
l

LnM + Ft—H LnM(R—H) LnM(R)(H) (1-1)

Functionalization, in contrast, involves replacement of a C—H hydrogen by an

organic functional group G (Eq 1.2).

C—H

 

C—G (1.2)

In order to catalyze the functionalization of C—H bonds by a transition metal
complex; the initial activation step shown in Eq. 1 should be followed by a secondary
functionalization step. Functionalization has proved to be more difficult than the
activation step, and a common reaction of alkyl hydride complexes is the reverse of Eq
1.1, which reforms the alkane. The requirement to carry out functionalization with good
chemo-, regio-, stereo-, and enantioselectivity has further increased the challenges

associated with catalytic transformations.

Hydrocarbons are some of the least reactive organic compounds. Their lack of
reactivity is attributed to high bond energies of C—H bonds (typically 90-104 kcal/mol),
very low acidity/basicity, and low bond polarity. Since hydrocarbons are the most
abundant organic raw material available, there is huge interest in their selective
functionalization.

Non-transition metal based approaches for hydrocarbon functionalization include
electrophillic aromatic substitution,‘ directed ortho metalation/electrophillic addition,2
free radical reactions,3 and superacid mediated transformations.4 Less explored but
potentially highly useful areas include metathesis reactions of C—H and 8—H bonds,5 and
reactions of unactivated C—H bonds with dioxiranes.6 The uncatalyzed reactions typically
give functionalization at the most substituted carbon atom (except for the free radical
benzylic activation) often with limited selectivity.

In the past three decades, a variety of transition metal catalysts have been
developed for the functionalization of C—H bonds. These new powerful methods can
transform the C—H bond into C—C, c—o, C—N, C—B, C—Si, or C—halogen bonds.7 Most of
these reactions involve insertion of a low valent transition metal into the least hindered
C—H bond, and are often highly selective.

Although all of these catalysts promote the same general transformations (C—H —+
C—G), they can operate within two very different mechanistic manifolds. Sanford has
termed these two mechanisms as ‘inner-sphere’ and ‘outer-sphere’ mechanisms.7
Alternative terminology, introduced by Crabtree, labels these mechanisms

‘organometallic’ and ‘coordination’ respectively.8

Inner-sphere Mechanism
The ‘inner-sphere’ C—H bond functionalization mechanism involves two discrete
steps:
(i) cleavage of a C—H bond to afford a transition metal alkyl/aryl species and
(ii) functionalization of the nascent C—M bond with either an external reagent or

at the metal center (Eq 1.3).

(i) C-H cleavage (ii) Functionalization
C—H + cat. [M] : C—[M] t C—G (1.3)

 

 

The key distinguishing feature of this mechanism is the formation of a discrete
organometallic intermediate, and the structural and electronic requirements of this
intermediate dictate the regio- and stereo selectivity of functionalization. These
transformations often proceed with high selectivity for the less sterically hindered C—H
bonds of a molecule; however, other factors, including the ligand environment at the
metal center and the mechanism of the C—H bond cleavage step, can also influence
selectivity in these systems.

Outer-sphere Mechanism

The ‘outer-sphere mechanism’ for C—H bond functionalization mimics biological
oxidation reactions catalyzed by enzymes such as cytochrome P450 and methane
monooxygenase (MMO). These processes proceed via

(i) formation of a high oxidation state metal complex containing an activated
ligand X (typically a metal oxo—, imido—, or carbene species) followed by
(ii) reaction of ligand X with a C—H bond. This latter step can proceed by either

direct insertion or H—atom abstraction/radical rebound (Eq 1.4).

Direct Insertion

H
i r l ‘C ———i
(i) Oxidation

cat. [M] = [M]=X + C—H C—X—H (1.4)

i e [M]=X—H + (3 _i

H Atom Abstraction/
Rebound

 

 

 

The key distinguishing feature of the outer—sphere mechanism is that the
alkane/arene substrate does not interact directly with the transition metal center but
instead reacts with a coordinated ligand. These transformations involve build up of
radical and/or cationic character at carbon, and therefore typically show high selectivity
for weaker C—H bonds (e.g. those that are benzylic, allylic, 3°, or O. to heteroatoms).

Arenes are often more reactive than alkanes in OH bond cleavage reactions, in
spite of greater strength of arene vs. alkane C—H bonds. Arenes are more reactive
kinetically, probably because the arene C—H bond is less hindered and metal can interact
with the ring prior to C—H cleavage, and more stable thermodynamically, because of the
stronger aryl vs. alkyl C—M bonds in the product.

Functionalization of Aromatic Hydrocarbons

In 1825 Faraday reported that benzene and nitric acid react,l but Mitscherlich was
the first to determine that nitrobenzene was the product in 1834.9 In the intervening years,
electrophillic aromatic substitution (EAS) has evolved as the workhorse for aromatic
functionalization.

The regioselectivities for electrophillic aromatic substitution are governed by the
number, type, and relative placement of substituents in the aromatic system, and that

substituents typically fall into two classes"): (i) ortho, para-directors that typically

activate the aromatic system to electrophillic substitution and (ii) meta-directors that
operate by virtue of ortho, para deactivation.

The major limitation of electrophillic aromatic substitution is its inability to
prepare diverse meta substituted aromatics. For example, it took ten steps starting from

TNT to prepare a relatively simple phenolll (Figure 1.1).

 

 

 

\l/
\Ԥ
1. H 80 ,Na Cr 0 1. N328. EtOH
2. HZOAc? heai 2 7 02N N02 2. NaNOz, HCI Br N02
H 3. KOCN. MeOH 3. CuBr
2. = '
'—
OMe OMe
1. Sn. HCI
2. conc. H2804
3. NaNOz. HCI
4. CuCl Br CI
OH
1.1

Figure 1.1. Synthesis of a meta-substituted phenol by electrophillic aromatic

substitution.

Nucleophilic aromatic substitution is another approach for aromatic
functionalization, however requirement of harsh basic conditions limits its wide
applicability. Wittig in 193812 and Gilman in 1939‘3 reported ‘Directed ortho metalation’
methodology for aromatic functionalization (Figure 1.2). Although it has proved to be a

very useful technique, the functional groups must not react with organolithium reagents.

©DMG RLi CEDMG E+ @DMG
Li E

Figure 1.2. Aromatic functionalization via directed ortho metalation.

W

Organoboron Compounds

Organoboron compounds are synthetically valuable intermediates. The C—B bond
of an organoboron compound can easily be transformed into a variety of functional
groups.'4 Organoboron compounds have also been extensively used in cross-coupling

reactions. '5

Although trialkylboranes are air/moisture sensitive, the oxygenated
organoboranes are air/moisture stable and can be easily handled. The di-oxygenated
organoboranes, called boronic acids or boronic esters, are the most commonly used

organoboranes. The carbon attached to boron in organoboranes has a partial negative

charge making these compounds as ‘shelf stable carbanions’.l6

R.$,R R,$,R R,E'3,OH HO,$,OH R,l'3,OR
H" OH OH OH 013'
borane borinic acid boronic acid boric acid boronic ester

Figure 1.3. Oxygenated organoboron compounds.

Synthesis of Alkyl and Alkenyl Boranes

Organoboranes were first synthesized by Frankland in 1860 by the reaction of

dialkylzinc and trialkoxyborane'7"9 (Figure 1.4).

3 Zn(CZH5)2 + 2 B(OCQH5)3 ——-——> 2 3(02H513 + 3 20(002Hslz
1.2

Figure 1.4. Preparation of the first organoborane compound, 1.2.

The discovery of Grignard reagents led to the development of more versatile
synthesis based on the reaction of these reagents with borontrifluoride etherate or
alkoxyboranes.20 Hewever prior formation of reactive organometallics limited the use of

this route.

 

Another possible route was the reaction of hydrocarbons with diborane. Early
studies indicated that alkenes reacted with diborane at high temperature to form trialkyl
boranes?l In 1957, Brown and Subba Rao reported that in the presence of organic ethers,
diborane could be added to olefins with remarkable ease and speed at room temperature
to form the corresponding organoboranes in high yield (Figure 1.5).22 Similarly, alkenyl

boranes were prepared by hydroboration of alkynes.

 

3 \—-—— + 1/2 B2H5 ———-> (A)3B
Fl H

R : H + H-B —————> >=<
H /B--

Figure 1.5. Hydroboration of alkenes and alkynes.

The resulting aliphatic boranes were extensively employed in organic syntheses
resulting in the 1979 Nobel Prize being awarded to H. C Brown (shared with G. Wittig).
Mannig and Noth reported the first examples of transition metal catalyzed hydroboration
in 1985.23 The chemo-, regio-, and stereoselectivities of metal catalyzed reactions were
generally found to be complementary to those of uncatalyzed reaction.

Synthesis of Aromatic Boronates

Aryl boronic acids and esters are the most popular and widely used
organoboranes. Their popularity in medicinal chemistry is due in large part to their role
as cross-coupling partners for the synthesis of biaryl units, which are present in structure
of several pharmaceutical drugs.

As oppose to the preparation of alkenyl boranes via hydroboration of alkynes,

aromatic boranes cannot be easily prepared by hydroboration since benzyne intermediates

A I

would be required. Thus aromatic boronate esters have been traditionally prepared in
three steps by (1) halogenation (2) conversion of aryl halide to Grignard reagent (3)
reaction of Grignard reagent with trialkyl borate to yield aryl boronate esters (Figure

1.6).24

.«:28—-. c2298 Gm
RQ—H /‘ r -MgBr(OR) RA / ( )2

Figure 1.6. Traditional route for the synthesis of aryl boronic acids.

 

Directed ortho metalation (DOM) followed by trapping the resulting aryl lithium
reagent with trialkylborates has also been used to prepare aryl boronic acids (Figure
1.7).‘6‘25'26 However this methodology suffers from the disadvantage of the need to use
cryogenic conditions. The use of aryl magnesium/lithium reagents also limits functional

group compatibility.

HO
LTMP >4
©DMG B(OiPr)3 CCDMG HO ©:DMG
THF . Toluene T ,o
-78 °C 8(0’Pr)2 e\)<
o

 

Figure 1.7. Synthesis of aryl boronic esters via directed ortho metalation.

One of the earliest methods for the preparation of aryl boronic acids involved the
reactions between diaryl mercury compounds and boron trihalide. Since organomercurial
compounds are toxic, this reaction has remained unpopular. In search of other reagents
for this reaction, alkyl/aryl silanes and stannanes were found to undergo easily

transmetallation with boron tribromide (Figure 1.8).27

“—-

 

— . BBr3 — H30+ ‘—
RQ—SIMeg, R)‘ / BBrz ———* RQ’BmHh

Figure 1.8. Synthesis of aryl boronic acids from trialkyl aryl silanes.

Transition Metal Catalyzed Aromatic C—B Bond Formation

In 1995, Miyaura et al. reported the palladium catalyzed direct conversion of aryl
halides to arylboronate esters (Figure 1.9).28 This methodology bypassed the need to
generate aryl magnesium/lithium reagents from aryl halides, and hence increased the

functional group tolerances during the preparation of aryl boronic esters.

— 0. ,0 PdC'2(dppf) — ,0
R \ o o KOAc,DMSO R/‘ o
13

 

Figure 1.9. Palladium catalyzed borylation of aryl halides.

In 2000, Strongin and Willis reported a palladium catalyzed coupling of aryl
diazonium tetrafluoroborate salts with bis(pinacolato)diboron to synthesize aryl boronic
esters (Figure 1.10).29 The reaction proceeded under mild reaction conditions in the
absence of a base to afford various functionalized arylboronic esters including

haloarylboronic esters.

CB. 89 PdC|( (dppf) — ,0
MeOH, 40°C R ‘ 0

Figure 1.10. Palladium catalyzed borylation of aryl diazonium tetrafluoroborate salts.

 

O’m

‘u

 

Transition metal catalyzed cycloaddition of alkynyl boronate esters with diynes

has also been utilized for the preparation of aryl boronic esters (Figure 1.11).”32

 

 

_{_ Cp‘RuCI(COD) [B
/——_.—_ > O
HO _: R2

R2

 

Figure 1.11. Synthesis of aryl boronic esters via cycloaddition of alkynyl boronate esters

with diynes.

Since huge feedstocks of aromatic and heteroaromatic hydrocarbons are easily
available, direct conversion of aromatic C—H bond to the CB bond would be the ideal

approach for the synthesis of aryl boronic esters (Figure 1.12).

Pd catalyst, BgPinz or HBPin, Base, DMSO

| l

— [Ci] _ CI Mg — M CI B(OR)3 08 OR
\ H —’ \ ——> \ > \
HQ— R/‘ / R” / g -MgCl(OR) RA / ( )2

 

 

H—B(OR)2 l

 

IO
BZPInZ = B-B HBPin = H-B\
O
1.3 1.4

Figure 1.12. Different routes for the preparation of aryl boronic esters.

10

Uncatalyzed C—H Bond Borylation Reactions

In 1948, Hurd reported that at elevated temperatures, diborane reacts with several
hydrocarbons such as alkenes, alkynes, paraffins, and benzene.“ Benzene underwent
substitution reaction to form phenylboron compounds, which upon alkaline workup gave
phenylboronic acid. These reactions were carried out in stainless steel vessels and hence
they might not be truly uncatalyzed.

Koster and Rotermund discovered in 1960 that pyrolysis of triorganoboranes
yielded bicycloorganoborane 1.5, alkene, and molecular hydrogen (Figure 1.13).33 A
four-centered mechanism was proposed for the observed cleavage of C—H and the

formation of C-B bonds (Scheme 1.1).

250-350 °C
(W)SB > O? + 2 C8H16 + 2 H2

1.5

 

Figure 1.13. Pyrolysis of tri-n-octylborane.

Scheme 1.1. The four-centered mechanism of C—H/B—H dehydrogenation reactions.

T

--O--UJ—

7
Knochel observed similar intramolecular C—H activations of tert-butyl and phenyl

mu 3 in or anoboranes in solutions.34 Relativel small activation barriers (s 30 kcal
g P g Y

mol") have been predicted for intermolecular dehydrogenation reactions between borane

and hydrocarbons that occur via four-centered transition states.5

11

Transition Metal Mediated Aromatic C—H Activation/Borylation
In 1995, Hartwig et al. reported the stoichiometric functionalization of arenes and

alkenes by (CO)5Mn(BCat) (1.6), (CO)5MRe(BCat) (1.7), and CpFe(CO)2(BCat) (1.8)

under photochemical conditions (Figure 1.14).35

(CO)5M(BCat) + Q i» Q—ch + HBCat + others
1.9

M 2 Mn 1.6, 45%
M = Re 1.7, 55%

CpFe(CO)2(BCat) + Q A» @BCat + others

1.8 87%

,0
BCat = 8‘
0

Figure 1.14. Transition metal mediated photochemical aromatic borylation.

Hartwig et al. also examined the photochemical stoichiometric reactions of
CpFe(CO)2(BCat) (1.8) in a mono-substituted arene solvents.36 They observed the
formation of only meta- and para—substituted arylboronate esters except anisole, which

showed substantial amounts of ortho-substituted product (Table 1.1).

Table 1.1. Ratio of product isomers from reaction of CpFe(CO)2(BCat) with Csst.

 

 

 

X 0 m p

Me - 1.1 1.0

OMe 1.0 1.6 1.1

CI - 1.5 1.0

CF3 — 1.5 1.0

NMe2 - 1.0 8.0
12

 

Transition Metal Catalyzed Aromatic C—H Activation/Borylation

In 1994, Rablen and Hartwig reported calculation of B—H and B—C bond
dissociation energies for a series of borane reagents.“38 From the established
thermochemical and computational data, the reaction in Eq 1.5 was calculated to be

essentially thermoneutral.39 Hence, catalysis should be thermodynamically feasible.

CH4 + HBCat = CH3BCat + H2 ; A H° = +1.1 kcal/mol (1.5)
The first catalytic, thermal aromatic borylation was reported by Iverson and Smith

in 1999 by using Cp*Ir(PMe3)(H)(BPin) (1.10) as a precatlyst (Figure 1.15).39 With about

3 TON, this was also the first demonstration of catalytic viability of Eq. 1.5.

 

17 mol%
: I :
M P/ "V”H
e3 BPin
1.10 ,
CBHG + HBPin > CsHsBPIn + H2
150 °C, 120 h
1.11
53 °/o

Figure 1.15. First transition metal catalyzed aromatic C-H activation/borylation.

In 2000, Hartwig et al. reported that the rhodium complex Cp*Rh(n4-C6Me6)
(1.12) catalyzes the formation of linear alkyl boranes from alkanes and borane reagents

under thermal conditions (Figure 1.16).40

 

5 mol%
CP*Rh(7I4'CeM96)
n-Octane + HBPin 1 '12 > n-Octyl-BPin + H2
150 °C
1 .13
65%

Fig ure 1.16. Thermal, catalytic, regiospecific functionalization of n-octane.

13

if

Cho and Smith in 2000 reported thermal catalytic borylations of substituted
arenes using Cp*1r(PMe3)(H)(BPin) (1.10) or Cp*Rh(n4-C6Me6) (1.12).4|
Regioselectivities in this new catalytic aromatic borylation protocol were governed by
sterics and hence were complementary to the traditional electrophillic aromatic
substitution chemistry. For example, borylation of toluene gave a 2:1 statistical mixture
of m- and p-C6H4MeBPin (Figure 1.17). 1,3-di-substituted arene was selectively
functionalized on the 5-position (Figure 1.18). Heterocyclic substrate such as
2,6-di-methylpyridine was selectively borylated at the 4-position. Several functional
groups including heteroatom substituents were tolerated. Iridium catalyst 1.10 was more
selective for aromatic C—H activation vs. benzylic or C—F activation as compared to the
rhodium catalyst 1.12. Electron deficient arenes were more reactive than electron rich
ones. Borylation of C6D6 with HBPin in the presence of m-C6H4Me(BPin) (1.14b) did not
isomerize m-C6H4Me(BPin) or reduced it to toluene, indicating that the isomer

distribution was kinetically determined.

 

Me 20 mol%
Cp' Ir(PM1e§,) (H)( BPin) BPin
+ HBPin
150 °C, 511h7, 91% yield> BPin
BPin
0.12 1.83 1.00
1.14a 1.14b 1.140

Figure 1.17. Statistical product distribution in sterically directed catalytic thermal

borylation of mono substituted arene.

l4

 

 

M9 Me , 20 mol% Cp*|r(PMe3)(H)(BPin) Me Me
+ HBPIn >
150 °c, 151 h, 60% yield

BPin
1.15 1.16

Figure 1.18. Regioselective borylation of 1,3—substituted arene.

Tse and Smith showed in 2001 that catalytic borylation could also be performed
by using stoichiometric arenes in an inert solvent like cyclohexane.42 Several
1,3-substituted arenes were selectively borylated on the 5-position using
Cp*Rh(n4-C6Me6) (1.12) precatalyst. 1,2-di-methoxybenzene was selectively borylated
on the 4-position. TIPS protected pyrrole was selectively borylated on the 3-position.
Attempted borylation of m-di—chlorobenzene resulted in the formation mixture of
products, including those from dechlorination, indicating the incompatibility of
halogenated arenes with rhodium precatalyst 1.12.

Since iridium-based catalysts were more selective for aromatic C—H activation vs.
the rhodium-based catalyst, detailed study of the iridium system was required in order to
improve the turnover numbers. Mechanistic studies by Smith and co-workers43 revealed
that the active catalysts in the form of iridium phosphine species were generated by Cp*
loss from Cp*Ir(PMe)3(H)(BPin) (1.10). Active catalysts could also be generated by a
combination of (Ind)Ir(COD) (1.17) and phosphine ligands. Commercially available
precatalyst such as [Ir(COD)Cl]2 (1.18) were also effective. Chelating phosphine
substantially increased catalytic activity and TONS as high as 4500 were obtained with
1,2-bis—(dimethylphosphino)-ethane (dmpe) (1.19). This catalyst was highly selective for

aromatic C—H bond activation as compared to aromatic C—Halogen or benzylic C—H

15

activation (Figure 1.19). Several functional groups including C—Halogen bonds were

"W cycle was proposed (Figure 1.20).

9‘ F12 2 mol% (Ind)Ir(COD) (1.17) R‘ R2
0 + HBPin =
2 mol% dmpe/dppe, 150 °C

tolerated. A mechanism involving Ir

 

BPin
R‘, R2 = Cl, Br, I, OMe, COZMe
dmpe : Mezp/VPMez dppe = PhZP/VPPIIQ
1.19 1.20
Figure 1.19. Improved catalysts for aromatic C—H activation/borylation.
BPin
R-H f H’ lr‘BPin \z R“BPln
R
[er|(COD)] or .
2 HBPm’ BPin l n V l TpirBPin
' r'" r ce
w —-(—\l—'—> (x—Ir Lfi’i‘n 50-5000 tfiymovus k—h {H
l L’ L’
(060) BP
in
H-H ’K. (Ll-kg?“ /\H-BPin
(\L = bisphosphine H A m

Figure 1.20. Catalytic cycle for iridium catalyzed aromatic C—H activation/borylation.

Shortly after Smith’s report, Hartwig and coworkers showed that a combination of
[lr(COD)Cl]2 (1.18) and 2,2‘-bipyridine (1.22) could also catalyze aromatic borylation
(Figure 1.21).44 Regioselectivities and functional group tolerance in this system were

similar to the one reported by Smith.4M3

16

25 mol% lr(l), L A

 

BzPinz + 2 Ar-H 2 Ar-BPin
26-100°C
R n
lr(|)=[lr(COD)Cl]2 (1.18) L_ _ — R=H (1.22)
moorsbcu2 (1.21) - \ mi N / t-Bu(1.23)

Figure 1.21. lr/bpy catalyzed aromatic C—H activation/borylation.

In the same year, Miyaura and Hartwig reported catalyst system consisting of
[Ir(OMe)(COD)]2 (1.24), 4,4'-di-t-butyl-2,2'-bipyridine (dtbpy) (1.23), and BzPinz (1.3)
to be effective for borylation of several electron deficient arenes at room temperature.45
The reaction could also be carried out with HBPin46 ( 1.4) and the substrate scope was
expanded to simple heteroaromatics.47'48

A detailed mechanistic study was reported by Hartwig in 2005 where
[Ir(dtbpy)(COE)(BPin)3] (1.25) was identified as the resting state of catalyst.” Kinetic

studies showed that the active catalyst is generated by the reversible dissociation of COE,

and the resulting reactive intermediate [Ir(dtbpy)(BPin)3] cleaves the arene C—H bond in

VI“ III/V

the rate determining step. Ir cycle was ruled out and Ir cycle was identified to be
consistent with experimental results. TONS were increased up to 25,000.

Several reports have Since appeared in literature where other precatlyst/ligand
combinations have also been shown to carry out aromatic borylation. Chart 1.1

summarizes different types of catalysts/ligands systems which have been employed in

aromatic C—H borylation.

l7

Chart 1.1. Different catalysts systems used for aromatic borylation.

 

 

Entry Inventor Year Precatalyst Ligand
1 Smith39 1999 Cp'lr(PMea)(H)(BPin) -
2 Smith41 2000 Cp'Rh(CGMeS) -
3 Marder50 2001 [RhCl(P’Pr3)2(N2)] —
(Ind)Ir(COD) Mezp/VPMee
4 Smith43 2002 or or
[lr(COD)CI]2 thp/Vppha
5 Hartwig/Miyaura“ 2002 [lr(COD)CI]2 bpy: \ , \ /
N N
tBu tBu
6 Miyaura/Hartwig45 2002 [lr(OMe)(COD)l2 dtbpy: \ / \ /
N N
__ ’Pr
7 Nishida/Tagata 2004 [Ir(COD)Cl]2 N N
’Pr
8 Hartwig/Miyaura49 2005 [lr(dtbpy)(COE)(BPin)3] ._
M
[Rh(COD)CI]2 e ,N.
9 Murata55 2006 or \ N BH
[Ir(COD)CI]2 3
Me
Me
[Rh(COD)CI]2 N
10 Herrmann56 2006 or [I >
[lr(COD)Cl]2 N
Me
11 Yinghuai57 2007 [Ir(-o-O-CEH4-CHzN-CHzPh)(COD)]

/N /l
I

\ |N\ \N

IN\ N/ |\
/ N/

 

18

Marder et al. showed in 2001 that [RhCl(P’Pr3)2(N2)] (1.26) was an efficient
catalyst for the borylation of aromatic and benzylic C—H bonds with HBPin.50 This
catalyst system was highly selective for benzylic functionalization of toluene, p-xylene,
and mesitylene. DFT calculations at B3PW91 level indicated that [Rh(‘Pr3)2(H)] is the
active species which oxidatively add to the C—H bond leading to an n3-benzyl complex
which is the key to determining the unusual benzylic regioselectivity.“ Ishiyama and
Miyaura reported in 2001 that 10% Pd/C was an effective catalyst for benzylic borylation
of alkyl benzenes.5‘2

Nishida andiTagata reported that a combination of [IrCl(COD)]2 precatalyst and
2,6-diisopropyl-N—(2-pyridylmethylene)-aniline (1.27) ligand was effective for aromatic
borylation at 80 °C.53 n-Octane was a suitable solvent for several substrates while DME
was better for indole. The yields tended to improve with smaller amounts of catalyst.

Beller et a1. studied the selective borylation of arene C—H vs. benzylic C—H bonds
in o-xylene.54 Using [Ir(COD)Cl]2 with 8 equiv of bpy, they observed exclusive aromatic
C—H borylation on the 4-position. In contrast, use of [Rh(COD)(acac)] (1.28) or
[Rh(COD)Cl]2 (1.29) with bpy resulted in selective benzylic borylation. Simple
heteroaromatic substrates were also borylated on positions adjacent to the heteroatom.

Murata has shown that hydrotris(pyrazolyI)borate complexes of rhodium and
iridium can catalyze aromatic borylation around 100-120 °C.55 The presence of
heteroatom functional groups did not interfere with the outcome of iridium catalyzed

reaction, however the rhodium system lacked this wide applicability.

l9

Herrmann et al. have reported that bis-(N-heterocyclic)-carbene complexes of
iridium (I) Show significant catalytic performance in the direct borylation of arenes.56
Halogenated benzenes including iodobenzene were found to be borylated at 40 °C in 9-12
h with 89-100% GC yields.

Yinghuai et al. have reported iridium (I) salicylaldiminato-cyclooctadiene
complexes as reusable catalysts for C—H bond borylation of arenes with BzPinz.57 Among
the several ligands tested, tetra-Z-pyridinylpyrazine (TPy) was found to be the best ligand
for this system. Catalytic performance was enhanced when a solvent mixture of
dichloromethane and the ionic liquid, tributyltetradecylphosphonium
dodecylbenzenesulfonate (TBPD) was used. In borylation of monosubstituted arenes, the
ratios of meta- to para-isomers in the products ranged from 1.521 for toluene to 1.1:] for
anisole. The preference for para-substitution could further be enhanced by the use of
ionic liquid as solvent. The yields were better for electron deficient arenes than those for
electron rich arenes.

Mkhalid et al. have shown that the ligand dtbpy (1.23) used in aromatic borylation
can itself be borylated when used in excess.58 Although cycloalkene ligands are present in
commonly used iridium borylation precatalysts, Olsson and Szabo have reported that
catalytic borylation of unactivated cycloalkenes took place under the typical aromatic

borylation conditions.59

20

The substrate scope of iridium catalyzed aromatic borylation has been extended to
other aromatic systems (Figure 1.22). Kurotobi et al. have shown that iridium-catalyzed
borylation introduces the boryl substituent at the 2-position of azulene, a position difficult
to functionalize by other means.60 Plenio et al. utilized iridium catalyzed borylation for
the synthesis of borylated ferrocenes and half sandwich compounds.6| Coventry et al.
have reported the selective borylation in polycyclic aromatics such as naphthalene,
pyrene, and perylene.62 Complex systems such as meso-arylporphyrins,63 functionalized
porphyrinsf’4 and corrole65 have also been borylated. More recently, Smith et al. have
described the regioselective borylation of 2-Substituted indoles on the 7-position.66 Lo et

al. also observed identical reactivity/selectivity for 2-substituted indoles.67

 

BPin
H
. N
Azulene60 lndoles’5‘5
CGF5 AI
, BPin BPin
PinB F11
Fe (3er
@412
Ferrocenes61 Corrole65 Porphyrin54

Figure 1.22. Regioselective borylation in some complex aromatic systems.

21

The intermediate boronate ester can further be utilized without isolation. For
example, Holmes et al. reported a one-pot protocol for borylation/Suzuki coupling of
1,3-di-substituted arenes."8 Maleczka and co-workers showed that intermediate boronic
ester can be oxidized without isolation to synthesize previously unknown/difficult to
synthesize phenols."9 Shi et al. have used the intermediate boronate esters to synthesize
deuterium labeled aromatics.70 Hartwig has reported that the intermediate boronic ester
can be converted to aryl trifluoroborates/aryl boronic acids7| and aryl halides.72 The
boronic ester can also sequentially be transformed to anilines/aryl ethers after conversion

to boronic acids,73 The atom diversity introduced via boronate esters is shown in Figure

1.23.
n x
ng OH R X
D Ar
Ar BPin BF3K
NHAr “0" Cl
Br

Figure 1.23. Diverse functional groups introduced via boronate ester.

22

H1:

 

Cross-Coupling Reactions

Transition metal catalyzed cross coupling reactions of organometals represent the
most widely applicable organic Skeleton construction method discovered and developed
over the past several decades, allowing the synthetic chemists to synthesize practically

almost all types of organic compounds.”75

Transition metal catalyst
R‘E + R2x +7 til-R?-

 

E = B (Suzuki-Miyaura)
Mg (Kumada-Tamao, Corriu)
Sn (Migita-Kasugi, Stille)
Zn (Negishi)
Si (Tamao-Kumada, Hiyama-Hatanaka) .....

Figure 1.24. Metal catalyzed cross-coupling reactions.

Unlike Grignard reagents, organoboron compounds are air and water stable. The
C—B bond in organoboranes is highly covalent, thus limiting the use of organoboranes
reagents in ionic reactions. Low reactivity of organoboranes can be overcome by
coordination of a negatively charged base to the boron atom to make it tetra-coordinate.

In 1979, Miyaura and Suzuki reported the first example of cross-coupling reaction
involving organoboron compounds.76 Several advantages including tolerance of a broad
variety of functional groups, non toxic and mild reaction conditions, air and water
stability of reagents, and easy separation of inorganic boron compounds, has made the

Suzuki reaction as the reaction of choice for the construction of aryl-aryl bonds.

23

During the past decade, extensive research has been carried out by Buchwald &
Hartwig groups to extend the cross-coupling chemistry to C—Heteroatom couplings such
as C—N and C—0 bond forming reactions.”78 Transition metal catalyzed arylations of
amines and alcohols now have become the preferred method for the preparation of aryl
amines and aryl ethers

The catalytic cycle for all these reactions typically consists of oxidative addition,

transmetallation/insertion, and reductive elimination steps.

Rl-RZ [Ml 92x
reductive oxidative
elimination addition

F12 R2
/
1M]\ iMi’
EX Fi‘ E
transmetalation

Figure 1.25. General catalytic cycle for cross-coupling reactions.

The reaction between aryl/alkenyl halides and alkynes to synthesize internal
alkynes, firstly introduced by Sonogashira,79 is another highly useful cross coupling

reaction.

24

Wan.

This thesis will describe our efforts to extend the scope and applications of iridium
catalyzed aromatic borylations. Chapter 2 describes the regioselective borylation ortho to
cyano groups in 4-Substituted benzonitriles. Synthesis of a variety of substituted
borylated thiophenes are discussed in Chapter 3. Efforts to improve regioselectivities in
iridium catalyzed aromatic borylations by ligand modification are presented in Chapter 4.

Since aromatic C-Halogen bonds survive during iridium catalyzed aromatic
borylation; we became interested if it is possible to carry out selective cross coupling on
the C—Halogen bond, subsequent to borylation step, while keeping the BPin group intact.
Our efforts in this regard to synthesize aromatic amino boronate esters, aromatic alkynyl

boronate esters, and aromatic thioether boronate esters are presented in Chapter 5 and 6.

 

 

X
Z
R It catalyzed
borylation
R1 ,R2
i i X N
Sonogashira
coupling amination
Z BPin Z BPin Z BPin
C-S
coupling
SR
2 BPin

Figure 1.26. One-pot borylation/cross—coupling reactions.

25

5-Coordinate, l6-electron, bi-dentate ligated iridium tris-boryl complexes have
been proposed to be the active catalysts in the iridium catalyzed aromatic borylation.
From mechanistic studies, the support for these intermediates is strong, but 5-coordinate
complexes have eluded isolation. Preparation and reactions of some 5-coordinate, iridium

tris-boryl complexes are described in Chapter 7.

26

BIBLIOGRAPHY

(1) Faraday, M. Philos. Trans. Roy. Soc. (London) 1825, 115, 440-466.
(2) Snieckus, V. Chemical Reviews 1990, 90, 879-933.
(3) Fokin, A. A.; Schreiner, P. R. Chemical Reviews 2002, 102, 1551-1593.

(4) Olah, G. A.; Schlosbe.Rh Journal of the American Chemical Society 1968,
90, 2726-2727.

(5) Goldfuss, B.; Knochel, P.; Bromm, L. 0.; Knapp, K. Angewandte Chemie-
International Edition 2000, 39, 4136-4139.

(6) Yang, D.; Wong, M. K.; Wang, X. C.; Tang, Y. C. Journal of the
American Chemical Society 1998, 120, 661 1-6612.

(7) Dick, A. R.; Sanford, M. S. Tetrahedron 2006, 62, 2439-2463.

(8) Crabtree, R. H. Journal Of The Chemical Society-Dalton Transactions
2001, 2437-2450.

(9) Mitscherlich, E. Justus Liebigs Ann. Chem. 1834, 12, 308.
(10) Holleman, A. F. Chemical Reviews 1924, 1, 187-230.

(11) Hodgson, H. H.; Wignall, J. S. Journal of the Chemical Society 1926,
2077-2079.

(12) Wittig, G.; Pockels, U.; Droge, H. Berichte Der Deutschen Chemischen
Gesellschaft 1938, 71, 1903-1912.

(13) Gilman, H.; Bebb, R. L. Journal Of The American Chemical Society 1939,
61, 109-112. ’

27

(14) Mikhaaeilov, B. M.; Bubnov, 6. N.; Mikhamilov, B. M. Organoboron
compounds in organic synthesis; Rev. English ed.; Harwood Academic: Chur,
Switzerland ; New York, NY, USA, 1984.

(15) Miyaura, N.; Suzuki, A. Chemical Reviews 1995, 95, 2457-2483.

(16) Lysen, M.; Hansen, H. M.; Begtrup, M.; Kristensen, J. L. J. Org. Chem.
2006, 71, 2518-2520.

(17) Frankland, E. Proc. Roy. Soc. (London) 1860, 10, 568.

(18) Frankland, E. Journal of Chemical Society 1862, 15, 363.

(19) Frankland, E.; Duppa, B. F. Justus Liehig Ann. Chem. 1860, 115, 319.

(20) Krause, E.; Nitsche, R. Berichte Der Deutschen Chemischen Gesellschaft
1921, 54, 2784-2791.

(21) Hurd, D. T. Journal of the American Chemical Society 1948, 70, 2053-
2055.

(22) Brown, H. C.; Rao, B. C. S. Journal Of Organic Chemistry 1957, 22,
1136-1137.

(23) Mannig, D.; Noth, H. Angewandte Chemie-International Edition In
English 1985, 24, 878-879.

(24) Konig, W.; Scharrnbeck, W. Journal Fur Praktische Chemie-Leipzig
1930, 128, 153-170.

(25) Caron, S.; Hawkins, .1. M. Journal Of Organic Chemistry 1998, 63, 2054-
2055.

(26) Kristensen, J.; Lysen, M.; Vedso, P.; Begtrup, M. Organic Letters 2001, 3,
1435-1437.

28

(27) Haubold, W.; Herdtle, J.; Gollinger, W.; Einholz, W. Journal of
Organometallic Chemistry 1986, 315, 1-8.

(28) Ishiyama, T.; Murata, M.; Miyaura, N. Journal Of Organic Chemistry
1995, 60, 7508-7510.

(29) Willis, D. M.; Strongin, R. M. Tetrahedron Letters 2000, 41, 8683-8686.

(30) Gandon, V.; Leca, D.; Aechtner, T.; Vollhardt, K. P. C.; Malacria, M.;
Aubert, C. Organic Letters 2004, 6, 3405-3407.

(31) Yamamoto, Y.; Hattori, K.; Ishii, J.; Nishiyama, H. Tetrahedron 2006, 62,
4294-4305.

(32) Yamamoto, Y.; Hattori, K.; Ishii, J.; Nishiyama, H.; Itoh, K. Chemical
Communications 2005, 443 8-4440.

(33) Koster, R.; Rotermund, G. Angewandte Chemie-International Edition
1960, 72, 563-563.

(34) Laaziri, H.; Bromm, L. 0.; Lhermitte, F.; Gschwind, R. M.; Knochel, P.
Journal Of The American Chemical Society 1999, 121, 6940-6941.

(35) Waltz, K. M.; He, X. M.; Muhoro, C.; Hartwig, J. F. Journal Of The
American Chemical Society 1995, 117, 11357-11358.

(36) Waltz, K. M.; Muhoro, C. N.; Hartwig, J. F. Organometallics 1999, 18,
3383-3393.

(37) Rablen, P. R.; Hartwig, J. F.; Nolan, S. P. Journal Of The American
Chemical Society 1994, 116, 4121-4122.

(38) Rablen, P. R.; Hartwig, J. F. Journal Of The American Chemical Society
1996, 118, 4648-4653.

(39) Iverson, C. N.; Smith, M. R. Journal Of The American Chemical Society
1999, 121, 7696-7697.

29

 

(40) Chen, H. Y.; Schlecht, S.; Semple, T. C.; Hartwig, J. F. Science 2000, 287,
1995-1997.

(41) Cho, J. Y.; Iverson, C. N.; Smith, M. R. Journal Of The American
Chemical Society 2000, 122, 12868-12869.

(42) Tse, M. K.; Cho, J. Y.; Smith, M. R. Organic Letters 2001, 3, 2831-2833.

(43) Cho, J. Y.; Tse, M. K.; Holmes, D.; Maleczka, R. E.; Smith, M. R. Science
2002, 295, 305-308.

(44) Ishiyama, T.; Takagi, J.; Ishida, K.; Miyaura, N.; Anastasi, N. R.; Hartwig,
J. F. Journal Of The American Chemical Society 2002, 124, 390-391.

(45) Ishiyama, T.; Takagi, J.; Hartwig, J. F.; Miyaura, N. Angewandte Chemie-
International Edition 2002, 41, 3056-3058.

(46) Ishiyama, T.; Nobuta, Y.; Hartwig, J. F.; Miyaura, N. Chemical
Communications 2003, 2924-2925.

(47) Takagi, J.; Sato, K.; Hartwig. J. F .; Ishiyama, T.; Miyaura, N. Tetrahedron
Letters 2002, 43, 5649-5651.

(48) Ishiyama, T.; Takagi, J.; Yonekawa, Y.; Hartwig, J. F.; Miyaura, N.
Advanced Synthesis & Catalysis 2003, 345, 1103-1106.

(49) Boller, T. M.; Murphy, J. M.; Hapke, M.; Ishiyama, T.; Miyaura, N.;
Hartwig, J. F. Journal Of The American Chemical Society 2005, 127, 14263-14278.

(50) Shimada, S.; Batsanov, A. 8.; Howard, J. A. K.; Marder, T. B.
Angewandte Chemie-lnternational Edition 2001, 40, 2168-2171.

(51) Lam, W. H.; Lam, K. C.; Lin, Z. Y.; Shimada, S.; Perutz, R. N.; Marder,
T. B. Dalton Transactions 2004, 1556-1562.

(52) Ishiyama, T.; Ishida, K.; Takagi, J.; Miyaura, N. Chemistry Letters 2001,
1082-1083.

30

(53) Tagata, T.; Nishida, M. Advanced Synthesis & Catalysis 2004, 346, 1655-
1660.

(54) Mertins, K.; Zapf, A.; Beller, M. Journal Of Molecular Catalysis A-
Chemical 2004, 207, 21-25.

(55) Murata, M.; Odajima, H.; Watanabe, S.; Masuda, Y. Bulletin Of The
Chemical Society Of Japan 2006, 79, 1980-1982.

(56) Frey, G. D.; Rentzsch, C. F.; von Preysing, D.; Scherg, T.; Muhlhofer, M.;
Herdtweck, E.; Herrmann, W. A. Journal Of Organometallic Chemistry 2006, 691, 5725-
5738.

(57) Yinghuai, 2.; Yan, K. C.; Jizhong, L.; Hwei, C. 8.; Hon, Y. C.; Emi, A.;
Zhenshun, S.; Winata, M.; Hosmane, N. S.; Maguire, J. A. Journal Of Organometallic
Chemistry 2007, 692, 4244-4250.

(58) Mkhalid, I. A. 1.; Coventry, D. N.; Albesa-Jove, D.; Batsanov, A. S.;
Howard, J. A. K.; Perutz, R. N.; Marder, T. B. Angewandte Chemie-International Edition

2006, 45, 489-491.

(59) Olsson, V. J.; Szabo, K. J. Angewandte Chemie-lnternational Edition
2007, 46, 6891-6893.

(60) Kurotobi, K.; Miyauchi, M.; Takakura, K.; Murafuji, T.; Sugihara, Y.
European Journal Of Organic Chemistry 2003, 3663-3665.

(61) Datta, A.; Kollhofer, A.; Plenio, H. Chemical Communications 2004,
1508-1509.

(62) Coventry, D. N.; Batsanov, A. S.; Goeta, A. E.; Howard, J. A. K.; Marder,
T. B.; Perutz, R. N. Chemical Communications 2005, 2172-2174.

(63) Hata, H.; Shinokubo, H.; Osuka, A. Journal Of The American Chemical
Society 2005, 127, 8264-8265.

(64) Hata, H.; Yamaguchi, S.; Mori, G.; Nakazono, S.; Katoh, T.; Takatsu, K.;
Hiroto, S.; Shinokubo, H.; Osuka, A. Chemistry-An Asian Journal 2007, 2, 849-859.

31

(65) Hiroto, S.; Hisaki, 1.; Shinokubo, H.; Osuka, A. Angewandte Chemie-
International Edition 2005, 44, 6763-6766.

(66) Paul, S.; Chotana, G. A.; Holmes, D.; Reichle, R. C.; Maleczka, R. E.;
Smith, M. R. Journal Of The American Chemical Society 2006, 128, 15552-15553.

(67) Lo, W. F.; Kaiser, H. M.; Spannenberg, A.; Beller, M.; Tse, M. K.
Tetrahedron Letters 2007, 48, 371-375.

(68) Holmes, D.; Maleczka, R. E.; Smith, M. R. In Abstracts of Papers, 223rd
ACS National Meeting, Orlando, FL, ; American Chemical Society: Washington, DC; :
ORGN-380, 2002; Vol. 223.

(69) Maleczka, R. E.; Shi, F.; Holmes, D.; Smith, M. R. Journal Of The
American Chemical Society 2003, 125, 7792-7793.

(70) Shi, F.; Smith, M. R.; Maleczka, R. E. Unpublished results.

(71) Murphy, J. M.; Tzschucke, C. C.; Hartwig, J. F. Organic Letters 2007, 9,
757-760.

(72) Murphy, J. M.; Liao, X.; Hartwig, J. F. Journal of the American Chemical
Society 2007, 129, 15434-15435.

(73) Tzschucke, C. G; Murphy, J. M.; Hartwig, J. F. Organic Letters 2007, 9,
761-764.

(74) Meijere, A. d.; Diederich, F. Metal-catalyzed cross-coupling reactions;
2nd, completely rev. and en]. ed.; Wiley-VCH: Weinheim ; [Chichester], 2004.

(75) Diederich, F.; Stang, P. J. Metal-catalyzed cross-coupling reactions;
Wiley-VCH: New York, 1998.

(76) Miyaura, N.; Yamada, K.; Suzuki, A. Tetrahedron Letters 1979, 3437-
3440.

(77) Wolfe, J. P.; Wagaw, S.; Marcoux, J. F.; Buchwald, S. L. Accounts of
Chemical Research 1998, 31, 805-818.

32

 

(78) Hartwig, J. F. Accounts of Chemical Research 1998, 31, 852-860.

(79) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975, 4467-
4470.

33

 

 

CHAPTER 2
Sterically Directed Functionalization of Aromatic C-H Bonds:

Selective Borylation ortho to Cyano Groups in Arencs and Heterocycles
Introduction

Aromatic hydrocarbons are fundamental chemical building blocks, and their
reactivity is a cornerstone of organic chemistry. Their utility derives largely from the
regiochemical fidelity embodied in electrophilic aromatic substitutions.I While steric
effects can influence electrophilic aromatic substitution, electronic effects typically
dominate. For electrophilic aromatic substitution (EAS) reactions, substituents on
aromatic rings fall into two classes: ortho, para directors and meta directors. When
directing groups are positioned to work in concert, regioselectivity can be complete as in
the classic example of nitration at the 3-postion of 4-bromobenzonitrile (Scheme 2.1,
electronically preferred product, FG = N02).2 For most di-substituted benzenes, EAS
does not usually offer well-defined regiochemical outcomes. For example, two of the
three possible arrangements of directing groups in 1,4-Substituted benzenes give poor

regioselectivity (Scheme 2.1).

34

 

Scheme 2.1. Regiochemical trends in electrophilic aromatic substitution for

1,4-substituted benzenes.

ortho/para directors meta directors

No No m2

Activated to EAS but
poor regioselectivity

Deactivated to EAS and

Excellent regioselectivity poor regioselectivity

 

ortho/para director meta director
«— e o .. ——-—-
F6 F9-
Electronically preferred Sterically preferred

For the functionalization at positions meta to ortho, para directors and/or ortho to
meta directors, alternate methods to electrophilic aromatic substitutions are required. In
the case of certain meta directing substituents, directed ortho metalation (DoM)
constitutes a powerful method for functionalization at the adjacent positions, provided
that the substituent is a sufficiently strong directed metalation group (DMG).3 For
di-substituted benzenes, the regioselectivity of DoM depends on the positions of the
substituents and their ranking in the DMG hierarchy. 1,3-Subsituted benzenes can often
be derivatized selectively at the 2-position because DMG’s can act in concert to direct
metalation.

In contrast, DMG’s can compete in 1,2- and 1,4-substituted benzenes. Therefore
high regioselectivities are typically realized when there is a substantial difference in
relative DMG powers. For example, while DoM protocols can be effective for
functionalizing ortho to cyano groups in simple aromatic nitrilesf‘5 the presence of other
groups can subvert the selectivity. Sometimes the regiochemical outcome is unexpected.

For instance, competitive 2,5-dilithiation of 4-bromobenzonitrile occurs with LDA6 and

35

 

deprotonation at the 3-position has been reported with the hindered phosphazene base,
1’4-t-Bu,7 even though the DMG ranking of CN is greater than Br. Prior to the publication
of results described in this chapter, there were no documented transformations of
4-bromobenzonitrile that were selective for the 2-position8‘9 (See page 46 for work
published afterwards). Moreover, examples of functionalization at the 2-position in other
4-substituted benzonitriles are limited, and there are no general approaches toward this
end.'°'l2 This is unfortunate because aryl nitriles have a rich chemistry, and are
particularly useful entries into heterocyclic systems.”'4

An alternate strategy for functionalizing benzonitriles that can potentially
complement electrophilic aromatic substitutions and DoM’s is to differentiate positions
based on steric effects (Scheme 2.1). Since the first report by Ittel and co-workers in
1976,'5 there have been several reports of transition metal mediated C—H activations
where steric, not electronic, effects are the overriding factors in regioselection. More
recently, significant progress has been made in coupling C—H activation with subsequent
transformations of the nascent M—C bond to design new catalytic processes.’6 Since
1999, we,”20 and others,”26 have been particularly interested in utilizing Ir—catalyzed
borylations of arenes to tap the unique regioselectivities available to sterically directed
C—H activations. We reasoned that borylation ortho to nitrile groups should be possible
for appropriate substrates since the cyano group is only slightly larger than fluoride (vide
infra). Our initial attempts to borylate benzonitriles with pinacolborane (HBPin) using Ir
phosphine systems at elevated temperatures gave complex mixtures due to competitive
reduction of the nitrile. More active Ir catalysts developed by Hartwig, Ishiyama, and

Miyaura overcome this problem. These Ir dipyridyl catalysts operate at room

36

 

temperature, and examples have been reported showing that the nitrile group is
compatible with the borylation conditions?”25 However, data is available for only three
substrates, none of which addressed our regiochemical hypothesis. Herein, we describe
results for the borylations ortho to cyano groups of benzonitriles.
Results

We first examined borylations of 4-substituted benzonitriles. As most substrates
were poorly soluble in saturated hydrocarbons, borylations were typically carried out in
THF solvent using the catalyst constituted from a 1:2 ratio of [Ir(OMe)(COD)]2 (1.24)
and dtbpy (1.23) as indicated in Scheme 2.2. The results for monoborylation reactions are
given in Table 2.1. The reaction times roughly correspond to relative reactivities and
yields are for isolated products with respect to the limiting reagent. Either HBPin ( 1.4) or
BzPinz (1.3) can be used with shorter reaction times required for the latter reagent. For
entries 1-3, 5-7, and 11, diborylation can be significant when the benzonitrile is the
limiting reagent. For these substrates, a benzonitrilezborane reagent ratio of 4:1 was used

to minimize diborylation.

37

Scheme 2.2. Catalytic borylation of 4-substituted benzonitriles.

 

ON C” C”
HBPin Of szlnz BPin
1.5 mol% [Ir(OMe)(COD)]2, ‘ +
3.0 mol% dtbpy, v ~
THF, 25 °C BPin
2 Z Z
2.x 218 2'Xb

Table 2.1. Regioselectivities for borylation of 4-substituted benzonitriles according to

 

 

Scheme 2.2.

Entry Z Borane (equiv) Time (h) % yield %2.xa:%2.xb
1 F HBPin (0.25) 8 71 11:89 (8:92)
(2.1a:2.1b)

2 Cl HBPin (0.25) 36 76 80:20 (81 :19)
(2.23:2.2b)
3 Br HBPin (0.25) 48 73 95:5 (97:3)
(2.33:2.3b)

4 l B2Pin2 (1.0) 40 70 >99:1 (>99:1)
(2.43:2.4b)
5 Me HBPin (0.25) 72 64 94:6 (92:8)
(2.5a:2.5b)

6 OMe HBPin (0.25) 24 65 67:33 (67:33)
(2.68:2.6b)

7 SMe szine (0.25) 18 55 90:10 (87:13)
(2.7a:2.7b)

8 NMe2 B2Pin2 (1.0) 72 58 >99:1 (>99:1)
(2.83:2.8b)

9 COzMe BzPinz (0.8) 48 65 >99:1 (>99:1)
(2.9a:2.9b)

10 NHAc BgPinz (1.6) 18 62 >99:1 (>99:1)

(2.10a:2.10b)

11 CF3 HBPin (0.25) 24 68 >99:1 (>99:1)

(2.11a:2.11b)

 

Isomer ratios for isolated products are in parentheses.

For 4-halobenzonitriles, the extent of borylation at the 3-position (isomer b)

diminishes in the order F > Cl > Br > I. This trend is consistent with the ordering of steric

38

energies for substituents on a benzene ring F < CN < Cl < Br < I (vide infra). However,
the regioselectivities are also consistent with the thermodynamic ordering of ortho-C—H
acidities is F > CN > c1 from the literature.27'28 Thus, rationalization of the regiochemical
outcome is shackled with the age-old dilemma of definitively separating steric and
electronic effects. Nevertheless, a compelling case can be made for steric directing effects
as outlined below.

There are several approaches for evaluating steric effects.29 Following a course
recommended by I-ngold,30 Taft developed a parameter, Es, to account for steric effects on
hydrolysis and esterification rates of o-benzoate esters.31 It was later shown that Es values
could be quantitatively related to van der Waals radii,32 and values have been calculated
for substituents absent in Taft’s original work.33 Dubois later revised Tafi’s definition,
introducing the Taft-Dubois steric paramater, E 's.34 Despite their demonstrated utility, Es
and E 's values are nonetheless empirical and the database of values is still limited.
Alternatively, the energy difference between equatorial and axial conformers of
monosubstituted cyclohexanes (the A value) has been invoked as a measure of steric
effects.” Although the equatorial site is indeed favored from a steric standpoint,
cyclohexane conformational energies are not immune to electronic effects. Hence, A
values are poor predictors of steric differences for electronically disparate substituents.
For our purposes, although there is no E 's value in the literature for CN, the Es value that
is typically quoted places CN between F and Cl, which seems reasonable.”
Unfortunately, the value does not appear in the primary literature that is cited.33 A values
are of little help as the value for CN is lower than that of F,37 and general agreement

between A and Es values is poor.

39

Calculations of steric energies have been addressed using modern computational
methods. We felt that a good, albeit crude, model for our purposes was that employed by
Fujita and co-workers for evaluating the steric effects in the acid-catalyzed hydrolysis of
o-benzamides.38’39 In essence, their approach involves calculating the difference in
enthalpies for 2-substituted toluenes and tert-butylbenzenes relative to toluene and
tert-butylbenzene to extract steric enthalpies, denoted as AAHs(Z), for substituents Z,
relative to hydrogen. For consistency, the dihedral angles for the methyl and tert-butyl
groups were constrained as shown in Chart 2.1.38 Since CN and other substituents in
Table 2.1 were not included in the previous report, we recalculated the series.40 Table 2.2
lists these AAHs(Z) values along with calculated and experimental ratios of 2- and

3-borylated benzonitriles.4|

 

Chart 2.1
U M9
H H 2 Me ‘ Me 2
0 = 0° 9 = 0°
Z-Me Z-t—Bu

AAHS(Z) = [AHflZ-t—Bu) — AH¢°(H-t-Bu)] - [AHflZ-Me) — AH¢°(H-Me)]

Table 2.2. Calculated steric enthalpies (AAHs) for o—benzene substituents Z and isomer

ratios for borylation.‘

 

 

Z AAHs(Z) Kcal/mol" %a:°/eb calcb °/ea:%b observed°

H 0 - -
ON 3.21 1 - -

F 1 .535 6:94 8:92
CI 4.133 83:17 81:19
Br 5.405 98:2 97:3

I 7.759 >99:1 >99:1

CH3 5.532 98:2 92:8
OMe 2.013 31 :69 67:33d
SMe 3.682 66:34 37:13d
NM62 5.039 96:4 >99:1
002Me 4.856 94:6 >99:1
NHAc 5.166 96:4 >99:1
CF3 8.845 >99:1 >99:1

 

“AAH3(Z) values computed according to the method in ref. 38.
bRef. 40. cGC-FID ratios from Table 2.1. dIsomer ratio was
determind by NMR integration.

Agreement between the calculated and experimental isomer ratios is surprisingly
good. The halide data correlates best, while selectivities for COzMe, NMez, and NHAc
substituents are better than the calculated values. To gauge whether aromatic borylation

is likely to be more sensitive to steric effects, it is instructive to consider putative

41

transition states for acid-catalyzed hydrolysis of an o-benzamide (X) and Ir-catalyzed C—

H activation (Y) in Chart 2.2.
Chart 2.2
BPin
H2? N...,_llr,...lBPin
H N—p N” :‘TBPin
2 ‘\ z . \
OH 20H
X Y

First, transition state X more closely resembles the steric model in Chart 2.1 from
which AAHs(Z) values are calculated. Moreover, transition state Y should be more
sensitive to the sterics of Z because an Ir—C bond ultimately forms ortho to Z, whereas
attack by the less hindered water molecule is one carbon removed in transition state X.

The poorest agreement between calculated and observed isomer ratios in Table
2.2 is for Z = OMe, where the borylation is favored at the more hindered position.
Although this could simply result from inherent deficiencies in the model, there is reason
to believe electronic effects contribute to the regioselectivity. Specifically, while
borylation of benzonitrile (2.12) gives a nearly statistical 2.15:1 ratio of meta to para
isomers (Figure 2.1), anisole (2.13) borylation favors the meta isomer 4:1 (Figure 2.2).
After taking statistics into account, this corresponds to a 2:1 preference for meta vs. para
borylation.18 Given that CN and OMe groups are nearly isosteric, the identical 2:1

preference for borylation meta to OMe may have electronic origins.

42

ON ON ON ON

HBPin P, B
4 . 1.5 mol% [|r(OMe)(COD)]2, '”
equw > + +
3.0 mol% dtbpy, ,
PinB .

THF, r.t., 12 h, 77%

 

 

BPin
5.7 64.4 29.9
2.12 2.12a 2.12b 2.12c
Figure 2.1. Product distribution in catalytic borylation of benzonitrile.
OMe HBPin Pins OMe OMe OMe
4 . 1.5 mol% [lr(OMe)(COD)]2.
equw > + +
3.0 mol% dtbpy, P' B
THF, r.t., 24 h, 82% 'n .
BPin
2.1 78.9 19
2.13 2.13a 2.13!) 2.130

Figure 2.2. Product distribution in catalytic borylation of anisole.

To strengthen what is a circumstantial case for sterics overriding electronics in
borylations of 4-benzonitriles, we turned to 1,3-di-subsituted CN and F benzenes, where
C—H bonds flanked by 0-2 ortho hydrogens are present. Under DoM conditions,
1,3-dicyano and 1,3-difluorbenzene are known to react selectively at the 2-position as
shown in Scheme 2.3.42‘43 If selectivities of Ir catalyzed borylations of CN and F
substituted arenes are sterically directed, the propensity for borylation in the
1,3-disubstituted benzenes should follow the order 5- > 4- > 2-. As indicated in Scheme
2.3, this is indeed the case. Furthermore, only 1,3-difluorobenzene exhibits significant
borylation at the 2-position (2.15c), consistent with the lower steric requirement for F
relative to CN. Murai has invoked CN to Ru p-bonding to account for selective C—H
activation ortho to CN.44 However, from the data in Scheme 2.3, the borylation ortho to
H vs. CN is favored by a factor of 5.7 in the present system. Thus, sterically directed

regioselectivity is the only satisfactory explanation for the regiochemistry in these

43

A4

borylations. Based on these results and the data in Table 2.2, we favor steric directing

effects to account for the selectivities in Table 2.1.

Scheme 2.3.

Directed ortho-metaI/ation

 

Electronic/cholera Dlrectlon

 

Z Z Z
LiTMP, THF, -78 °C # , Me3SiCl _
_ TMPH ' Ll W M8381
Z Z Z
Z = CN, F
Aromatic borylation Sterlc Direction
2 1.0 equiv HBPin, Z 2 3'31" Z
1.5 mol% [lr(OMe)(COD)]2, _ . .
O 3.0 mol% d'bpy, ' BP'” + + P'”3
2 THF. 25 C 2 Z Z
2.x 2.xa 2.xb 2.xc
2
CN 1: = 14 'CN' 74 26 not detected
F x = 15 F 50 33 17

Additional features of the reactions in Table 2.1 merit comment. First, the
2-borylated products for entries 2-5 and 6-11 are new compounds. In fact,
4-F-2-BPinC6H3CN (2.1a),45 4-MeO-2-BPinC6H3CN (2.6a),46 and
4-MeO-3—BPinC6H3CN (2.6b)47 are the only reported 2,4-benzonitriles with BPin group
at the 2-position. Moreover, introduction of the BPin group using other methods, such as
Miyaura’s cross-coupling reactions of alkoxydiboron reagents and aryl halides, are
inconvenient because access to the 2-halogenated compounds is extremely limited.48
Entries 8-10 highlight the complementary nature of sterically directed borylations to
DOM protocols, where hydrogens ortho to amine, ester, and amide groups react
preferentially.49'SO Thus, aromatic borylation provides the most general approach to

elaborating the 2 positions of 4-substituted benzonitriles. Lastly, it should be noted that

44

t

entries 7 and 10 are the first examples of functional group tolerance for SMe and NHAc
substituents, respectively, in Ir-catalyzed C—H borylations.

After the publication of results described in this chapter, Kristensen et al. and
co-workers reported a directed ortho metalation route for the introduction of boronic ester
group on the 2-position in 4-substituted benzonitriles when the 4-substituent is OMe,
CF3, F, Cl, and Br (Figure 2.3).“ Regioselectivities similar to described in this chapter
were observed (however they did not examine the regioselectivity for 4-ester substituted
benzonitrile, for which our system is highly selective for functionalization ortho to the

cyano group).

CN _ CN 0 CN
1. LTMP, B(O’Pr)3 ['3

2. Neopentylglycol _ O
THF,-78°C—rr.t. '

g!
2 Z Z O

R = OCH3, CF3, F, Cl, Br

 

Figure 2.3. Directed ortho metalation for the preparation of 2-borylated benzonitriles.

Zhu et al. have used the borylation procedure described in this chapter to
synthesize 4-NMe2-2-BPinC6H3CN (2.8a) and its corresponding boronic acid.52 They
found these compounds to be selective fluorescent sensors for saccharides and fluoride
ion.

The regioselectivities in Table 2.2 are not necessarily limited to di-substituted
benzenes. In addition to diborylation of 4-benzonitriles (vide infra), we also note that
4-bromo-2—fluorobenzonitrile is borylated according to Eq 2.1, affording a 5:95 ratio of
5- and 6-borylated products (2.16b and 2.16:: respectively). This is a particularly

attractive reaction because 1,2-benzisoxazoles and other heterocycles can be obtained by

45

substitution of fluoride followed by ring-forming condensation with the cyano group.53
Similarly, borylation of 3,4-dichlorobenzonitrile yields the 5- and 6-borylated isomers in
a 20:80 ratio (2.17b and 2.17a respectively). For both substrates, the selectivity for
borylation ortho to CN vs. halide is virtually identical to that for the corresponding

4-halobenzonitriles in Table 2.1.

 

Br Br
1.0 equiv HBPin,
1.5 mol% [il’(OMe)(COD)]2, A (2.1)
3.0 mol% d’bpy, V ,
F THF, 25 °c F BP'”
CN CN
(2.16a) 85% yield,

95% isomeric purity

In order to avoid diborylation, excess arene was used for several entries in Table
2.1. We were curious as to how efficiently the diborylated products could be formed and
whether compounds with isomeric purities sufficiently high as to be synthetically useful
could be obtained. The reactions were typically run in THF with a 4:1 ratio of HBPin to

arene at twice the catalyst loading for monoborylation. The results are given in Table 2.3.

 

Table 2.3. Diborylation of 4-substituted benzonitriles.

 

 

23 %yield Time (h)
F F
PinB BPin PinB
F 92 24
BPin
ON ON
2.183 54°/o 2.18b 460/0
(86%) (14%)
OMe OMe
PinB
OMec 81 48
PinB BPin BPin
CN CN
2.19a 20% 2.1% 80%
(33%) (60%)
C1 C1
PinB
Cl 82 48
PinB BPin BPin
CN CN
2.20a 20% 2.20b 80%
(56%) (44%)
CN
PinB
CN 71(1 2o _
BPin
ON
2.21!)
CF3
CF3 83 36 _
PinB BPin
CN
2.22a

 

8'Unless otherwise noted, all reactions were run in THF solution at 25 °C with 4.0 equiv

HBPin

and 6 mol%

[Ir].

t’lsomer

distribution

determind by GC-FID.

Calculated values using the selectivities in Table 2.1 (ref 54) are shown in
parantheses.°Reaction run at 60 °C. dIsolated as a single isomer after
recrystallization from 93:7 mixture of 2.5- and 2,6-borylated isomers.

Unlike

3,4-di-chlorobenzonitrile, the observed distribution of isomers is much different than a

the

situation

for 4-bromo-2-fluorobenzonitrile

47

simple extrapolation of selectivities from Table 2.1 predicts.54 In all cases the extent of
2,5-diborylation (isomer b) is significantly higher than expected, except for Z = CF;
where borylation ortho to CF; is likely prohibitive. The data suggest that the BPin group
has a directing role. To answer this question, we examined the regioselectivity for
PhBPin borylation in THF under similar reaction conditions (Eq 2.2). The reaction was
examined at low conversion to avoid skewing the data by borylation of m-C6H4(BPin)2.55
The para to meta ratio is 1.821, significantly greater than the 1:2 statistical ratio. This
translates to a 3.6:] selectivity for para vs. meta borylation after statistical corrections.
While we are reluctant to speculate on the origins of this selectivity, BPin clearly has a
para directing effect that likely contributes to the regioselectivities in Table 2.3. Lastly, it

should be noted that single isomers of diborylated products can readily be obtained for Z

 

= CN, or CF3.
BPin BPin BPin BPin
0.2 equiv HBPin, BPin
1.5 mol% [lr(OMe)(COD)]2, : G + + (22)
3.0 mol% dtbpy, .
THF, 25 °C BP'”
BPin
Undetected 36 64
2.238 2.23b 2.23c

We have also examined a limited number of heteroaromatic compounds to assess
whether the regioselectivities found for arenes will translate to other substrates (Scheme
2.4). Borylation of 1,5-dimethyl-2-pyrrolecarbonitrile gives an 85:15 ratio of two
regioisomers with the major isomer arising from borylation adjacent to the cyano group.
Similarly, 5-methyl-2-furonitrile also borylates predominantly adjacent to the cyano
group to give an 85:15 ratio of two borylated isomers. Borylation of

2-bromo-5-cyanothiophene was unsuccessful. Since the steric interactions between

48

 

adjacent positions diminish as aromatic rings contract, the decline in selectivity for the
S-membered heterocycles is not surprising. Two isomeric cyanopyridines were also
examined. 5-bromo-2-cyanopyridine undergoes borylation to afford an isomer mixture.
While borylation ortho to CN accounts for the major product, the degree of borylation
ortho to Br is substantially higher than that found for 4-bromobenzonitrile. Somewhat
surprisingly, 2—bromo-5—cyanopyridine gave no borylation products. Since halogen
substituted aromatic heterocycles tend to be more reactive than their carbocyclic

counterparts, side reactions that deactivate catalytically active species may be occuring.

 

 

 

 

 

Scheme 2.4.
M6 1.5 equiv HBPin, Me Me
Me N CN 1-5 mol % llrlOMe)(COD)]2. g Me N CN + Me N CN
U 3.0 mol % dtbpy, ’ \ / \ /
THF, r.t., 16 h, 80% BPin PinB
85 15
2.248 2.24b
1.5 equiv HBPin,
Me 0 CN 1.5 mol °/o [lr(OMe)(COD)]2, 2 Me 0 CN + Me 0 CN
U 3.0 mol °/. dtbpy, ' \ / \ /
. ., . h, 7°
THF,rt 05 9 /0 [Pin PinB
85 15
2.258 2.25b
1.5 equiv HBPin,
Br 3 CN 1.5 mol °/o [lr(OMe)(COD)]2,A ,
\ / 3.0 mol % dtbpy, 7 no borylation
2 26 THF, r.t., 24 h
Br 1.5 equiv HBPin, Br Br
— 1.5 mol % [lr(OMe)(COD)]2, ; — . —
\ /N 3.0 mol % dtbpy, ' \ /N + PinB \ /N
CN THF, r.t., 18 h, 810/0 PinB CN CN
67 . 33
2.278 ' 2.27b
NC 1.5 equiv HBPin,
— 1.5 mol % [Ir(OMe)(COD)]2, _ b I t'
\ x” 3.0 mol % dtbpy, ' "0 (”ya '0"
2 28 Br THF, r.t., 12 h

49

Conclusions

In summary, the steric directing effects that govern the regioselectivities in Ir
catalyzed borylations of aromatic and heteroaromatic compounds enable
functionalization of C—H bonds adjacent to cyano groups, when these positions are the
least hindered sites in the substrate. The regioselectivities for borylations complement
those found in electrophilic aromatic substitutions and certain DoM’s, and several
relatively simple borylated products have been prepared for the first time. Diborylations
of 4-benzonitriles favor para—disposed BPin groups when borylation at the 5-position is
possible. While it appears that similar trends in regioselectivities can be extended to
borylations of heteroaromatic nitriles, the substrate scope is narrower and the
regioselectivity is poorer than for carbocyclic aromatic substrates. We are currently
focusing on improving regioselectivities by modifying the Ir ligands, as well as sterically

differentiating other aromatic substituents.

50

 

Experimental Details and Spectroscopic Data
Materials
Pinacolborane (HBPin) and bis(174-l,5-cyclooctadiene)-di-p-methoxy-diiridium(I)

[11(0M€)(COD)12 were prepared per literature procedures.”57

Bis(pinacolato)diboron
(BzPinz) was purchased from Callery Chemical Company and was used without
purification. Tris(dibenzylidineacetone)dipalladiwn(O) (szdba3) was purchased from
Strem. 4,4'-Di-t-butyl-2,2'-bipyridine (dtbpy), tricyclohexylphosphine, and potassium
acetate were purchased from Aldrich. 1-Bromo-3,5-difluorobenzene,
2-bromo-1,3-difluorobenzene, l-bromo-2,4-dif1uorobenzene, and 4-iodobenzonitrile were
purchased from Alfa Aesar. 4-Bromobenzonitrile and 4-methoxybenzonitrile were
purchased from Lancaster Synthesis. 2-Bromo-4-methylbenzonitrile was purchased from
Trans World Chemicals. 5-Bromo-2-cyanopyridine and 2-bromo—5-cyanopyridine were
purchased from Matrix Scientific. All other benzonitriles were purchased from Aldrich.
All substrates were purified before use. Solid substrates were sublimed under vacuum.
S-Methyl-Z-furonitrile and 5-bromothiophene-2-carbonitrile were passed through
activated alumina. 1,4-Dioxane and n-hexane were refluxed over sodium, distilled, and

degassed. Tetrahydrofuran was used from a dry still packed with activated alumina. Silica

gel (230—400 Mesh) was purchased from EM Sciencem.

51

General Methods

All reactions were monitored by a Varian CP-3800 GC-FID (column type:
WCOT Fused silica 30m x 0.25mm ID coating CP-SIL 8 CB); GC-FID method: 70 °C, 2
min.; 20 °C/min, 9 min.; 250 °C, 20 min.; 1.8 mL/min flow rate. All reported yields are
for isolated materials.

IH and '3 C NMR spectra were recorded on a Varian [nova-300 (300.1 1 and 75.47
MHz respectively), Varian VXR-SOO, or Varian Unity-SOO-plus spectrometer (499.74 and
125.67 MHz respectively) and referenced to residual solvent signals. llB spectra were
recorded on a Varian VXR-300 operating at 96.29 MHz and were referenced to neat
BFyEtzO as the external standard. 19F spectra were recorded on a Varian Inova-300
operating at 282.36 MHz and were referenced to neat CFCI3 as the external standard. All
coupling constants are apparent J values measured at the indicated field strengths. All
l-dimensional NOE experiments were obtained using the Varian implementation of the
DPFGSE-NOE experiment58 (hereafter termed NOESYID). All 2-dimensional
experiments were run using z-axis pulse field gradients. Elemental analyses were
performed at Michigan State University using a Perkin Elmer Series II 2400 CHNS/O
Analyzer. GC-MS data were obtained using a Varian Saturn 2200 GC/MS (column type:
WCOT Fused silica 30m x 0.25mm ID coating CP—SIL 8 CB). High-resolution mass
spectra were obtained at the Michigan State University Mass Spectrometry Service
Center with a JOEL-AXSOS mass spectrometer (resolution 7000). Melting points were
measured on a MEL-TEMP® capillary melting apparatus and are uncorrected.

Note: The general methods describes here also corresponds to Chapters 3-7.

52

 

General Procedure

Unless otherwise specified, all reactions were carried out in THF solutions with 3
mol % [Ir] at 25 °C in 20 mL vials in a glove box under a nitrogen atmosphere.
Substrates which gave a significant amount of both isomers were borylated employing an
excess of benzonitrile to minimize diborylation (General procedure A), otherwise, excess
borane was employed (General procedure B). The major isomer for the borylation of
4-methylbenzonitrile was identified by preparing an authentic sample using a slightly
modified literature procedure.59 The regioisomers in all other cases were assigned by
NMR spectroscopy ('3 C for substrates which have fluorine, while gHMBC and
NOESYID were used for substrates without fluorine). Ratios of the major versus minor
isomer were determined in the crude reaction mixtures. Yields are based on the limiting
reagent.

General Procedure A (Borane as limiting reactant)

In a glove box, a 20 mL vial, equipped with a magnetic stirring bar, was charged
with [Ir(OMe)(COD)]2 (5 mg, 7.5 10'3 mmol, 3 mol % lr), 4,4'-di-tert—butyl-
2,2'-bipyridine (dtbpy) (4 mg, 1.5 10“2 mmol, 3 mol %), and pinacolborane (HBPin) (73
uL, 64 mg, 0.5 mmol, 1 equiv). These reagents were dissolved in 2 mL of THF, the
corresponding benzonitrile (2.00 mmol, 4.00 equiv) was added, and the mixture was
stirred at room temperature until the reaction was judged complete by GC-FID. Solvent
was removed under reduced pressure. The crude material was dissolved in CHzClz and
passed through a plug of silica gel to remove metal byproducts. Kugelrohr distillation

gave analytically pure samples.

53

 

General Procedure B (Benzonitrile as limiting reactant)

In a glove box, a 20 mL vial, equipped with a magnetic stirring bar, was charged
with [Ir(OMe)(COD)]2 (10 mg, 1.5 10’2 mmol, 3 mol % Ir), dtbpy (8 mg, 3.0 10‘2 mmol,
3 mol %), and excess HBPin or BzPinz (1.1 to 3.2 equiv of boron). These reagents were
dissolved in 3 mL of THF, the corresponding benzonitrile (1 mmol, 1 equiv) was added,
and the mixture was stirred at room temperature until the reaction was judged complete
by GC-FID. Solvent was removed under reduced pressure. The crude material was
dissolved in CHzClz and passed through a plug of silica gel to furnish the desired
borylated product.

General Procedure C (Diborylation)

In a glove box, a 20 mL vial, equipped with a magnetic stirring bar, was charged
with [Ir(OMe)(COD)]z (20 mg, 0.03 mmol, 6 mol % Ir), dtbpy (16 mg, 0.06 mmol, 6 mol
%), and excess HBPin (4.00 equivalent of boron). These reagents were dissolved in 3 mL
of THF, the corresponding benzonitrile (1 mmol, 1 equiv) was added, and the mixture
was stirred at room temperature until the reaction was judged complete by GC-FID.
Solvent was removed under reduced pressure. The crude material was dissolved in

CHzClz and passed through a plug of silica gel to furnish the desired borylated product.

54

Regioisomer assignment by NMR spectroscopy

2
Hbs 43H,

Hc 6 2 BPin
7CN

 

Isomer 8 Isomer b

From gHMBC NMR experiments, the two regioisomers for the borylation of
4-substituted benzonitriles can be distinguished unambiguously. In Isomer a, carbon
atoms represented as C1 and C4 on the benzene ring, as well as C7 (nitrile carbon) are the
three quaternary carbon atoms in the 100-170 ppm region (quaternary carbon C2 is
typically not observed due to broadening from and coupling with boron). These three
quaternary carbon atoms should show cross peaks due to long range H—C couplings
(3JC-H), which can be observed using gHMBC spectroscopy. In the gHMBC spectrum,
carbon atoms C4 and C7 should show one cross peak each to proton Hc, whereas carbon
atom Cl should show two cross peaks to protons Ha and Nb. Therefore the resulting
number of cross peaks for C1, C4, and C7 should be 2, l, and 1, respectively.

In Isomer b, carbon atoms represented as C1 ', C4', on the benzene ring, as well as
C7’ (nitrile carbon) are the three quaternary carbon atoms in the 100-170 ppm region
(quaternary carbon C3' is typically not observed due to broadening from and coupling
with boron). These three quaternary carbon atoms should show cross peaks due to long
range H-C couplings (3Jc-H). In the gHMBC spectrum, carbon atoms C4' and C7' should
show two cross peaks each, to protons Hd and He, whereas carbon atom Cl' should show
only one cross peak to proton Hf. Therefore the resulting number of cross peaks for C1 ',
C4', and C7' should be 1, 2, and 2, respectively. Hence isomers a and b can be

unambiguously assigned from gHMBC data.

55

 

For isomer 8, with proton Hc unambiguously assigned by gHMBC, Ha and Hb can
be assigned from their multiplicities. Proton Ha appears as a doublet, coupled to proton
Hb with J 2 2-3 Hz. Proton Hb appears as a doublet of doublets due to coupling to protons
Ha and He. Carbon atoms C3, C5, and C6 were then assigned from the correlations in the
gHMQC spectra. Carbon atom C7 (nitrile carbon) usually appears around 6 119.
Depending on the substituent, carbon atom C4 was usually found shifted downfield
around 6 130-170 (except in 4-iodobenzonitrile for which it appears around 8 100).
Carbon atom C1 is shifted upfield, and was usually found around 8 100-115. Similarly,
all the carbons of isomer b can be assigned.

In the five membered heterocycles, the 4J1”; coupling was used together with
gHMBC and NOESYID spectroscopy to identify the major isomer. Regioisomers in the
fluorine containing benzonitriles were assigned by '3 C spectroscopy (with the help of the
fact that the boron bearing carbon is not observed due to broadening from and coupling
with boron). In case of monoborylation of 1,3-di-cyanobenzene, and diborylation of
4-substituted benzonitriles, 1H NMR spectroscopy was employed to assign the major and

minor isomers.

56

 

 

Table 2.1, Entry 1. Borylation of 4—fluorobenzonitrile (2.18 + 2.1b).

Hc 6 2 BPin

CN
7

11
2.1a 2.1 b

 

General procedure A was applied to 4-fluorobenzonitrile (242 mg, 2.00 mmol,
4.00 equiv) and HBPin (73 ML, 64 mg, 0.5 mol, 1 equiv) with a reaction time of 8 h.
The ratio of the two isomers in the crude reaction mixture by GC-FID was 11:89.
Kugelrohr distillation furnished a mixture of the two isomeric borylated products (89 mg,
72% yield) as a white solid. The ratio of the two isomers in the isolated product by
GC-FID was 8:92. 13 C NMR spectroscopy was used to assign the major isomer as
4-fluoro-3-(4,4,5,5-tetrarnethyl-1,3,2-dioxaborolane-2-y1)-benzoniuile. 1H NMR (CDC13,
500 MHz): 6 (2.1a) 7.67 (dd, J= 8.8 Hz, 4.1..-. = 4.9 Hz, 1 H, Hc), 7.52 (dd, 3h“: = 8.5
Hz, J= 2.9 Hz, 1 H, Ha), 7.17 (dt, J= 8.3, 2.9 Hz, 1 H, Hb) 1.34 (br s, 12 H, 4 CH3 of
BPin), (2.1b) 8.04 (dd, 4J1”. = 5.4 Hz, J = 2.2 Hz, 1 H, Hd), 7.7 (ddd, J = 8.5, 2.2 Hz,
4J1”: 4.9 Hz, 1 H, He), 7.1 (t, J= 8.5 Hz, 1 H, Hf), 1.32 (br s, 12 H, 4 CH3 of BPin); 13C
NMR {‘H) (CDCl3, 125 MHz): 6 (2.1a) 164.2 (d, 'Jc-p= 257.1 Hz, C4), 135.9 (d, 3Jc-p=
8.8 Hz, C6), 122.8 (d, 2J0. = 21.0 Hz, C3), 118.5 (d, 2J0. = 22.2 Hz, C5), 118.1 (nitrile
C7), 113.1 (CI), 85.1 (2 C), 24.7 (4 CH3 of BPin), (2.1b) 169.0 (d, 'Jc-p= 261.3 Hz, C4'
), 141.6 (d, 3Jc.F = 9.6 Hz, C2' ), 137.0 (d, 3Jc-p = 10.5 Hz, C6' ), 117.9 (nitrile C7' ),
116.7 (d, 90F: 25.6 Hz, CS' ), 108.2 (d, 4.10.: 3.8 Hz, Cl' ), 84.5 (2 C), 24.7 (4 CH3 of
BPin); “B NMR (CDC13, 96 MHz): 6 29.92; '91: NMR(CDC13, 282 MHz): 6 (2.1b) —

92.62 (m), (2.18) —104.84 (111); FT-IR (neat)17: 3076, 2982, 2934, 2231, 1608, I487,

57

 

1429, 1412, 1373, 1350, 1236, 1143, 1070, 964, 852, 835, 571 cm"; GC-MS (131) m/z (%
relative intensity): (2.1a) 1W 247 (29), 232 (97), 206 (100), 189 (74), 148 (97), 121 (25),
(2.1b) M" 247 (26), 232 (100), 205 (12), 188 (20); Anal. Calcd for C13H15BFN02: C,
63.20; H, 6.12; N, 5.67. Found: C, 63.52; H, 6.20; N, 5.56; HRMS (El): m/z 247.1171
[(M“); C|3HlsBFN02: 247.1180].

Table 2.1, Entry 2. Borylation of 4-chlorobenzonitrile (2.28 + 2.2b).

Cl
Hb 5 43 H,

Hc 6 2 BPin

CN
7

80
2.28 2.2b

 

General procedure A was applied to 4-chlorobenzonitrile (550 mg, 4.00 mmol,
4.00 equiv) and HBPin (145 11L, 128 mg, 1 mmol) with a reaction time of 36 h. The ratio
of the two isomers in the crude reaction mixture by GC-FID was 80:20. Kugelrohr
distillation furnished a mixture of the two isomeric borylated products (200 mg, 76%,
yield) as a white solid. The ratio of the two isomers in the isolated product by GC-FID
was 81:19. gHMBC spectroscopy was used to assign the major isomer as 4—chloro-2-
(4,4,5,5-tetramethy1-l,3,2-dioxaborolane-2-yI)-benzonitrile. 1H NMR (CDCI3, 300 MHz):
6 (2.28) 7.80 (d, J = 2.2 Hz, 1 H, Ha), 7.57 (d, J = 8.3 Hz, 1 H, Hc), 7.45 (dd, J = 8.3, 2.2
Hz, 1 H, Hb), 1.33 (br s, 12 H, 4 CH3 of BPin), (2.2b) 7.94 (d, J = 2.2 Hz, 1 H, Hd), 7.56
(dd, J= 8.3, 2.2 Hz, 1 H, IL), 7.41 (d, J= 8.3 Hz, 1 H, Hf), 1.32 (br s, 12 H, 4 CH3 of
BPin); 13C NMR {‘H} (CDC13, 75 MHz): 6 (2.2a) 138.5 (C4), 135.8 (C3), 134.5 (C6),
131.2 (C5), 118.0 (nitrile C7), 115.3 (CI), 85.0 (2 C), 24.6 (4 CH3 of BPin), (2.2b) 144.5

(C4' ), 140.1 (C2' ), 134.6 (C6' ), 130.2 (CS' ), 117.8 (nitrile C7' ), 110.2 (Cl' ), 84.7 (2

58

 

C), 24.6 (4 CH3 of BPin); ”B NMR (CDCI3, 96 MHz): 6 29.59; FT-IR (neat) v: 2982,
2228,1587,1554,1479,1402,1373,1333,1271,1215,1169,1144,1103,1065,1042,
965, 870, 847, 831 cm"; GC-MS (El) m/z (% relative intensity): (2.28) M+ 263 (24), 248
(65), 222 (100), 205 (31), 164(32), 137 (11), (2.2b) 114* 263 (1), 248 (27), 228 (100), 186
(60), 164 (15), 142 (6); Anal. Calcd for CI3H35BCIN02: C, 59.25; H, 5.74; N, 5.32.
Found: C, 58.90; H, 5.74; N, 5.10.

Table 2.1, Entry 3. Borylation of 4-bromobenzonitrile (2.38 + 2.3b).

 

Br
Ht) 5 4 3 Ha
H6 5 2 BPin
CN
7
95 5
2.38 2.3b

General procedure A was applied to 4-bromobenzonitrile (364 mg, 2.00 mol, 4
equiv) and HBPin (73 11L, 64 mg, 0.5 mmol) with a reaction time of 48 h. The ratio of the
two isomers in the crude reaction mixture by GC-FID was 95:5. Kugelrohr distillation
furnished a mixture of the two isomeric borylated products (112 mg, 73% yield) as a
white solid. The ratio of the two isomers in the isolated product by GC-FID was 97:3.
gHMBC spectroscopy was used to assign the major isomer as 4-bromo-2-(4,4,5,5-
tetramethyl-l,3,2-dioxaborolane-2-yl)-benzonitri1e. lH NMR(CDC13, 500 MHz): 8 (2.38)
7.97 (d, J= 2.0 Hz, 1 H, Ha), 7.62 (dd, J= 8.3, 2.0 Hz, 1 H, Hb), 7.50 (d, J= 8.3 Hz, 1 H,
Hc), 1.33 (br s, 12 H, 4 CH3 of BPin); 13C NMR {‘H} (CDC13, 125 MHz): 6 (2.38) 138.8
(C3), 134.5 (C6), 134.2 (C5), 127.1 (C4), 118.1 (nitrile C7), 115.8 (CI), 85.0 (2 C), 24.7
(4 CH3 of BPin); ”B NMR (CDCI3, 96 MHz): 6 29.92; FT-IR (neat): 17': 2980, 2228,

1582, 1551, 1480, 1416, 1399, 1373, 1335, 1271, 1144, 1084, 1069, 963, 862, 841, 763,

59

673 cm]; GC-MS (EI) m/z (% relative intensity): M 307 (16), 292 (51), 266 (100), 251
(45), 228 (17), 170 (15); Anal. Calcd for C33H15BBrN02: C, 50.70; H, 4.91; N, 4.55.
Found: C, 50.29; H, 4.75; N, 4.57; HRMS (El): m/z 307.0376 [(m; Calcd for
C13H15BBrN02: 307.0379].

Table 2.1, Entry 4. 4-iodo-2-(4,4,5,5-tetr8methyl-1,3,2-dioxaborolan-2-

yl)benzonitrile (2.48).

4
Hbs 3H,,l

Hc 6 2 BPin

CN
7

2.48

General procedure B was applied to 4-iodobenzonitrile (229 mg, 1 mol, 1
equivalent) and BzPinz (254 mg, 1.00 mmol, 2.00 equivalents of boron) with a reaction
time of 40 h. Only one isomer was observed in crude reaction mixture by GC-F ID and by
1H NMR spectroscopy. Solvent was removed under reduced pressure, and the crude
mixture was eluted with CHzClz through a plug of silica gel to afford the single pure
isomer (255 mg, 71% yield, mp 77-79 °C) as a white solid. gHMBC spectroscopy was
used to assign the single isomer as 4-iodo-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-
yl)benzonitrile. 1H NMR (CDCI3, 500 MHz): 8 (2.48) 8.19 (d, J = 2.0 Hz, 1 H, Ha), 7.85
(dd, J= 8.3, 2.0 Hz, 1 H, Hb), 7.36 (d, J= 8.3 Hz, 1 H, Hc), 1.34 (br s, 12 H, 4 CH3nof
BPin); 13C NMR {‘H} (CDCI3, 125 MHz): 6 (2.48) 144.6 (C3), 140.1 (C5), 134.3 (C6),
118.3 (nitrile C7), 116.3 (C1), 99.8 (C4), 85.1 (2 C), 24.7 (4 CH3 of BPin); “B NMR
(CDCI3, 96 MHz): 8 29.77; FT-IR (neat) 17: 2980, 2228, 1576, 1545, 1480, 1414, 1395,

1374, 1335, 1271, 1140, 1071, 963, 859, 839, 826, 673 cm}; GC-MS (EI) m/z (% relative

6O

 

intensity): M+ 355 (42), 340 (75), 314 (100), 297 (72), 256 (77), 228 (11); Anal. Calcd
for C13H13BIN02: C, 43.99; H, 4.26; N, 3.95. Found: C, 44.17; H, 4.44; N, 3.88.

Table 2.1, Entry 5. Borylation of 4—methylbenzonitrile (2.58 + 2.5b).

 

Me
Hb 5 4 3 Ha
Hc 6 2 BPin
CN
7
94 6
2.58 2.5b

General procedure A was applied to 4-methylbenzonitrile (468 mg, 4.00 mmol)
and HBPin (145 (AL, 128 mg, 1 mmol) using 6 mol % [Ir] with a reaction time of 72 h.
The ratio of the two isomers in the crude reaction mixture by GC-FID was 94:6.
Kugelrohr distillation furnished a mixture of the two isomeric borylated products (156
mg, 64% yield) as colorless oil which solidified on standing. The ratio of the two isomers
in the isolated product by GC-F ID was 92:8. The major isomer was assigned as 4-methyl-
2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-benzonitrile by the NOESYID
spectrum and by preparing an authentic sample using a slightly modified literature
procedure.”9 1H NMR (CDCI3, 500 MHz): 6 (2.5a) 7.67 (br s, 1 H, Ha), 7.57 (d, J = 7.9
Hz, 1 H, Hb or Hc), 7.30 (d, J= 7.9 Hz, 1 H, Hb or Hc), 2.38(s, 3 H), 1.36 (br s, 12 H, 4
CH3 of BPin); ”C NMR {1H} (CDCI3, 125 MHz): 6 (2.5a) 142.2 (C4), 136.5, 133.4,
131.8 (C3, C5 and C6), 119.2 (nitrile C7), 114.2 (C1), 84.7 (2 C), 24.8 (4 CH3 of BPin),
21.5 (CH3); ”B NMR (CDCI3, 96 MHz): 6 30.36; FT-IR (neat) 17: 2980, 2932, 2226,
1603, 1491, 1447, 1408, 1391, 1381, 1373, 1346, 1265, 1213, 1140, 1069, 965, 853, 828,
675, 661 cm’l; GC-MS (E1) m/z (% relative intensity): M+ 243 (46), 228 (70), 202 (100),

185 (52), 144 (92), 117 (25); Anal. Calcd for ClangBNOZ: C, 69.17; H, 7.46; N, 5.76.

61

Found: C, 68.74; H, 7.64; N, 5.62; HRMS (El): m/z 243.1425 [(M+); Calcd for
C34H13BN02: 243.1431].

Preparation of an authentic sample of 4—methy1-2-(4,4,5,5-tetr8methyl-1,3,2-
dioxaboroIane-Z-yl)-benzonitrile (2.58).

In a glove box, a 100 mL schlenk flask, equipped with a magnetic stirring bar,
was charged with Pd2(dba)3 (14 mg, 0.015 mol, 3 mol % Pd) and
tricyclohexylphosphine (PCy3, 20 mg, 0.072 mmol, 7.2 mol %). Dioxane (6 mL) was
added and the resulting mixture was stirred for 30 minutes at room temperature. BzPinz
(280 mg, 1.1 mmol), KOAc (147 mg, 1.5 mmol), and 2-bromo-4-methylbenzonitrile (196
mg, 1 mmol) were added successively. The schlenk flask was brought to a schlenk line. A
condenser was attached, and the flask was flushed with nitrogen. The reaction mixture
was stirred at 80 °C for 12 h. The mixture was treated with water (5 mL), and the product
was extracted with ether, washed with brine, and dried over MgSOa. Kugelrohr
distillation furnished the desired product (151 mg, 62% yield) as a colorless oil. Its
spectral data matched the major isomer (2.5A) obtained from the catalytic borylation of
4-methylbenzonitrile described earlier.

Table 2.1, Entry 6. Borylation of 4-methoxylbenzonitrile (2.68 + 2.6b).

OMe
HI, 5 43 Ha

Hc 6 2 BPin

CN
7

67
2.68 2.6b

 

General procedure A was applied to 4-methoxybenzonitrile (266 mg, 2.00 mmol,

4.00 equiv) and HBPin (73 11L, 64 mg, 0.5 mmol) with a reaction time of 24 h. The ratio

62

 

of the two isomers in the crude reaction mixture by 1H NMR spectroscopy was 67:33.
Kugelrohr distillation furnished a mixture of the two isomeric borylated products (84 mg,
65% yield) as colorless oil. The ratio of the two isomers in the isolated product by 1H
NMR spectroscopy was 67:33. The NOESYID and gHMBC spectra were used to assign
the major isomer as 4-methoxy-2-(4,4,5,S-tetramethyl-l,3,2—dioxaborolane-2-yl)-
benzonitrile. 1H NMR (CDCI3, 500 MHz): 6 (2.68) 7.59 (d, J = 8.5 Hz, 1 H, He), 7.31 (d,
J== 2.9 Hz, 1 H, Ha), 6.97 (dd, J= 8.5, 2.9 Hz, 1 H, Hb), 3.84 (s, 3 H), 1.35 (br s, 12 H, 4
CH3 of BPin), (2.6b) 7.93 (d, J = 2.4 Hz, 1 H, Hd), 7.65 (dd, J = 8.8, 2.4 Hz, 1 H, He),
6.87 (d, J= 8.8 Hz, 1 H, Hf), 3.85 (s, 3 H), 1.32 (br s, 12 H, 4 CH3 of BPin); 13C NMR
{1H} (CDCI3, 125 MHz): 6 (2.68) 161.7 (C4), 135.3 (C6), 120.6 (C3), 119.3 (nitrile C7),
117.0 (C5), 108.8 (CI), 84.8 (2 C), 55.5 (OCH3), 24.73 (4 CH3 of BPin), (2.6b) 166.9
(C4’ ), 140.9 (C2' ), 136.6 (C6' ), 119.2 (nitrile C7' ), 110.7 (CS' ), 103.6 (Cl' ), 84.1 (2
C), 55.5 (OCH3), 24.7 (4 CH3 of BPin); “B NMR (CDCI3, 96 MHz): 6 30.50; FT-IR
(neat) 17: 2980, 2942, 2842, 2224, 1601, 1493, 1466, 1449, 1424, 1412, 1373, 1345,
1271, 1238, 1144, 1060, 1030, 965, 853, 830 cm"; i GC-MS (E1) m/z (% relative
intensity): M+ 259 (100), 244 (61), 232 (9), 216 (73), 201 (65), 186 (25), 174 (20), 160
(79); HRMS (El): m/z 259.1383 KM"); Calcd for C14HstNO3I 259.1380].

Table 2.1, Entry 7. Borylation of 4-thiometylbenzonitrile (2.78 + 2.7b).

SMe

Hc 6 2 BPin

CN
7

90
2.7a

 

63

General procedure A was applied to 4-thiomethylbenzonitrile (298 mg, 2.00
mmol, 2.00 equivalents) and BzPinz (127 mg, 0.5 mol, 1 equivalent of boron) at 80 °C
with a reaction time of 18 h. The ratio of the two isomers in the crude reaction mixture by
1H NMR spectroscopy was 90:10. Kugelrohr distillation gave a fraction (155 mg)
containing two isomers along with small amount of d’bpy. Passing a CH2C12 solution of
that fraction through a plug of silica furnished a mixture of two isomeric borylated
products (150 mg, 55% yield) as a white solid. The ratio of the two isomers in the
isolated product by 1H NMR spectroscopy was 87:13. The NOESYID and gHMBC
spectra were used to assign the major isomer as 4-thiomethyI-2-(4,4,5,5-tetramethyl-
l,3,2-dioxaborolane-2-yl)-benzonitrile. lH NMR(CDC13, 500 MHz): 6 (2.78) 7.63 (d, J =
2.0 Hz, 1 H, Ha), 7.54 (d, J = 8.3 Hz, 1 H, He), 7.27 (dd, J = 8.3, 2.0 Hz, 1 H, Hb), 2.48
(s, 3 H), 1.35 (br s, 12 H, 4 CH3 of BPin), (2.7b) 7.92 (d, J = 2.0 Hz, 1 H, Hd), 7.56 (dd, J
= 8.3, 2.0 Hz, 1 H, He), 7.14 (d, J= 8.3 Hz, 1 H, Hf), 2.44 (s, 3 H), 1.34 (br s, 12 H, 4
CH3 of BPin); ”C NMR {'H} (CDCI3, 125 MHz): 6 (2.7a) 144.7 (C4), 133.4 (C6), 132.2
(C3), 127.1 (C5), 119.1 (nitrile C7), 112.4 (CI), 84.8 (2 C), 24.7 (4 CH3 of BPin), 14.61
(SCH3), (2.7b) 152.7 (C4' ), 139.3 (C2' ), 134.1 (C6' ), 122.9 (C5' ), 119.0 (nitrile C7' ),
106.7 (Cl' ), 84.6 (2 C), 24.7 (4 CH3 of BPin), 15.0 (SCH3); 11B NMR (CDCI3, 96 MHz):
6 30.27; FT-IR (neat) 17': 2980, 2928, 2224, 1584, 1547, 1483, 1397, 1381, 1373, 1345,
1269, 1213, 1167, 1142, 1107, 1059, 963, 871, 847, 825, 769, 741, 669 cm"; GC—MS
(EI) m/z (% relative intensity): M 275 (100), 260 (26), 232 (41), 217 (46), 202 (9), 190
(10), 175 (54); Anal. Calcd for C34H33BNOZS: C, 61.11; H, 6.59; N, 5.09. Found: C,
61.24; H, 6.95; N, 5.05; HRMS (EI): m/z 275.1157 [(m; Calcd for C34H13BN0282

275.1151].

 

Table 2.1, Entry 8. 4-(Dimethylamino)-2-(4,4,5,5-tetr8methyl-1,3,2-dioxaborolan-2-

yl)benzonitrile (2.88).

NM62
H, 5 43 H,

H, 6 2 BPin

CN
7

2.88

General procedure B was applied to 4-dimethylaminobenzonitrile (146 mg, 1
mol, 1 equivalent) and B2Pin2 (254 mg, 1.00 mmol, 2.00 equivalents of boron) using 6
mol % [Ir] with a reaction time of 72 h. Only one isomer was observed in the crude
reaction mixture by GC-FID and by 1H NMR spectroscopy. Solvent was removed under
reduced pressure, and the crude mixture was eluted with CH2C12 through a plug of silica
gel to afford the single pure isomer (180 mg, 66% yield, mp 110—1 11 °C) as a white solid.
The NOESYID and gHMBC spectra were used to assign the single isomer as
4-dimethylamino-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolane-2-yl)benzonitn'le. 1H NMR
(CDCI3, 300 MHz): 6 (2.88) 7.48 (d, J = 8.8 Hz, 1 H, Hc), 7.04 (d, J = 2.9 Hz, 1 H, Ha),
6.67 (dd, J= 8.8, 2.9 Hz, 1 H, Hb), 3.01(s, 6 H), 1.35 (br s, 12 H, 4 CH3 of BPin); ”C
NMR {1H} (CDCI3, 75 MHz): 6 (2.88) 151.4 (C4), 134.8 (C6), 120.7 (nitrile C7), 118.1
(C3), 113.2 (C5), 102.3 (CI), 84.5 (2 C), 39.9 (CH3), 24.7 (4 CH3 of BPin); 11B NMR
(CDCI3, 96 MHz): 6 30.5; FT-IR (neat) 17: 2980, 2932, 2815, 2213, 1597, 1553, 1508,
1485, 1429, 1416, 1374, 1337, 1271, 1230, 1169, 1144, 1053, 968, 847, 816 cm];
GC-MS (EI) m/z (% relative intensity): M+ 272 (100), 257 (7), 229 (11), 214 (11), 189
(6), 173 (23); Anal. Calcd for C15H21BN202: C, 66.2; H, 7.78; N, 10.29. Found: C, 66.54;

H, 7.76; N, 10.06.

65

 

Table 2.1, Entry 9. Methyl 4-cyano-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-
yl)benzoate (2.98).

COzMe
Hb 5 4 3 H,

Hc 6 2 BPin

CN
7

2.98

General procedure B was applied to methyl 4-cyanobenzoate (161 mg, 1 mol, 1
equivalent) and BzPinz (203 mg, 0.80 mmol, 1.60 equivalents of boron) with a reaction
time of 48 h. Only one isomer was observed in the crude reaction mixture by GC-F ID
and by 1H NMR spectroscopy. Solvent was removed under reduced pressure, and the
crude mixture was eluted with CH2C12 through a plug of silica gel to afford the single
pure isomer (190 mg, 66% yield, mp 136-137 °C) as a white solid. The NOESYID and
gHMBC spectra were used to assign the single isomer as methyl 4-cyano-3-(4,4,5,5-
tetramethyl-l,3,2-dioxaborolane-2-yl)benzoate. 1H NMR (CDCI3, 300 MHz): 6 (2.98)
8.49 (d, J= 1.7 Hz, 1H, Ha), 8.14 (dd, J= 8.1, 1.9 Hz, 1H, Hb), 7.75 (d, J= 8.1 Hz, 1 H,
Hc), 3.93 (s, 3 H), 1.37 (br s, 12 H, 4 CH3 of BPin); 13C NMR {1H} (CDCI3, 75 MHz): 6
(2.98) 165.6 (C=O), 136.6 (C3), 133.4 (C6), 132.7 (C4), 131.9 (C5), 121.1 (Cl), 118.1
(nitrile C7), 85.1 (2 C), 52.6 (CH3), 24.8 (4 CH3 of BPin); “B NMR (CDCI3, 96 MHz): 6
30.1; FT-IR (neat) i": 2980, 2954, 2230, 1721, 1603, 1487, 1410, 1375, 1337, 1279,
1251, 1144, 1115, 1069, 976, 851, 770, 654 cm"; GC-MS (E1) m/z (% relative intensity):
M 287 (5), 272 (32), 256 (20), 244 (100), 229 (18), 188 (26), 156 (14); Anal. Calcd for
C35H13BNO4: C, 62.75; H, 6.32; N, 4.88. Found: C, 62.33; H, 6.26; N, 4.79. HRMS (E1):

m/z 287.1327 [(IVF); Calcd for C15H13BNO4: 287.1329].

66

Table 2.1, Entry 10. N-(4-cyano-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-

yl)phenyl)8cet8mide (2.108).

NHCOMe
Hbs 43H,

Hc 6 2 BPin

CN
7

2108

General procedure B was applied to 4'-cyanoacetanilide (160 mg, 1 mol, 1
equivalent) and BzPinz (406 mg, 1.60 mmol, 3.20 equivalents of boron) using 8 mol %
[Ir] with a reaction time of 18 h. One borylated isomer was observed in the crude reaction
mixture by GC-FID and by 1H NMR spectroscopy along with a small amount of
borylated/reduced (reduction of carbonyl group to CH2) as a side product. Solvent was
removed under reduced pressure. Column chromatography (ether, R; 0.5) gave a mixture
of the desired product and pinacol (239 mg). Kugelrohr distillation furnished the desired
product (177 mg, 62% yield, mp 178-180 °C) as a white solid. The gHMBC spectrum
was used to assign the single isomer as 4'-cyano-3'-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolane-Z-yI)-acetanilide. 1H NMR (CDCI3, 500 MHz): 6 (2.108) 7.99 (dd, J = 8.3,
2.0 Hz, 1 H, Hb), 7.85 (s, 1 H, N-H), 7.77 (d, J= 2.4 Hz, 1 H, Ha), 7.63 (d, J= 8.3 Hz, 1
H, Hc), 2.18 (s, 3 H), 1.32 (br s, 12 H, 4 CH3 of BPin); ”C NMR {‘H} (CDCI3, 75 MHz):
6 (2.108) 168.8 (C=O), 141.1 (C4), 134.7 (C6), 125.9 (C3), 121.5 (C5), 119 (nitrile C7),
111.6 (CI), 84.8 (2 C), 24.7 (4 CH3 of BPin), 24.6 (CH3); llB NMR(CDC13, 96 MHz): 6
30.52; FT-IR (neat) 17: 3319, 3104, 2980, 2934, 2225, 1701, 1678, 1601, 1578, 1532,
1497, 1416, 1373, 1344, 1302, 1258, 1140, 1063, 965, 853, 800, 743, 675 cm]; GC-MS

(El) m/z (% relative intensity): M+ 286 (100), 271 ( 18), 253 (32), 244 (89), 228 (68), 201

67

(42), 187 (68), 158 (13), 144 (58); HRMS (El): m/z 286.1493 [(M); Calcd for
C15H193N203: 286.1489].
Table 2.1, Entry 11. 2—(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)—4-

(trifluoromethyl)benzonitrile (2.1 18).

CF3
Hb5 43H,

Hc 6 2 BPin

CN
7

2J18

General procedure B was applied to 4-(trifluoromethyl)-benzonitrile (171 mg, 1
mol, 1 equiv) and HBPin (175 11L, 154 mg, 1.20 mmol) in n-hexane (3 mL) with a
reaction time of 12 h. One monoborylated product and one diborylated product were
observed in the crude reaction mixture by GC-FID (90:10). Solvent was removed under
reduced pressure. The crude mixture was eluted with CHzClz through a plug of silica gel.
Sublimation furnished the desired single monoborylated product (203 mg, 68% yield, mp
79-80 °C) as a white solid. 13C NMR spectroscopy was used to assign the single isomer
as 2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-y1)-4-(trifluoromethyl)benzonitri1e. lH
NMR(CDC13, 500 MHz): 6 (2.118) 8.12 (s, 1 H, Ha), 7.81 (d, J= 7.8 Hz, 1 H, Hb or Hc),
7.76 (d, J= 7.8 Hz, 1 H, Hb or Hc), 1.38 (br s, 12 H, 4 CH3 of BPin); ”C NMR {'H}
(CDCI3, 125 MHz): 6 (2.118) 133.7 (C6), 133.3 (q, 2Jc-1== 33.2 Hz, C4), 132.5 (q, 3Jc-p =
2.1 Hz, C3), 127.8 (q, 3Jc-p = 3.3 Hz, C5), 122.1 (q, 'Jop = 273 Hz, CF3), 120.7 (C1),
117.6 (nitrile C7), 85.3 (2 C), 24.7 (4 CH3 of BPin); “B NMR (CDCI3, 96 MHz): 6 30.03;
”F NMR (CDCI3, 282 MHz): 6 —63.4; FT-IR (neat) v: 2982, 2234, 1613, 1574, 1423,

1354, 1306, 1271, 1175, 1142, 1082, 1065, 965, 878, 849, 675 cm]; LRMS (% rel. int):

68

m/e 297 M (23), 282 (100), 256 (81), 239 (27), 198 (19), 171 (10); HRMS (E1): m/z
297.1144 [(M); Calcd for C14H15BF3N02: 297.1148].

Borylation of benzonitrile (2.128 + 2.12b + 2.12c).

ON ON ON
WU £5
PinB

BPin
5.7 64.4 29.9
2.1 28 2.1 21) 2.1 2c

General procedure A was applied to benzonitrile (412 mg, 4 mol, 4 equiv) and
HBPin (145 ML, 128 mg, 1 mol, 1 equiv) with a reaction time of 12 h. The ratio of the
three isomers in the crude reaction mixture by GC-FID was 5.7:64.4:29.9. Solvent and
excess substrate were removed under reduced pressure. The crude mixture was eluted
with CH2C12 through a plug of silica gel to afford a mixture of the three isomeric
borylated products (176 mg, 77% combined yield) as a white solid. 1H NMR, gCOSY,
and gHMBC spectroscopy were used to assign the major isomer as 3-(4,4,5,5-
tetrarnethyl-l,3,2-dioxaboroIane-2-yl)benzonitn'le. 1H NMR (CDCI3, 300 MHz): 6
(2.12b-meta isomer) 8.07-8.05 (br s, 1 H), 7.98 (td, J = 7.5, 1.2 Hz, 1 H), 7.71-7.67 (m, 1
H), 7.44 (dt, J = 7.5, 0.7 Hz, 1 H), 1.32 (br s, 12 H, 4 CH3 of BPin), (2.12c-para isomer)
7.87-7.84 (m, 2 H), 7.62-7.59 (m, 2 H), 1.32 (br s, 12 H, 4 CH3 of BPin); ”C NMR {'H}
(CDCI3, 75 MHz): 6 (2.12b-meta isomer) 138.7 (CH), 138.3 (CH), 134.3 (CH), 128.3
(CH), 118.7 (C), 112 (C), 84.4 (2 C), 24.8 (4 CH3 of BPin), (2.12c-para isomer) 135
(CH), 131 (CH), 118.7 (C), 114.4 (C), 84.7 (2 C), 24.8 (4 CH3 of BPin); 11B NMR
(CDCI3, 96 MHz): 6 31.2; FT-IR (neat) it": 3063, 2980, 2934, 2230, 1603, 1483, 1398,

1360, 1329, 1271, 1143, 1088, 964, 880, 849, 700, 653 cm]; GC-MS (E1) m/z (% relative

69

 

 

intensity): (2.12b-meta isomer) M+ 229 (11), 230 MH (29), 214 (100), 186 (10), 143 (44),
(2.12c-para isomer) M 229 (5), 230 M+I (14), 186 (9), 143 (41); HRMS (El): m/z
229.1271 [(M); Calcd for C.3H,,BN02: 229.1274].

Borylation of anisole (2.138 + 2.13b + 2.13c).

OMe OMe OMe
”at: D
PinB
BPin
2.1 78.9 19
2.138 2.13b 2.13c

General procedure A was applied to anisole (432 mg, 4.00 mol, 4 equiv) and
HBPin (145 11L, 128 mg, 1 mmol) with a reaction time of 24 h. The ratio of the three
isomers in the crude reaction mixture by GC was 2.1:78.9:19. Solvent and excess
substrate were removed under reduced pressure. The crude mixture was eluted with
CHzClz through a plug of silica gel to afford a mixture of the three isomeric borylated
products (193 mg, 82% combined yield) as colorless oil. 1H NMR spectroscopy was used
to assign the major isomer as 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)anisole. 1H
NMR (CDCI3, 300 MHz): 6 (2.13b/meta isomer) 7.40-7.25 (m, 3 H), 7.00 (m, 1 H), 3.82
(s, 3 H), 1.33 (br s, 12 H, 4 CH3 of BPin), (2.13c/para isomer) 7.75-7.72 (m, 2 H), 6.89-
6.86 (m, 2 H), 3.81 (s, 3 H), 1.32 (br s, 12 H, 4 CH3 of BPin). The spectra were in

agreement with those described in the literature. '8

7O

Borylation of 1,3-dicyanobenzene (2.148 + 2.14b).

5 H141 12 Hc 13
NC 2 CN NC 6 78 CN
Ho Ho H, BPin

BPin ,
74 26
2.148 2.1411

General procedure A was applied to 1,3-dicyanobenzene (256 mg, 2.00 mmol,
4.00 equiv) and HBPin (73 11L, 64 mg, 0.5 mmol) with a reaction time of 12 h. The ratio
of the two isomers in the crude reaction mixture by lH NMR spectroscopy was 74:26.
Kugelrohr distillation furnished a mixture of the two isomeric borylated products (79 mg,
62% yield) as a white solid. The ratio of the two isomers in the isolated product by 1H
NMR spectroscopy was 77:23. 1H NMR spectroscopy was used to assign the major
isomer as 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isophthalonitrile. lH NMR
(CDCI3, 300 MHz): 6 (2.148) 8.24 (d, J = 1.7 Hz, 2 H, Hb), 7.96 (t, J = 1.7 Hz, 1 H, Ha),
1.33 (br s, 12 H, 4 CH3 of BPin), (2.14b) 7.99 (d, J = 7.8 Hz, 1 H, He), 7.92 (d, J = 1.4
Hz, 1 H, Hc), 7.80 (dd, J = 7.8, 1.4 Hz, 1 H, Hd), 1.36 (br s, 12 H, 4 CH3 of BPin); l3C
NMR {1H}(CDC13, 125 MHz): 6 (2.148) 141.8 (CH, C3), 137.1 (CH, C1), 116.7 (C,
nitrile C5), 113.5 (C, C2), 85.2 (2 C), 24.8 (4 CH3 of BPin), (2.14b) 136.6 (CH), 136.1
(CH), 134.4, (CH), 118.6 (C), 116.8 (C), 116.7 (C), 115.3 (C), 85.5 (2 C), 24.7 (4 CH3 of
BPin); ”B NMR (CDCI3, 96 MHz): 6 30.03; FT-IR (neat) a: 3073, 2982, 2237, 1595,
1418, 1398, 1374, 1339, 1233, 1215, 1169, 1144, 1129, 1064, 966, 897, 849, 698 cm'l;
GC-MS (EI) m/z (% relative intensity): M+ 254 (7), 239 (100), 211 (15), 196 (4), 168
(43), 155 (7); Anal. Calcd for C14HtsBN202: C, 66.18; H, 5.95; N, 11.02. Found: C, 66;

H, 6.02; N, 10.81.

71

Borylation of 1,3-difluorobenzene (2.158 + 2.15b + 2.15c).

BPin
F F F, : :F F, i ,F
; BPin
BPin
50 33 17
2.158 2.15b 2.15c

General procedure A was applied to 1,3-fluorobenzene (228 mg, 2.00 mol, 4
equiv) and HBPin (73 11L, 64 mg, 0.5 mol, 1 equiv) with a reaction time of 1 h. The
ratio of the three isomers in the crude reaction mixture by GC-F ID was 50:33:17, with
GC-FID retention time of 7.92, 8.17, and 8.35 minutes respectively. '3 C NMR
spectroscopy and authentic sample preparation were used for making regioisomeric
assignments. Authentic samples of each isomer were synthesized using a slightly
modified literature procedures9
Preparation of authentic samples of borylated 1,3-difluorobenzenes.

In a glove box, a 100 mL schlenk flask, equipped with a magnetic stirring bar,
was charged with Pd2(dba)3 (14 mg, 0.015 mol, 3 mol% Pd) and
tricyclohexylphosphine (PCy3, 20 mg, 0.072 mmol, 7.2 mol%). Dioxane (6 mL) was
added and the resulting mixture was stirred for 30 minutes at room temperature. BzPinz
(280 mg, 1.1 mmol), KOAc (147 mg, 1.5 rmnol), and the corresponding bromo
substituted 1,3-difluorobenzene (193 mg, 1 mmol) were added successively. The schlenk
flask was brought to a schlenk line. A condenser was attached, and the flask was flushed
with nitrogen. The reaction mixture was stirred at 80 °C for 12 h. The mixture was treated

with water (5 mL), and the product was extracted with ether, washed with brine, and

72

dried over MgSO4. Crude material was eluted with CHzClz through a plug of silica gel to
afford the desired product Characterization data for each isomer is described below.
2-(3,5-difluorophenyI)-4,4,5,5-tetr8methyl-1,3,2-dioxaborolane (2.158).

161 mg (67% yield, mp 47-48 °C); GC—FID retention time 7.92 minute; 1H NMR
(CDCI3, 300 MHz): 6 7.28-7.24 (m, 2 H), 6.85 (tt, 2JH.F = 9.1 Hz, 4.11..H = 2.5 Hz, 1 H),
1.32 (s, 12 H, 4 CH3 of BPin); ”C NMR {'H} (CDCI3, 75 MHz): 6 162.7 (dd, 'Jc.F =
249.8 Hz, 3J0, = 12.1 Hz, C), 116.8 (m, 2 CH), 106.5 (t, 2.1.3., = 25.2 Hz, CH), 84.4 (2
C), 24.8 (4 CH3 of BPin); “B NMR (CDCI3, 96 MHz): 6 31.1; ”F NMR(CDC13, 282
MHz): 6 -1lO.8 (m); FT-IR (neat) 1‘7: 2924, 2853, 1367, 1259, 1022, 800 cm"; GC-MS
(EI) m/z (% relative intensity): M+ 240 (16), 225 (100), 197 (13), 154 (58); Anal. Calcd
for CnHUBonz: C, 60.04; H, 6.30. Found: C, 59.94; H, 6.31; HRMS (E1): m/z 240.1139
[(M‘); Calcd for C12HlsBF202: 240.1133].
2-(2,4-difluorophenyl)—4,4,5,5-tetramethyl-l,3,2-dioxaborolane (2.15b).

170 mg (71% yield, mp 39-40 °C); GC-FID retention time 8.17 minute; 1H NMR
(CDCI3, 300 MHz): 6 7.74-7.66 (m, 1 H), 6.88-6.81 (m, 1 H), 6.78-6.71 (m, 1 H), 1.33 (s,
12 H, 4 CH3 of BPin); ”C NMR {‘H} (CDCI3, 75 MHz): 6 168.5 (dd, RIC-.. = 175.8 Hz,
3J0; = 12.1 Hz, C), 165.2 (dd, ‘Jar = 174.7 Hz, 3.103: = 12.1 Hz, C), 138.2 (t, 3JC-F = 10.1
Hz, CH), 111.1 (dd, 2J0,- = 20.1 Hz, “J.;.F = 3.5 Hz, CH), 103.7 (dd, 220.: 27.9 Hz, 2Jar
= 24.4 Hz, CH), 84.0 (2 C), 24.8 (4 CH3 of BPin); ”B NMR (CDCI3, 96 MHz): 6 30.7;
”F NMR(CDC13, 282 MHz): 6 —105.2 (m), -98.6 (m); FT-IR (neat) 17: 3074, 2982, 2934,
1614,1593,1421,1387,1356,1331,1263,1143,1107,1070,960,856,733,652,576

om"; GC-MS (E1) m/z (% relative intensity): M+ 240 (51), 225 (100), 197(9), 181 (45),

73

141 (65); Anal. Calcd for C12H35BF202: C, 60.04; H, 6.30. Found: C, 59.71; H, 6.26;
HRMS (FAB): m/z 240.1134 [(M*); Calcd for CnHtsBonzz 240.1133].
2-(2,6-dif1uorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.15c).

172 mg (72% yield, mp 50—51 °C); GC—FID retention time 8.35 minute; 1H NMR
(CDCI3, 300 MHz): 6 7.38-7.28 (m, 1 H), 6.86-6.77 (m, 2 H), 1.36 (s, 12 H, 4 CH3 of
BPin); ”C NMR {'H} (CDCI3, 75 MHz): 6 166.7 (dd, ‘Jc.F = 250.3 Hz, 3Jc-r: = 13.1 Hz,
C), 132.9 (t, we... = 10.3 Hz, CH), 111.2-110.8 (m, 2 CH), 84.3 (2 C), 24.8 (4 CH3 of
BPin); “B NMR (CDCI3, 96 MHz): 6 30.6; ”F NMR(CDC13, 282 MHz): 6 ~100.6 (m);
FT-IR (neat) 1‘": 2988, 2930, 1626, 1458, 1383, 1354, 1334, 1138, 1095, 1053, 985, 850,
825, 792, 671, 559 cm'l; GC-MS (EI) m/z (% relative intensity): IVE 240 (26), 225 (100),
197(5), 181 (68); Anal. Calcd for CtzHlsBonz: C, 60.04; H, 6.30. Found: C, 60.02; H,
6.42.

Borylation of 2-fluoro-4-bromobenzonitrile (2.168 + 2.16b).

 

Br
HD 5 43 H,
PinB 6 2 F
CN
7
95 5
2.168 2.16b

General procedure B was applied to 2-fluoro-4-bromobenzonitrile (200 mg, 1
mol, 1 equivalent) and HBPin (290 11L, 256 mg, 2.00 mmol, 2.00 equiv) with a reaction
time of 9 h. The ratio of the two monoborylated isomers in the crude reaction mixture by
1H NMR spectroscopy was 95:5. A small amount of diborylated product was also
observed. Solvent was removed under reduced pressure, and the crude mixture was eluted

with CHzClz through a plug of silica gel. Sublimation afforded a mixture of two isomeric

74

 

borylated products (278 mg, 85% combined yield) as a white solid. The ratio of the two
monoborylated isomers in the isolated product by 1H NMR spectroscopy was 95:5. 1H
NMR spectroscopy were used to assign the major isomer as 2-fluoro-4-bromo-6-(4,4,5,5-
tetramethyl-l,3,2-dioxaborolane-2-y1)benzonitrile. 1H NMR (CDC13, 500 MHz): 6
(2.168) 7.77 (d, J= 1.7 Hz, 1 H, Hb), 7.44 (dd, 2JHr = 8.3 Hz, J= 1.7 Hz, 1 H, Ha), 1.35
(br s, 12 H, 4 CH3 of BPin), (2.16b) 7.90 (d, 3J1” = 7.5 Hz, 1 H, Hd), 7.42 (d, 2J1“: = 8.5
Hz, 1 H, Hc), 1.35 (br s, 12 H, 4 CH3 of BPin); ”C NMR {'H} (CDCI3, 75 MHz): 6
(2.168) 163.3 (d, ‘JC.F =262.8 Hz, C, C2), 134.6 (d, “JC.F = 4 Hz, CH, C5), 127.8 (d, 3.7g.F
= 8 Hz, C, C4), 122 (d, ZJC.F = 23 Hz, CH, C3), 112.9 (nitrile, C, C7), 104.6 (d, 21,-..- =
14.1 Hz, C, C1), 85.4 (2 C), 24.7 (4 CH3 of BPin); “B NMR (CDCI3, 96 MHz): 6 29.94;
”F NMR(CDC13, 282 MHz): 6 (2.168) -1039 (d, J = 7.9 Hz); FT-IR (neat) v”: 3086,
2986,2934,2237,1590,1557,1462,1408,1375,1358,1329,1140,972,985,880,843,
742, 665 cm"; GC-MS (E1) m/z (% relative intensity): M+ 325 (15), 310 (37), 284 (67),
267 (34), 246 (31), 226 (57); Anal. Calcd for C13H14BBrFNOZ: C, 47.90; H, 4.33; N, 4.3.
Found: C, 48.15, H, 4.28; N, 4.16.

Borylation of 3,4—dichlorobenzonitrile (2.178 + 2.17b).

Cl
HD 5 43C1

PinB 5 2 Ha
CN
7

 

80
2.178 2.17!)

General procedure B was applied to 3,4-dichlorobenzonitri1e (172 mg, 1 mol, 1
equiv) and HBPin (218 11L, 192 mg, 1.50 mmol, 1.50 equivalent) with a reaction time of

18 h. The ratio of the two monoborylated isomers in the crude reaction mixture by IH

75

NMR spectroscopy was 80:20. Solvent was removed under reduced pressure and the
crude mixture was eluted with CH2C12 through a plug of silica gel to afford a mixture of
two isomeric borylated products (265 mg, 89% combined) as a white solid. The ratio of
the two monoborylated isomers in the isolated product by 1H NMR spectroscopy was
81:19. 1H NMR spectroscopy was used to assign the major isomer as 4,5-dichloro-2-
(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)benzonitrile. 1H NMR (CDCI3, 500 MHz):
6 (2.178) 7.92 (s, 1 H), 7.73 (s, 1 H), 1.35 (br s, 12 H, 4 CH3 of BPin), (2.17b) 7.84 (d, J
= 2 Hz, 1 H), 7.74 (d, J= 2 Hz, 1 H), 1.35 (br s, 12 H, 4 CH3 of BPin); 13C NMR {1H}
(CDCI3, 125 MHz): 6 (2.178) 137.7 (CH), 137.1 (C), 135.8 (C), 134.8 (CH), 116.9 (C),
116.6 (C), 85.3 (2 C), 24.7 (4 CH3 of BPin), (2.17b) 142.7 (C), 137.6 (CH), 135 (CH),
134.3 (C), 116.8 (C), 111.3 (C), 85 (2 C), 24.7 (4 CH3 of BPin); 11B NMR (CDCI3, 96
MHz): 6 29.9; FT-IR (neat) 17': 2982, 2234, 1580, 1535, 1472, 1383, 1342, 1304, 1142,
1084, 964, 910, 850, 669 cm'l; GC-MS (El) m/z (% relative intensity): (2.178) M+ 297
(22), 282 (60), 256 (100), 239 (48), 198 (41), (2.17b) M+ 297 (1), 282 (28), 262 (100),
220 (80); Anal. Calcd for C13H14BC12N02: C, 52.40; H, 4.74; N, 4.70. Found: C, 52.42;
H, 4.79; N, 4.55; HRMS (E1): m/z 297.0500 [(MU; Calcd for C13H14BC12N02: 297.0495].

Table 2.3, Entry 1. Diborylation of 4-fluorobenzonitri1e (2.188 + 2.18b).

PinB 5 4 3 BPin

Ha 6 2H8

CN
7

54
2.188

 

General procedure C was applied to 4-fluorobenzonitrile (121 mg, 1 mol, 1

equiv) and HBPin (580 uL, 512 mg, 4.00 mmol, 4.00 equiv) with a reaction time of 24 h.

76

The ratio of the two isomers in the crude reaction mixture by 1H NMR spectroscopy was
54:46. Solvent was removed under reduced pressure, and the crude mixture was eluted
with CHzClz through a plug of silica gel to afford a mixture of two isomeric diborylated
products (343 mg, 92% combined yield) as a white solid. The ratio of the two diborylated
isomers in the isolated product by 1H NMR spectroscopy was 53:47. 1H, 13C NMR and
gHMBC spectroscopy were used to assign the major isomer as 4—fuoro-3,5-bis-(4,4,5,5-
tetrarnethyl-1,3,2-dioxaborolane-2-yl)benzonitrile. lH NMR (CDCI3, 500 MHz): 6
(2.188) 8.1 ((1, 4J1“: = 4.9 Hz, 2 H, Ha), 1.28 (br s, 24 H, 8 CH3 of BPin), (2.18b) 8.04 (d,
4J1“: = 5.4 Hz, 1 H, Hc), 7.46 (d, 3J1” = 8.8 Hz, 1 H, Hb), 1.32 (br s, 12 H, 4 CH3 of
BPin), 1.31 (br s, 12 H, 4 CH3 of BPin); ”C NMR {'H} (CDCI3, 125 MHz): 6 (2.188)
172 (d, 1.101: = 266 Hz, C4), 143.9 ((1, 3J0; = 10.9 Hz, C2), 117.9 (nitrile C), 108 (d, 4J0}:
= 3.6 Hz, CI), 84.4 (4 C), 24.7 (8 CH3 of BPin), (2.18b) 168.1 (d, 'Jop = 261.4 Hz, C4' ),
142.6 (d, 3J1”. = 8.8 Hz, C6' ), 122.6 (d, 2J¢-p --= 23.8 Hz, C3' ), 118.1 (nitrile C7' ), 112.6
(d, 9,-.= 3.6 Hz, Cl' ), 85 (2 C), 84.5 (2 C), 24.7 (4 CH3 of BPin); ”B NMR (CDCI3, 96
MHz): 6 29.8; ”F NMR(CDC13, 282 MHz): 6 (2.188) —81.8 (m), (2.18b) —94.9 (m);
FT-IR (neat) 17: 2980, 2934, 2232, 1599, 1497, 1437, 1414, 1373, 1334, 1267, 1215,
1142, 1095, 966, 889, 848, 584 cm"; GC-MS (E1) m/z (% relative intensity): (2.188) M+
373 (4), 358 (59), 353 (100), 315 (22), 253 (45), (2.18b) 373 M (32), 358 (68), 331
(100), 315 (53), 274 (39); Anal. Calcd for C19H26B2FNO4: C, 61.17; H, 7.03; N, 3.75.

Found: C, 61.37,; H, 6.83; N, 3.82.

77

Table 2.3, Entry 2. Diborylation of 4—methoxybenzonitrile(2.l9a + 2.1%).

OMe
H, 5 43 H,

PinB 6 2 BPin

CN
7

20
2.198

 

General procedure C was applied to 4—methoxybenzonit1ile (133 mg, 1 mol, 1
equiv) and HBPin (580 11L, 512 mg, 4.00 mmol, 4.00 equivalent) at 60 °C for 48 h. The
ratio of the two diborylated isomers in the crude reaction mixture by IH NMR
spectroscopy was 80:20. Solvent was removed under reduced pressure, and the crude
mixture was eluted with CHzClz through a plug of silica gel to afford a mixture of two
isomeric diborylated products (310 mg, 81% combined yield) as a white solid. The ratio
of the two diborylated isomers in the isolated product by 1H NMR spectroscopy was
80:20. 1H NMR and gHMBC spectroscopy were used to assign the major isomer as
4-methoxy-2,5-bis-(4,4,5,5-tetramethyl—l,3,2-dioxaborolane-2-yl)benzonitri1e. 1H NMR
(C6D5, 500 MHz): 6 (2.198) 7.61 (s, 2H, Ha), 3.08 (s, 3H), 1.11 (br s, 24 H, 8 CH3 of
BPin), (2.19b) 8.42 (s, 1 H, Hc), 7.36 (s, 1 H, Hb), 3.20 (s, 3 H), 1.10 (br s, 12 H, 4 CH3
of BPin), 1.06 (br s, 12 H, 4 CH3 of BPin); ”C NMR {'H} (C61), 125 MHz): 6 (2.19a)
160.8 (C4), 123.4 (C3), 118.6 (nitrile C7), 114.9 (C1), 84.6 (4 C), 24.8 (8 CH3 of BPin),
(2.19b) 166.3 (C4' ), 143.1 (C6' ), 137.4 (br, C2' ), 122.1 (br, C5' ), 119.32 (nitrile, C7' ),
117.36 (C3' ), 110.1 (Cl' ), 84.8 (2 C), 83.8 (2 C), 24.79 (4 CH3 of BPin), 24.76 (4 CH3
of BPin); llB NMR (CDCI3, 96 MHz): 6 30.90; FT-IR (neat) it”: 2980, 2936, 2224, 1601,

1503, 1398, 1373, 1337, 1244, 1142, 1094, 964, 858 cm"; GC-MS (El) m/z (% relative

78

intensity): M+ 385 (100), 370 (63), 343 (98), 327 (53), 286 (41); Anal. Calcd for
ConngzNost C, 62.38; H, 7.59; N, 3.64. Found: C, 62.36; H, 7.41; N, 3.69.

Table 2.3, Entry 3. Diborylation of 4—chlorobenzonitrile (2.208 + 2.20b).

 

20
2.208 2.20!)

General procedure C was applied to 4-chlorobenzonitrile (138 mg, 1 mol, 1
equiv) and HBPin (580 11L, 512 mg, 4 mol, 4 equivalent) with a reaction time of 48 h.
The ratio of the two diborylated isomers in the crude reaction mixture by GC-FID was
80:20. Solvent was removed under reduced pressure, and the crude mixture was eluted
with CHzClz through a plug of silica gel to afford a mixture of two isomeric diborylated
products (320 mg, 82% combined yield) as a white solid. The ratio of the two diborylated
isomers in the isolated product by GC-FID was 80:20. 1H NMR and gHMBC
spectroscopy were used to assign the major isomer as 4-chloro-2,5-bis-(4,4,5,5-
tetramethyl-l,3,2-dioxaborolane-2-y1)benzonitrile. 1H NMR (CDCI3, 500 MHz): 6
(2.208) 7.83 (s, 2 H, Ha), 1.349 (br s, 24 H, 8 CH3 of BPin), (2.20b) 7.97 (s, 1 H), 7.80 (s,
1 H), 1.35 (br s, 12 H, 4 CH3 of BPin), 1.34 (br s, 12 H, 4 CH3 of BPin); ”C NMR {'H}
(CDCI3, 125 MHz): 6 (2.208) 137.7 (C4), 137.3 (C3), 119.7(C1), 117.6 (nitrile C7),
85.04 (4 C), 24.7 (8 CH3 of BPin), (2.20b) 143.6 (C4' ), 141.2 (C6' ), 136.5 (C3' ), 118.2
(nitrile, C7' ), 114.8 (Cl' ), 85.1 (2 C), 84.8 (2 C), 24.7 (8 CH3 of BPin); 1’B NMR
(CDCI3, 96 MHz): 6 30.25; FT-IR (neat) V: 2980, 2230, 1591, 1383, 1341, 1269, 1142,

1 122, 1088, 962, 855 cm'l; GC-MS (EI) m/z (% relative intensity): (2.208) M 389 (36),

79

374 (64), 348 (23), 290 (53), 248 (49), 207 (100), (2.20b) M 389 (30), 374 (57), 354
(100), 347 (88), 331 (39), 312 (37), 290(35): Anal. Calcd for C39H26B2C1NO4: C, 58.59;
H, 6.73; N, 3.6. Found: C, 58.27, H, 6.78; N, 3.41; HRMS (E1): m/z 389.1746 [(M);
Calcd for C19H2632C1N04: 389.1736].

Table 2.3, Entry 4. Diborylation of 1,4-dicyanobenzene (2.218 + 2.21b).

 

CN
H. 4 3 H.
PinB 2 BPin
CN
7 93
2.218 2.21b

General procedure C was applied to 1,4-dicyanobenzene (128 mg, 1 mol, 1
equiv) and HBPin (580 11L, 512 mg, 4.00 mmol, 4.00 equivalent) with a reaction time of
20 h. The ratio of the two diborylated isomers in the crude reaction mixture by GC-FID
was 93:7. Solvent was removed under reduced pressure. Crystallization from
THF/pentane gave the major isomer (270 mg, 71% yield, mp 242-245 °C) as a white
solid. 13C NMR spectroscopy were used to assign the major isomer as 2,5-bis(4,4,5,5-
tetrarnethyl-l,3,2-dioxaborolan-2-yl)terephthalonilrile. 1H NMR (CDCI3, 500 MHz): 6
(2.218) 8.15 (s, 2H,), 1.37 (br s, 24 H, 8 CH3 of BPin), (2.21b) 8.16 (s, 2 H), 1.37 (br s,
24 H, 8 CH3 of BPin); ”C NMR {‘H} (CDCI3, 75 MHz): 6 (2.21b) 140.1 (C3', 2 CH),
135.4 (br, C2’, 2 C), 120.1 (Cl', 2 C), 117.4 (nitrile, 2 C), 85.4 (4 C), 24.7 (8 CH3 of
BPin); 11B NMR (CDCI3, 96 MHz): 6 30.16; FT-IR (neat) 17': 2984, 2230, 1497, 1416,
1391, 1347, 1287, 1267, 1169, 1140, 1100, 962, 927, 855, 814, 711, 598 cm"; GC-MS

(El) m/z (% relative intensity): (2.21b) W 380 (35), 365 (69) , 339 (100), 322 (69), 281

80

(46); Anal. Calcd for C20H26B2N204: C, 63.21; H, 6.90; N, 7.37. Found: C, 63.39, H,
7.19; N, 7.02.
Table 2.3, Entry 5. 2,6-bis(4,4,5,5—tetramethyl-1,3,2-dioxaborolan-2-yI)-4-

(trifluoromethyl)benzonitrile (2.228).

CF3
H. 4 3 H.
PinB 2 BPin
CN
2.228

General procedure C was applied to 4-(trifluoromethyl)-benzonitrile (171 mg, 1
mol, 1 equiv) and HBPin (580 11L, 512 mg, 4.00 mmol, 4.00 equivalent) with a reaction
time of 36 h. Solvent was removed under reduced pressure, and the crude mixture was
eluted with CHzClz through a plug of silica gel to afford single diborylated isomer (350
mg, 83% yield) as a white solid. 13C NMR spectroscopy were used to assign the single
isomer as 2,6-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)-
benzonitrile. lH NMR(CDC13, 300 MHz): 6 (2.228) 8.12 (s, 2 H), 1.37 (br s, 24 H, 8 CH3
of BPin); ”C NMR {1H} (CDCI3, 75 MHz): 6 (2.22a) 133.9 (q, 3.1.... = 3 Hz, C3), 132 (q,
2J¢-p = 32.2 Hz, C4), 125 (nitrile, C), 123.3 (q, 1J6]: = 273 Hz, CF3), 117.1 (C1), 85.2 (2
C), 24.7 (8 CH3 of BPin); “B NMR (CDCI3, 96 MHz): 6 30.14; ”F NMR(CDC13, 282
MHz): 6 —63.3; FT-IR (neat) 1'": 2982, 2936, 2234, 1582, 1469, 1431, 1383, 1373, 1334,
1319, 1290, 1269, 1245, 1140, 1080, 966, 883, 846, 690 cm"; GC-MS (E1) m/z (%
relative intensity): M” 423 (45), 408 (100), 382 (36), 324 (45), 282 (62); Anal. Calcd for
C20H2632F3NO4: C, 56.78; H, 6.19; N, 3.31. Found: C, 56.81; H, 5.92; N, 3.29; HRMS

(E1): m/z 423.1999 [(M+); Calcd for C20H2632F3NO4: 423.2000].

81

Borylation of PhBPin (2.238 + 2.23b + 2.23c).

BPin BPin BPin
“it: if)
PinB
BPin
0 35.4 64.6
2.238 2.23b 2.23c

General procedure B was applied to benzene (78 mg, 1 mol, 1 equiv) and
HBPin (175 11L, 153.6 mg, 1.20 mmol, 1.20 equivalents) with a reaction time of 24 h.
The first equivalent of borane generates PhBPin in situ and the remaining 0.2 equivalents
give the two diborylated isomers. PhBPin and the two diborylated isomers were present
at the end of reaction. The GC-FID ratio of the two diborylated isomers was 64.6:35.4. A
mixture of the two diborylated isomers was isolated (51 mg). lH NMR spectroscopy was
used to assign the major isomer as 1,4-bis(4,4,5,5-tetramethy1—1,3,2-dioxaborolane-2-
yl)benzene. 1H NMR (CDCI3, 300 MHz): 6 (2.23b/meta isomer) 8.25 (d, J = 1 Hz, 1 H),
7.88 (dd, J= 7.3, 1.5 Hz, 2 H), 7.35 (td, J= 7.3, 1 Hz, 1 H), 1.31 (s, 24 H, 8 CH3 of
BPin), (2.23c/para isomer) 7.78 (s, 4 H), 1.32 (s, 24 H, 8 CH3 of BPin). The spectra were
in agreement with those described in the literature.60

Borylation of 1,S-dimethyl-Z-pyrrolecarbonitrile (2.248 + 2.24b).

Me Me
Me5';‘20N Me 5'1‘12'c
o \ / 7 6' \ / 7'

4 3 3'
BPin PinB

85 15

2.24a 2.24b

General procedure B was applied to 1,5-dimethyl-2-pyrrolecarbonitri1e (240 mg,

2 mol, 1 equiv) and HBPin (435 uL, 384 mg, 3.00 mmol, 1.50 equivalents) with a

82

reaction time of 16 h. The ratio of the two isomers in the crude reaction mixture by
GC-F ID was 85:15. Solvent was removed under reduced pressure, and the crude mixture
was eluted with CH2C12 through a plug of silica gel to afford a mixture of two isomeric
borylated products (394 mg, 80% combined yield) as a white solid. The ratio of the two
isomers in the isolated product by GC-FID was 82:18. The NOESYID and gHMBC
spectra were used to assign the major isomer as 1,5-dimethyl-3-(4,4,5,5-tetramethyl-
1,3,2-dioxaborolane-2-yl)-2—pyrrolecarbonitrile. 1H NMR (CDCI3, 300 MHz): 6 (2.248)
6.21 (d, 4JH-H= 0.7 Hz, 1 H, pyrrol ring H), 3.63 (s, 3 H, NCH3), 2.21 (d, 4JH-H= 0.7 Hz, 3
H, CH3 on pyrrol ring), 1.30 (br s, 12 H, 4 CH3 of BPin), (2.24b) 7.03 (s, 1 H, pyrrol ring
H), 3.6 (s, 3 H, NCH3), 2.41 (s, 3 H, CH3 on pyrrol ring), 1.27 (s, 12 H, 4 CH3 of BPin);
”C NMR {1H} (CDCI3, 125 MHz): 6 (2.248) 135.4 (C5), 114 (C4), 113.8 (nitrile C7),
109.6 (C2), 83.0 (2 C), 32.0 (NCH3), 24.3 (4 CH3 of BPin), 11.8 (CH3), (2.24b) 143.9
(CS’ ), 125.2 (C3' ), 113.7 (nitrile C7' ), 103.8 (C2' ), 82.6 (2 C), 31.8 (NCH3), 24.4 (4
CH3 of BPin), 11.9 (CH3); ”8 NMR (CDCI3, 96 MHz): 6 32.75; FT-IR (neat) it: 2980.
2934, 2735, 1561, 1501, 1441, 1408, 1390, 1379, 1371, 1313, 1262, 1187, 1167, 1144,
1111, 1017, 860, 835, 708 cm'l; GC-MS (E1) m/z (% relative intensity): (2.248) M” 246
(100), 231 (19), 203 (12), 189 (16), 160 (13), 146 (20), (2.24b) M+ 246 (100), 231 (20),
189 (51), 160 (21), 146 (43); Anal. Calcd for C13H19BN202: C, 63.44; H, 7.78; N, 11.38.
Found: C, 63.34; H, 7.78; N, 11.34.

Borylation of S-methyl-Z-furonitrile (2.258 + 2.25b).

Me5920N Me5'QZCN
4 3 4' 3'
BPin PinB
85 15
2.258 2.251)

83

General procedure B was applied to 5—methyl-2-furonitrile (210 uL, 214 mg, 2
mmol, 1 equiv) and HBPin (435 ML, 384 mg, 3.00 mmol, 1.50 equivalents) with a
reaction time of 0.5 h. The ratio of the two isomers in the crude reaction mixture by
GC-FID was 85:15. Solvent was removed under reduced pressure, and the crude mixture
was eluted with CHzClz through a plug of silica gel to afford a mixture of two isomeric
borylated products (456 mg, 97% combined yield) as a white solid. The ratio of the two
isomers in the isolated product by GC was 90:10. The NOESYlD and gHMBC spectra
were used to assign the major isomer as 5-methyl-3-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolane-Z-yl)—2-furonitri1e. lH NMR(CDC13, 300 MHz): 6 (2.25a) 6.23 (d, 4J3-“ =
1.0 Hz, 1 H, furan ring H), 2.29 ((1, 4J1“; = 1.0 Hz, 3 H, CH3 on furan ring), 1.27 (br s,
12H, 4 CH3 of BPin), (2.25b) 7.12 (s, 1 H, furan ring H), 2.46 (s, 3 H, CH3 on furan
ring), 1.25 (s, 12 H, 4 CH3 of BPin); 13C NMR {1H} (CDC13, 75 MHz): 6 (2.25a) 157.6
(C5), 130.4 (C2), 111.9 (nitrile C7), 111.5 (C4), 84.3 (2 C), 24.6 (4 CH3 of BPin), 13.4
(CH3), (2.25b) 167 (CS' ), 127.4 (C3' ), 124.1 (C2' ), 111.7 (nitrile C7' ), 83.8 (2 C), 24.7
(4 CH3 of BPin), 14.2 (CH3); “B NMR (CDClg, 96 MHz): 5 28.9; FT-IR (neat) a: 2982,
2934, 1595, 1543, 1446, 1428, 1408, 1392, 1381, 1373, 1335, 1302, 1228, 1169, 1143,
1043, 963, 855, 804, 712 cm]; GC-MS (El) m/z (% relative intensity): (2.25a) M 233
(89), 218 (42), 203 (20), 190 (64), 175 (59), 149 (100), 134 (47), (2.25b) M+ 233 (100),
218 (81), 191 (54), 175 (62), 149 (53), 133 (63); Anal. Calcd for C12H16BN03: C, 61.84;

H, 6.92; N, 6.01. Found: C, 62.25; H, 7.0; N, 5.80.

84

Borylation of 5-bromo—2-cyanopyridine (2.2711 + 2.27b).

Ha BPin
PinB 3 4\5 Br Hc 3' 4x5 Br
2 l , 6 2' l , 6'
NC 1N Hb NC 1|N Hd
7 7'
67 33
2.278 2.27b

General procedure B was applied to 5-bromo-2-cyanopyridine (183 mg, 1 mol,
1 equiv) and HBPin (290 (AL, 256 mg, 2.00 mmol, 2.00 equiv) with a reaction time of 18
h. The ratio of the two isomers in the crude reaction mixture by 1H NMR spectroscopy
was 67:33. Kugelrohr distillation furnished a mixture of the two isomeric borylated
products (253.5 mg, 81% combined) as a white solid. The ratio of the two isomers in the
isolated product by 1H NMR spectroscopy was 64:36. 1H NMR and gHMBC
spectroscopy were used to assign the major isomer as 5-bromo-3—(4,4,5,5-tetramethyl-
1,3,2-dioxaborolane-2-yl)-2-cyanopyridine. lH NMR (CDCI3, 300 MHz): 6 (2.27a) 8.76
(d, J = 2.4 Hz, 1 H, Hb), 8.28 (d, J = 2.4 Hz, 1 H, Ha), 1.37 (br s, 12 H, 4 CH3 of BPin),
(2.27b) 8.76 (s, 1 H, Hd), 7.85 (s, 1 H, Hc), 1.36 (s, 12 H, 4 CH3 of BPin); l3C NMR {1H}
(CDCI3, 75 MHz): 6 (2.27a) 153.6 (C6), 145.8 (C4), 136.1 (C2), 124.4 (C5), 116.6
(nitrile C7), 85.7 (2 C), 24.8 (4 CH3 of BPin), (2.27b) 153.1 (C6' ), 134.5 (C3' ), 131.4
(C2' ), 130.1 (cs' ), 116.7 (nitrile C7' ), 85.6 (2 C), 24.8 (4 CH3 of BPin); “B NMR
(CDCI3, 96 MHz): 6 29.5; FT-IR (neat) {5: 3048, 2979, 2244, 1566, 1539, 1416, 1383,
1342, 1318, 1269, 1142, 1069, 1026, 964, 872, 847, 771 cm"; GC-MS (E1) m/z (%
relative intensity): (2.27a) M" 308 (41), 310 (M2+ 37), 293 (95), 267 (96), 250 (65), 229
(34), 209 (42), (2.27b) M 308 (7), 293 (33), 267 (17), 229 (100), 187 (91); Anal. Calcd

for C12H14BBrN202: C, 46.65; H, 4.57; N, 9.07. Found: C, 46.52; H, 4.48; N, 8.76.

85

BIBLIOGRAPHY

(1) Taylor, R. Electrophilic Aromatic Substitution; John Wiley and Sons: New
York, 1990.

(2) Schopff, M. Ber. 1890, 23, 3435-3440.

(3) Whisler, M. C.; MacNeil, S.; Snieckus, V.; Beak, P. Angewandte Chemie-
lnternational Edition 2004, 43, 2206-2225.

(4) Kristensen, J.; Lysen, M.; Vedso, P.; Begtrup, M. Organic Letters 2001, 3,
1435-1437.

(5) Pletnev, A. A.; Tian, Q. P.; Larock, R. C. Journal of Organic Chemistry
2002, 67, 9276-9287.

(6) Lulinski, S.; Serwatowski, J. Journal of Organic Chemistry 2003, 68,
9384-9388.

(7) Imahori, T.; Kondo, Y. Journal of the American Chemical Society 2003,
125, 8082-8083.

(8) The deprotonation at the 2-position of 4-bromobenzonitrile is cited as an
unpublished result in ref. 7.

(9) Alternatively, the nitrile group could be converted to a DMG, such as an
amide or ester. Subsequent DoM and reformation of the nitrile group could give 2-
substituted nitriles.

(10) Wang, C.; Russell, G. A.; Trahanovsky, W. S. Journal of Organic
Chemistry 1998, 63, 9956-9959.

(11) Kim, B. H.; Jeon, 1.; Han, T. H.; Park, H. J.; Jun, Y. M. Journal of the
Chemical Society-Perkin Transactions 1 2001, 2035-2039.

86

( 12) Sonoda, M.; Kakiuchi, F.; Chatani, N.; Murai, S. Bulletin of the Chemical
Society of Japan 1997, 70, 3117-3128.

(13) Meyers, A. I.; Sircar, J. C. In The Chemistry of the Functional Groups;
Patai, S., Rappoport, Z., Eds.; Wiley & Sons: New York: 1970.

(14) Fatiadi, A. J. In Supplement C: The Chemistry of the Triple-bonded
Functional Groups; Patai, S., Rappoport, Z., Eds.; Wiley & Sons: New York: 1983.

(15) Ittel, S. D.; Tolman, C. A.; English, A. D.; Jesson, J. P. Journal of the
American Chemical Society 1976, 98, 6073-6075.

(16) Goldberg, K. 1.; Goldman, A. S. Activation and F unctionalization of C—H
bonds; American Chemical Society: Washington DC, , 2004.

(17) Iverson, C. N.; Smith, M. R. Journal of the American Chemical Society
1999, 121, 7696-7697.

(18) Cho, J. Y.; Iverson, C. N.; Smith, M. R. Journal of the American Chemical
Society 2000, 122, 12868-12869.

(19) Cho, J. Y.; Tse, M. K.; Holmes, 1).; Maleczka, R. E.; Smith, M. R. Science
2002, 295, 305-308.

(20) Maleczka, R. E.; Shi, F.; Holmes, D.; Smith, M. R. Journal of the
American Chemical Society 2003, 125, 7792-7793.

(21) Ishiyama, T.; Takagi, J.; Ishida, K.; Miyaura, N.; Anastasi, N. R.; Hartwig,
J. F. Journal of the American Chemical Society 2002, 124, 390-391.

(22) Ishiyama, T.; Takagi, J.; Hartwig, J. F.; Miyaura, N. Angewandte Chemie-
International Edition 2002, 41, 3056-3058. '

(23) Takagi, J.; Sato, K.; Hartwig, J. F .; Ishiyama, T.; Miyaura, N. Tetrahedron
Letters 2002, 43, 5649-5651.

(24) Ishiyama, T.; Nobuta, Y.; Hartwig, J. F.; Miyaura, N. Chemical
Communications 2003, 2924-2925.

87

(25) Ishiyama, T.; Takagi, J.; Yonekawa, Y.; Hartwig, J. F.; Miyaura, N.
Advanced Synthesis & Catalysis 2003, 345, 1103-1106.

(26) Mertins, K.; Zapf, A.; Beller, M. Journal Of Molecular Catalysis A-
Chemical 2004, 207, 21-25.

(27) Stratakis, M.; Wang, P. G.; Streitwieser, A. Journal of Organic Chemistry
1996, 61, 3145-3150.

(28) Krizan, T. D.; Martin, J. C. Journal of the American Chemical Society
1983, 105, 6155-6157.

(29) White, D. P.; Anthony, J. C.; Oyefeso, A. 0. Journal of Organic
Chemistry 1999, 64, 7707-7716.

(30) Ingold, C. K. Journal of the Chemical Society 1930, 1032-1039.

(31) Taft, R. W. Journal of the American Chemical Society 1952, 74, 3120-
3128.

(32) Charton, M. Journal of the American Chemical Society 1969, 91, 615-618.
(33) Kutter, E.; Hansch, C. Journal of Medicinal Chemistry 1969, 12, 647-652.

(34) Macphee, J. A.; Panaye, A.; Dubois, J. E. Tetrahedron 1978, 34, 3553-
3562.

(35) Winstein, S.; Holness, N. J. Journal of the American Chemical Society
1955, 77, 5562-5578.

(36) Hansch, C.; Leo, A.; Hoekman, D. H. In Exploring QSAR: Hydrophobic,
Electronic, and Steric Constants; American Chemical Society: Washington, DC, 1995, p
227.

(37) Jensen, F. R.; Bushwell.Ch; Beck, B. H. Journal of the American
Chemical Society 1969, 91, 344-351.

88

(38) Sotomatsu, T.; Murata, Y.; F ujita, T. Journal of Computational Chemistry
1991,12, 135-138.

(39) ' Sotomatsu, T.; Fujita, T. Journal of Organic Chemistry 1989, 54, 4443-
4448.

(40) AM] calculations were carried out on an SGI Origin 3400 supercomputer
using SPARTAN SGl Version 5.1.3, Wavefunction, Inc., Irvine, CA.

(41) Because the isomer ratios reflect differences in relative rates, values were
calculated using AB = exp(—[AAHs(Z)—AAHs(CN)/RT]), T = values from Table 2.1.
This should not be expected to reproduce the experimental values; however, the net trend
should be reflected in the data if a steric model is appropriate.

(42) Krizan, T. D.; Martin, J. C. Journal of Organic Chemistry 1982, 47, 2681-
2682.

(43) Bennetau, B.; Rajarison, F.; Dunogues, J.; Babin, P. Tetrahedron 1993,
49, 10843-10854.

(44) Kakiuchi, F.; Sonoda, M.; Tsujimoto, T.; Chatani, N.; Murai, S. Chemistry
Letters 1999, 1083-1084.

(45) Blackaby, W. P.; Goodacre, S. C.; Hallett, D. J.; Jennings, A.; Lewis, R.
T.; Street, L. J.; Wilson, K. US, 2004, p 20

(46) Arnold, J.; Berg, 8.; Chessari, G.; Congreve, M.; Edwards, P.; Holenz, J.;
Kers, A.; Kolmodin, K.; Murray, C.; Patel, S.; Rakos, L; Rotticci, D.; Sylvester, M.;
Oehberg, L.; (Astrazeneca AB, Swed.; Astex Therapeutics Ltd.). Application: W0
WC, 2007, p l79pp.

(47) Kolesnikov, A.; Rai, R.; Shrader, W. D.; Torkelson, S. M.; Wesson, K. E.;
Young, W. B.; (Axys Pharmaceuticals, Inc., USA). Application: W0
W0, 2004, p 119 pp.

(48) Ishiyama, T.; Murata, M.; Miyaura, N. Journal of Organic Chemistry
1995, 60, 7508-7510.

89

(49) Clayden, J.; Menet, C. J. Tetrahedron Letters 2003, 44, 3059-3062.

(50) Jaroch, S.; Holscher, P.; Rehwinkel, H.; Sulzle, D.; Burton, G.; Hillmann,
M.; McDonald, F. M. Bioorganic & Medicinal Chemistry Letters 2002, 12, 2561-2564.

(51) Lysen, M.; Hansen, H. M.; Begtrup, M.; Kristensen, J. L. Journal Of
Organic Chemistry 2006, 71, 2518-2520.

(52) Tan, W.; Zhang, D. Q.; Wang, Z.; Liu, C. M.; Zhu, D. B. Journal of
Materials Chemistry 2007, 17, 1964-1968.

(53) Cui, J. R. J.; Araldi, G. L.; Reiner, J. E.; Reddy, K. M.; Kemp, S. J.; Ho, J.
2.; Siev, D. V.; Mamedova, L.; Gibson, T. S.; Gaudette, J. A.; Minami, N. K.; Anderson,
S. M.; Bradbury, A. E.; Nolan, T. G.; Semple, J. E. Bioorganic & Medicinal Chemistry
Letters 2002, 12, 2925-2930.

(54) Isomer distributions for diborylation where the BPin group does not affect
selectivity were calculated as follows. For 4-cholorbenzonitrile, borylation ortho to CN
vs. Cl is favored by a factor of 4, giving the 2-borylated isomer as the major product. In
the second borylation, selectivity ortho to CN is lowered by half because there are two
H's ortho to Cl and only one H ortho to CN in the monoborylated product. Applying
analogous arguments to the other monoborylated isomer, the percentages of 2,6—, 2,5-,
and 3,5-diborylated isomers can be calculated as 54%, 44%, and 2%, respectively. Isomer
ratios for the other substrates in Table 3 were calculated similarly.

(55) The experiment in Eq 2.2 was performed through the reaction of benzene
with 1.2 equivalents of HBPin in thf in the presence of Ir catalyst. The first equivalent of
borane generates PhBPin in situ and the remaining 0.2 equivalents give the diborylated
isomers.

(56) Tucker, C. B; Davidson, J.; Knochel, P. Journal of Organic Chemistry
1992, 57, 3482-3485.

(57) Uson, R.; Oro, L. A.; Cabeza, J. A. Inorganic Syntheses 1985, 23, 126-30.

(58) Stott, K.; Stonehouse, J.; Keeler, J.; Hwang, T. L.; Shaka, A. J. Journal of
the American Chemical Society 1995, 117, 4199-4200.

(59) Ishiyama, T.; Ishida, K.; Miyaura, N. Tetrahedron 2001, 57, 9813-9816.

90

(60) Tse, M. K.; Cho, J. Y.; Smith, M. R. Organic Letters 2001, 3, 2831-2833.

91

CHAPTER 3
Iridium Catalyzed Borylation of Substituted Thiophenes
Introduction

Thiophenes are an important class of five membered heterocycles. Substituted
thiophenes have found applications in several research areas such as natural product
synthesis, drug design, and material science.l Apart from ring closure protocols, direct
functionalizations of thiophene nucleus by electrophillic aromatic substitution,
halogen-metal exchange, and directed ortho metalation have traditionally been used to
synthesize poly-substituted thiophenes. These methods have certain limitations.
Electrophillic substitution usually takes place at the 2- and/or 5-position and is also
affected by the presence of a directing group, while the metalation approaches have
limited functional group tolerances.

Organoboranes are versatile organic intermediates. They have extensively been
employed in Suzuki cross-coupling reactions.2 The C-B bond has also been used to
introduce a wide variety of functional groups by substitution reactions.3 Apart from their
use as nucleophillic coupling partner in the Suzuki reaction, thiopheneboronic acids and
esters have also been used in diverse areas of research including organic electronics}6
preparation of radiolabeled compounds,7 as inhibitors,8 polymers,9 and sensing
materials. '0

Thiophene boronic acids have traditionally been prepared from organomagnesium
or lithium reagents. 2-Thiopheneboronic acid was firstly prepared by Krause and
Pomeranz in 1932 by the reaction of 2-thienylmagnesium bromide with boron

trifluoride.ll Later, Johnson et al. replaced boron trifluoride with trialkyl borate.l2 In

92

1957, 3-thiopheneboronic acid was prepared from 3-thienylmagnesium bromide and
trialkyl borate.I3 Due to the requirement of pregeneration of organometallic reagents
under cryogenic conditions, this methodology had limited functional group tolerance.
Transition metal catalyzed borylation of aryl and heteroaryl halides, introduced by
Miyaura in 1995, allowed the presence of broad range of functional groups.”'7 However,
a C—Halogen bond was still a prerequisite for introduction of boronic acid functionality.
In 1999, Iverson and Smith reported the first thermal catalytic aromatic C—H
activation borylation.l8 This method bypassed the need of C—Halogen bond for the
formation of C-B bond. The selectivity and activity of the catalyst system has been
improved over the years.”23 Now this system has become one of the most convenient
methodology for the selective, direct C—H functionalization of aromatic hydrocarbons.
Sterically governed regioselectivities in this protocol are complementary to those found

6
25‘2 approaches.

in electrophillic aromatic substitution24 and directed ortho metalation
Apart from aromatics, five and six membered heterocycles can also be borylated.

The application of this new methodology to the heteroaromatic systems was
firstly demonstrated by Cho and Smith in 2000,'9 when 2,6-di-methylpyridine was
regioselectively borylated on the 4-position. In 2001, Tse and Smith reported that
N-TIPS-pyrrole, a five membered heterocycle, could be selectively borylated on the
3-position.2| With more improved catalysts, selective C—H borylation of halogenated
heteroaromatic substrates was also achieved.20 In 2002, Miyaura and Hartwig reported
that five membered heterocycles could be selectively borylated on the 2-position.27 In

2005, we showed that 2,5-di-substituted five membered heterocycles could be borylated

on the 3--position.28 Borylation in more complex systems such as corrole29 and

93

porphyrins30 has also been reported. In 2006, we have reported the regioselective
borylation of 2-substituted indoles and benzofuran on the 7-position.3 '

Considering the importance and need for the ready availability of
polyfunctionalized thiophenes, we decided to study the iridium catalyzed C—H borylation
of substituted thiophenes. Herein, we describe our results on the borylation of mono-, di-,
and tri-substituted thiophenes.

Results and Discussion

2-Substituted thiophenes were borylated with Pinacolborane (HBPin) using 3 mol
% [Ir(OMe)COD]2/dtbpy catalyst loading at room temperature (Scheme 3.1). Typically,
borylation was complete within 1 h and the 5-borylated products were isolated in 82-97%
yields (Table 3.1). Apart from common functionalities in iridium catalyzed borylation
such as ester, alkoxy, chloro, and iodo, additional functional group tolerance to acyl
(COMe), and trimethylsilyl (TMS) groups was also observed. 2,3-Di-halo-substituted

thiophene (Table 1, entry 7) was also cleanly borylated under these conditions.

Scheme 3.1. Monoborylation of 2-substituted thiophenes.

1.2-1.5 equiv HBPin,

 

R S 1.5 mol% [lr(OMe)(COD)]2, L R S BPin
U 3 mol% dtbpy ' U
hexanes,nt

94

Table 3.1. Monoborylation of 2-substituted thiophenes according to scheme 3.1.

 

 

Entry Thiophene HBPin Time (h) Product %yield
equiv
S s .
Cl Cl BPin
1 1.2 0.25 7
U U 9
3.1
S S -
I I BPin
2 1.5 1 92
U U
3.2
S 3 .
MeO MeO BPin
3 1.2 1 2
U U 8
3.3
MeOC S MeOC S BPin
4 1.2 0.5
U U 85
3.4
S S -
5 M902C 1'5 05 M9020 BPIn 94
\ / \ /
3.5
S S -
TMS TMS BPin
6 1.5 0.5 93
U U
3.6
S s .
Cl CI BPin
7 1.5 0.20 78
m m
Br Br

3.7

 

The case becomes slightly complicated for 3-substituted thiophenes since there
are two open positions adjacent to the heteroatom that can potentially be borylated as
shown in Scheme 3.2. The regioselectivities observed in monoborylation of 3-substituted

thiophenes are shown in Table 3.2.

Scheme 3.2. Monoborylation of 3-substituted thiophenes.

 

1 equiv HBPin,
2 e uiv S 1.5 mol% “((OMGXCODMgé S BPin PinB S
q S\ /l 3 mol% dtbpy, 7 g + m
R hexanes, r.t. R R

3.xa 3.xb

95

Table 3.2. Monoborylation of 3-substituted thiophenes according to scheme 3.2.

 

 

Entry Thiophene Products Isomer Ratio %yield
a b 3.xa:3.xb
S 3 BPin PinB S
1 S\ /l g m 47:53 54
NC NC NC
3.8a 3.8b
S 3 BPin PinB S
2 S\ /l \ / m 78:22 66
Cl Cl Cl
3.9a 3.91)
S S BPin PinB S
3 §\ /7 \ / X] 89:11 72
Br Br Br
3.10a 3.10!)
S S BPin PinB S
4 S\ /l \ / \ / 89:11 67
Me Me Me
3.11a 3.111:
S S BPin
5 S\ /l \ / — >99:1 82
MeOC MeOC
3.12a
S S BPin
6 S\ /l \ / — >99:1 95
MGOZC M602C
3.138
S S BPin
7 S\ /l \ / — >99:1 79
TMS TMS
3.143
3 3 BPin PinB S
8 S\ /l g \ / 97:3 74
p-tolyl p-tolyl p-tolyl
3.153 3.15b

 

96

For smaller substituents such as chloro, bromo, and methyl, mixtures of two
borylated regioisomers were observed. The major product observed for these substrates
was the 5-borylated isomer (3.xa). The presence of small amounts of borylated isomer at
the 2-position indicates that the steric effects of ortho substituents decrease for 5-
membered rings relative to 6-membered rings.

In the case of 3-cyanothiophene, the ratio of 5- and 2-boryalted isomers was 47:53
respectively. This was surprising as we expected 5-borylated isomer to be the major
product. One possible explanation could be that the electron withdrawing inductive effect
of the 3-cyano group on the 2-position makes its C—~H bond more activated as compared
to the 5-position. The small steric demand of the cyano group and wider bond angles in a
5-membered ring may also facilitate borylation at the 2-position. Christophersen has
reported the preparation of the 2-borylated isomer by Pd catalyzed borylation of
2-bromo-3-cyanothiophene.l5 In their case, although the borylated product was formed in
45% yield based on NMR, all attempts to isolate the product failed due to complete
deborylation during aqueous workup. No such deborylation was observed in our case and
the product mixture was isolated in 54% yield.

For sterically bulky substituents, such as ester, acyl, and trimethylsilyl (TMS), a
single monoborylated isomer was observed. 3-Phenyl substitution also gives 97%
regioselectivity for the 5-borylated isomer without borylation of the phenyl ring. Good to
excellent regioselectivities for the 5-position in 3-substituted thiophenes observed here

are consistent with sterically directed aromatic borylation and silylation.32

97

Scheme 3.3. Monoborylation of 2,5-di-substituted thiophenes.

1.5-2 equiv HBPin,

 

R‘ S 92 1.5moI°/o[Ir(OMe)(COD)]g, t R‘ S R2 R‘ S R2
U 3 mol% dtbpy, U + U
hexanes, r.t. PinB BPin
3.xa 3.xb

Next we examined the borylation of 2,5-di-substituted thiophenes (Scheme 3.3
and Table 3.3). There is only one borylated product regioisomer possible for symmetrical
substrates. Complications were observed for electron-deficient as well as electron-rich
thiophenes for different reasons. Borylation of 2,5-di-chlorothiophene slows down after
initial rapid conversion, accompanied by precipitation of brown particles suggesting the
decomposition of catalyst. Nevertheless the conversion was complete in 20 h and the
product was isolated in 86% yield. The borylation of 2,5-di-bromothiophene was more
problematic, and only 89% conversion of the substrate was observed after 48 h at room
temperature with 9 mol% [Ir] catalyst loadings. The monoborylated product was isolated
in 56% yield. The reason for reduced catalytic activity after rapid initial conversion
could be that the C—halogen bonds in these cases are weak, and may compete with the
desired C-—H activation. Attempted catalytic borylation of electron-rich 2,5-di-
methylthiophene using the [Ir(OMe)(COD)]/dtbpy system at room temperature was also
very slow. Reduced activity due to electron rich behavior in this case was over come by
using (Ind)Ir(COD)/dmpe system at 150 °C and the monoborylated product was isolated

in 97% yield.

98

Table 3.3. Monoborylation of 2,5-di-substituted thiophenes according to scheme 3.3.

 

 

Entry Thiophene %[Ir] Time Products Isomer Ratio %yield
(h) 3 b 3.x323.xb
S S
Cl CI Cl CI
1 3 20 - — 86
U U
PinB
3.16
Br 3 Br Br 3 Br
2 9 48 - — 56
U W
PinB
3.17
S 8
Me Me Me Me
3 2 16 — — 97
U U
PinB
3.18
S S S
Cl Br Cl Br Cl Br .
4 6 28 67.33 87
U m x /
PinB BPin
3.193 3.1%
Cl 3 I Cl 3 I Cl 3 I .
5 3 20 85.15 89
U V \/
PinB BPin
3.203 3.20b
CI 3 Me CI 3 Me Cl 3 Me .
3 18 70.30 86
6 U U \ /
PinB BPin
3.213 3.21b
CI 3 TMS Cl 3 TMS .
7 3 6 _ 99.1 93
v V >
PinB
3.223
Me 8 Me
CI 5 Cl
3 12 — — -
8 \ / o \ / o
PinB
3.233
8 Me S Me
Br Br
9 3 12 - — —
\ / 0 \ / O
PinB
3.243

 

99

Unsymmetrical 2,5-disubstituted thiophenes yielded regioisomeric mixtures of
two monoborylated products (Table 3.3). The borylation takes place preferentially ortho
to the less bulky substituents. When the steric demands of the two substituents are
sufficiently different, as in the case of 2-chloro-5-trimethylsilylthiophene, a single
monoborylated product can be obtained in 93% yield. Attempted borylations of
2-chloro-5-acetyl thiophene and 2-bromo-5-acetyl thiophene were unsuccessful and the
reactions usually stopped after ~10% conversion. It is worthwhile to mention here that
borylation in small 5-membered heteroaromatic substrate such as 2-acetyl-5-methyl-furan
went to full conversion in 16 h (with 97:3 regioselectivity).

High regioselectivity of borylation for 2-chloro-5-trimethylsilylthiophene
prompted us to examine the diborylation of 2-substituted thiophenes. We reasoned that
since the BPin group attached to the 5-position via monoborylation is significantly
bulkier than the 2-substituent, the second borylation should regioselectively take place at
the 3-position. Indeed, diborylation of several 2-substituted thiophenes was found to be

highly regioselective (Scheme 3.4 and Table 3.4).

Scheme 3.4. Diborylation of 2-substituted thiophenes.

2.5-3 equiv HBPin,

 

R S 1.5 mol% [Ir(OMe)(COD)]z, ‘ R S BPin
U 3 mol% dtbpy, 7 U
hexanes, r.t. PinB

100

Table 3.4. Diborylation of 2-substituted thiophenes according to scheme 3.4.

 

 

Entry Thiophene HBPin Time (h) Product %yield
equiv
NC 3 NC 3 BPin
1 3 1
U U ..
BPin
3.25
S s .
Cl CI BPIn
2 . 1
BPin
3.26
Br 3 Br 3 BPin
3 2.5 12 92
U U
BPin
3.27
S s .
Me Me BPin
4 3 72
U m 9°
BPin
3.28
MeO S MeO S BPin
5 3 48 89
U \ /
BPin
3.29
S s .
TMS TMS BPin
6 3 72 —
U 82
BPin
3.303+3.30b
O S O S
BPin _
7 MeO \ / 3 36 MeOHIT
BPin
3.313+3.31b

 

The two boronic ester groups in these 3,5-diborylated thiophenes are chemically

different. It might be possible that various C-B bond transformations, such as protolytic

deborylation, fluorination, chlorination, bromination, iodination, cyanation, sulfonation,

101

Suzuki coupling etc., could selectively be carried out on the 5-BPin group, leading to new
3-BPin thiophene boronic esters as single regioisomers.

In the cases of 2-methyl thiophene and 2-methoxy thiophene, small amounts
(1.5-1.6% by GC-F ID) of a minor diborylated isomer were also observed. The GC-FID
retention times of these minor diborylated isomers were different from those observed for
diborylated products derived from 3-methyl/methoxy substituted thiophenes. Therefore
the minor diborylated isomers observed for 2-methyl/methoxy substituted thiophenes
could either be 4,5-diborylated or methyl/methoxy borylated products.

Attempted diborylation of 2-trimethylsilyl thiophene resulted in only 12%
diborylation (by GC-FID) after 72 h at 60 °C. Similarly, attempted diborylation of
methyl-2-thiophene carboxylate resulted in only 7% diborylation (mixture of two isomers
in 63:37 ratio by GC-FID) after 36 h at room temperature. These results suggest that
diborylation of 2-substituted thiophenes is only feasible when the 2-substituent is
relatively small. It is important to mention here that diborylation in small 5-membered
heterocyclic substrate such as methyl-2-furan-carboxylate did went to full conversion at
room temperature in 24 h to give two regioisomeric diborylated products. Hence
borylation ortho to bulky substituents such as BPin and ester is feasible in furans.

3-Substituted thiophenes can also be diborylated at 2- and 5-positions when the
3-substituent is nitrile, chloro, bromo, methyl, and p-tolyl (Scheme 3.5 and Table 3.5).
3-Trimethylsilyl thiophene went to only 18% diborylation after 48 h at 60 °C, while
attempted borylation of 3-acetyl thiophene with 3 equivalents of HBPin resulted in

reduction of the carbonyl group during diborylation.

102

It is worthwhile to note that during attempted diborylation of 2- and
3-trimethylsilyl thiophenes, formation of small amounts of BzPinz was observed from
HBPin. Since the C—H activation step during these attempted diborylations is highly
inhibited due to sterics; the side reaction of dehydrodimerization of HBPin becomes
significant. Marder has also observed the dehydrodimerization of HBPin to BzPinz during

benzylic borylation using [RhCl(P'Pr3)2(N2)] precursor catalyst.33

Scheme 3.5. Diborylation of 3-substituted thiophenes.

2.5-3 equiv HBPin,

 

S 1.5 mol% [Ir(OMe)(COD)]g, # pinB S 3pm
9 3 mol% dtbpy, , W
R hexanes, r.t. B

103

Table 3.5. Diborylation of 3-substituted thiophenes according to scheme 3.5.

 

Entry Thiophene HBPin Time (h) Product %yield
equw

 

2.5 0.5 BPin 3P1” 3.32 85

Z
O
/
U”
\
/
by)
\

S - S -
BPin BPin
2 2.5 1 3.33 91
§\ /7 V
Cl CI
3 BPin S BPin
3 2.5 1 . 9
S\ /7 V 334 5
Br Br
S - S -
BPin BPin
4 3 6 3.35 77
§\ /7 W
Me Me
8 - S -
BPin BPin
5 2.3 16 3.36 61
§\ /7 W
p-tolyl p—tolyl
S - S -
BPin BPin
6 3 48 3.37 —
U U
TMS TMS
. s .
24 BPin BPin 3.38 _

Me

\I
g
(D
OTC
CD
\
co
0 /
\

In 2,3,5-tri substituted thiophenes the 4-position is locked between two ortho
substituents. Since the bond angles in 5-membered heterocycles are wider than those in
6-memebered rings, we thought that the 4-position in 2,3,5-tri substituted thiophenes
might be accessible for borylation. However, only about 2% borylation was observed for
3-bromo-2,S-di-methylthiophene (3.39) under room temperature conditions using

[Ir(OMe)(COD)]z and dtbpy. The outcome was the same with (Ind)Ir(COD) and dmpe at

104

150 °C. Apart from steric hindrance for borylation, the electron-rich nature of
3-bromo-2,5-di-methylthiophene could also be responsible for this low reactivity.
Borylation of 3-bromo-2,5-di-chlorothiophene (3.40), an electron deficient substrate, was
attempted using [Ir(OMe)(COD)]2 and dtbpy at room temperature. The borylation stalled
after about 5% conversion. The borylation of this substrate was also tested using
(Ind)Ir(COD) and dmpe at 150 °C. The result was surprising as the single product
obtained in 73% isolated yield was found to be 3-bromo-2-chloro-5-

(4,4,5,5—tetramethyl— l ,3,2-dioxaborolane-2-yl)-thiophene 3.7 (Figure 3.1).

 

1.5 equiv HBPin, .
C' 8 CI 2.0 mol% (Ind)Ir(COD) 0' 8 BP'”
\ / 2.0 mol% dmpe \ / 73 %
Br 150 °C. 2 h ' Br
3.40 3.7

Figure 3.1. Attempted borylation of 3-bromo-2,5-di-chloro thiophene.

The product obtained here was found to be identical to one obtained by borylation
of 3-bromo-2-chloro thiophene (Table 1, entry 7). The result was interesting for several
reasons. Firstly, instead of a CH bond, a C—Cl bond is activated by the Iridium catalyst.
Secondly, the C—Cl bond was activated in preference to the C-Br bond. Finally, of the
two C—Cl bonds, the sterically more accessible chloride was selectively substituted.

At least two pathways could account for the observed product. The first involves
oxidative addition of C—Cl bond followed by reductive elimination of C—B bond. Another
possibility is first reduction of C—Cl bond to C—H bond followed by rapid borylation. The
mechanism of this reaction needs to be fully investigated.

Since 2,3,5-trisubstituted thiophenes could not be borylated to synthesize

tetra-substituted thiophenes, we looked for other possible routes for the desired final

105

product. Borylation of 2,5-di substituted thiophene (Table 3.3) followed by bromination
could also give the desired product. Although electrophillic aromatic C—H bromination of
aryl boronic esters (to synthesize brominated aryl boronic esters) is unknown, there are
examples where aryl/heteroaryl boronic acid have been brominatedu‘”35 We were
successful in brominating 2,5-dimethyl-3-(4,4,5,S-tetramethyl-l,3,2-dioxaborolane-2-yl)-
thiophene (3.18) using one equivalent of Brz in CHCl3 and the mono brominated product
3-bromo-2,5-dimethyl-4-(4,4,5,5-tetramcthyl-1,3,2—dioxaborolane-2-yl)-thiophene (3.41)
was isolated in 82% yield (Figure 3.2). Slight excess of bromine results in the

bromination of methyl groups (without any displacement of the BPin group) and hence

 

should be avoided.
Me 3 Me Me 3 Me
U Brzr CHCla t W 82 0/0
room temp, 2 min
PinB PinB Br
3.18 3.41

Figure 3.2. Bromination of thiophene boronic ester.

Attempted bromination of 2,5-di-chloro-3-(4,4,5,5-tetramethyl— l ,3,2-
dioxaborolane-Z-yl)-thiophene (3.16) with Br; in CHCI3 was ineffective even after 24 h at
100 °C. Bromination with NBS in acetonitrile36 resulted in mixture of products including
BPin substitution with Br (3.40) along with the desired C—H brominated product (3.42).

During our search for different routes for the desired tetra-substituted thiophene
product of this substrate, we found that the 2-trimethylsilyl group can easily be replaced

with Br using NBS in acetonitrile (Figure 3.3).

106

Cl 5 TMS
\ /

PinB
3.223

Cl 3 TMS
\ /
Me
3.43

NBS, acetonitrile

 

 

+ \ / 91%
room temp, 12 h .
PinB
3.193
NBS.acetonitrile 0' 5 Br
= \ / 91%
room temp, 12 h
Me
3.44

Figure 3.3. Substitution of trimethylsilyl group with bromine.

As mentioned earlier, catalytic borylation of 2-chloro-5-bromothiophene gave a
mixture of 3- and 4-borylated isomers in 67:33 ratio (3.193 and 3.19b, Table 3.3). Pure
3-borylated isomer 3.193 can be obtained by bromination of 2-chloro-3-BPin-5-
trimethylsilylthiophene 3.223 in 91% yield as shown in Figure 3.3. Trimethylsilyl group

in 2-chloro-3-BPin-5-trimethylsilylthiophene 3.223 was selectively substituted with

bromine under these conditions while keeping the BPin group completely intact.

107

The intermediate thiophene boronic esters can be employed in subsequent Suzuki

coupling without isolation as shown in Figure 3.4.

1. 1.5 equiv HBPin, 3.0 mol% dtbpy.
1.5 mol% [Ir(OMe)(COD)]g.

S hexanes, 25 °C, 0.5 h S
Mem 2. Pump down, 0.5 h Me \ / CF
3. 1.2 equiv 3-bromobenzotrifluorid; 3

2 mol% Pd(PPh3)4, 85 %
1.5 equiv K3PO4-nH20, 80 °C. 8 h 3 45

 

1. 1.5 equiv HBPin, 3.0 mol% dtbpy.
1.5 mol% [Ir(OMe)(COD)]z.
hexanes, 25 °C, 10 h

S S
CIUTMS 2. Pump down, 1 h Cl \ / TMS

3. 1.2 equiv 3-bromotoluene,
2 mol% Pd(PPh3)4,
1.5 SQUIV K3PO4'UH20, 61 0/0
80 C, 6 h 3.43
Me

Figure 3.4. One-pot borylation Suzuki coupling of thiophenes.

Conclusion

In conclusion, a variety of borylated di-, tri-, and tetra-substituted thiophenes have
been prepared by iridium catalyzed aromatic borylation. Under appropriate conditions,
selective electrophillic aromatic C—H bromination can be carried out on the thiophene
boronic esters. Further studies regarding Suzuki coupling with heteroaryl halides,
borylation of Suzuki coupled thiophenes, and electrophillic aromatic substitution
(bromination, nitration, etc) of aryl/heteroaryl boronic esters needs to be extensively

explored.

108

Experimental Details and Spectroscopic Data
Materials

Bis(r)4-1,5-cyclooctadiene)-di-,u-methoxy-diiridium(I) [Ir(OMe)(COD)]2 and
(nS-indenlecyclooctadiene)iridium(l) {(Ind)Ir(COD)} were prepared per the literature
procedures.”38 Pinacolborane (HBPin) was generously supplied by BASF and was
distilled before use. All commercially available chemicals were purified before use. Solid
substrates were sublimed under vacuum. Liquid substrates were distilled before use.
n-Hexane was refluxed over sodium, distilled, and degassed. Dimethoxy ethane (DME),
ether, and tetrahydrofuran were obtained from dry stills packed with activated alumina
and degassed before use. Silica gel (230—400 Mesh) was purchased from EMD I".

Regioisomer assignment of borylation products by IH NMR spectroscopy.

H S BPin PinB 3 H
meta coupling W W ortho coupling
0.7-1.2 Hz B H R H 4.5-5.0 Hz
3 b

From the lH NMR coupling constant J, the two regioisomer products obtained by
the borylation of 3-substituted thiophenes can be distinguished unambiguously. In case of
the 2,4-borylated product, the value of the four-bond (meta) coupling constant UH-” is
usually around 0.7-1.2 Hz. While in case of the 2,3-borylated product, the value of the
three-bond (ortho) coupling constant 3JH~H is usually around 4.5-5.0 Hz. Since these two
ranges of coupling constants are quite far apart, the two regioisomers can easily be
distinguished by the value of lH NMR coupling constant.

The regioisomeric assignments of borylated products of unsymmetrical 2,5-di-

substituted thiophenes are based on lH NMR Chemical shifts of the methine protons.

109

Syntheses of Substrates

a. 2-Trimethylsilylthiophene.

mew
2-Trimethylsilylthiophene was prepared per the literature procedure.39 The
product was isolated as colorless oil (31-33 °C at 0.01 mm Hg, 2.62 g, 56% yield). 1H
NMR (CDCI3, 500 MHz): 6 7.58 (dd, J= 4.6, 0.8 Hz, 1 H), 7.25 (dd, J= 3.3, 0.8 Hz, 1
H), 7.17 (dd, J= 4.6, 3.3, Hz, 1 H), 0.31 (s, 9 H, CH3 of TMS); 13C NMR {1H} (CDC13,
125 MHz): 6 140.1 (C), 133.9 (CH), 130.4 (CH), 128.1 (CH), -0.01 (3 CH3 of TMS).

b. 3-Trimethylsilylthiophene.

S

Q

TMS

3-Trimethylsilylthiophene was prepared per the literature procedure.40 The
product was isolated as colorless oil (34 °C at 0.01 mm Hg, 1.77 g, 57% yield). lH NMR
(CDCI3, 500 MHz): 6 7.42 (dd, J = 2.6, 1.1 Hz, 1 H), 7.38 (dd, J = 4.8, 2.6 Hz, 1 H), 7.17
(dd, J= 4.8, 1.1 Hz, 1 H), 0.25 (s, 9 H, CH3 of TMS); 13C NMR {'H} (CDCI3, 125 MHz):
6 141.2 (C), 131.39 (CH), 131.37 (CH), 125.6 (CH), —0.6 (3 CH3 ofTMS).

c. 3-p-Tolylthiophene.

\/

Me

110

3-p-Tolylthiophene was prepared by the Suzuki coupling of 3-bromothiophene
and p-tolylboronic acid.41 The product was isolated as a white solid (629 mg, 90% yield).
1H NMR (CDCI3, 500 MHz): 6 7.47-7.50 (m, 2 H), 7.39-7.40 (m, 1 H), 7.37-7.36 (m, 2
H), 7.20-7.19 (m, 2 H), 2.36 (s, 3 H); 13C NMR {‘H} (CDCI3, 125 MHz): 6 142.3 (C),
136.8 (C), 133.1 (C), 129.4 (CH), 126.3 (2 CH), 126.0 (CH), 119.6 (CH), 21.1 (CH3).

(1. 2-Chloro-5trimethylsilylthiophene.

2-Chloro-5-trimethylsilylthiophene was prepared by following the literature
procedure for the synthesis of 2-bromo-5-trimethylsilylthiophene.42 The product was
isolated as colorless oil (56-57 °C at 0.01 mm Hg, 2.61 g, 69% yield). lH NMR (CDC13,
500 MHz): 6 6.98 (d, J= 3.5 Hz, 1 H), 6.93 (d, J= 3.5 Hz, 1 H), 0.27 (s, 9 H, CH3 of
TMS); 13C NMR {‘H} (CDCI3, 125 MHz): 6 140.2 (C), 134.5 (C), 133.3 (CH), 127.4
(CH), -0.3 (3 CH3 of TMS); FT-IR (neat) 17: 2959, 1415, 1251, 1205, 1072, 964, 841 cm'
I; GC-MS (EI) m/z (% relative intensity): W 190 (34), 192 (13), 175 (100); Anal. Calcd
for C7H11C1SSi: C, 44.07; H, 5.81. Found: C, 43.59; H, 5.90; HRMS (EI): m/z 190.0036

[M+; Calcd for C7H11CISSi: 190.0039].

111

Catalytic Borylation of Substituted Thiophenes
Borylation using d'bpy Ligand
General Procedure A (Monoborylation with heteroaromatic substrate as the
limiting reactant)

The [Ir] catalyst was generated by a modified literature protocol,43 where in a
glove box, two separate test tubes were charged with [Ir(OMe)(COD)]z (10 mg, 0.015
mol, 3 mol% Ir) and dtbpy (8 mg, 0.03 mol, 3 mol%). Excess HBPin (1.5 to 2 equiv)
was added to the [Ir(OMe)(COD)]z test tube. n-Hexane (1 mL) was added to the d’bpy
containing test tube in order to dissolve the dtbpy. The d'bpy solution was then mixed
with the [Ir(OMe)(COD)]z and HBPin mixture. After mixing for one minute, the resulting
solution was transferred to the 20 mL scintillation vial equipped with a magnetic stirring
bar. Additional n-hexane (2 x 1 mL) was used to wash the test tubes and the washings
were transferred to the scintillation vial. Substituted thiophene (1 mol, 1 equiv) was
added to the scintillation vial. The reaction was stirred at room temperature and was
monitored by GC-FID/MS. After completion of the reaction, the volatile materials were
removed on a rotary evaporator. The crude material was dissolved in CHzClz and passed
through a short plug of silica to afford the corresponding borylated product.
General Procedure B (Monoborylation with HBPin as the limiting reactant)

In a glove box, two separate test tubes were charged with [Ir(OMe)(COD)]z (10
mg, 0.015 mol, 3 mol% Ir) and dtbpy (8 mg, 0.03 mol, 3 mol%). HBPin (1 mol, 1
equiv) was added to the [Ir(OMe)(COD)]z test tube. n-Hexane (1 mL) was added to the
d'bpy containing test tube in order to dissolve the dtbpy. The dtbpy solution was then

mixed with the [Ir(OMe)(COD)]2 and HBPin mixture. After mixing for one minute, the

112

resulting solution was transferred to the 20 mL scintillation vial equipped with a
magnetic stirring bar. Additional n-hexane (2 x 1 mL) was used to wash the test tubes
and the washings were transferred to the scintillation vial. Excess 3-substituted thiophene
(2-4 equiv) was added to the scintillation vial. The reaction was stirred at room
temperature and was monitored by GC-FID/MS. After completion of the reaction, the
volatile materials were removed on a rotary evaporator. The crude material was dissolved
in CH2C12 and passed through a short plug of silica to afford the corresponding borylated
isomeric mixture.
General Procedure C (Diborylation)

General procedure A was applied with 2.5-3 equivalents of HBPin.
Borylation with Phosphine Ligand
General Procedure D

In a glove box, (Ind)Ir(COD) (8.3 mg, 0.02 mmol, 2.00 mol% Ir) and dmpe (3
mg, 0.02 mmol, 2.00 mol%) were weighed in two separate test tubes. HBPin (218 11L,
190 mg, 1.50 mmol, 1.50 equiv) was added to the dmpe test tube and the resulting
solution was than mixed with (Ind)Ir(COD). This catalyst solution was added to a
Schlenk flask equipped with a magnetic stirring bar. Substituted thiophene (1 mol, 1
equiv) was added to the Schlenk flask. The Schlenk flask was closed, brought out of the
glove box, and was heated at 150 °C in an oil bath. The reaction was monitored by
GC-FID/MS. After completion of the reaction, the volatile materials were removed on a
rotary evaporator. The crude material was dissolved in CHzClz and passed through a short

plug of silica to afford the corresponding borylated product.

113

Table 3.1. Monoborylation of 2-substituted thiophenes
Table 3.1, Entry 1. 2-(5-chlorothiophen-2-yl)-4,4,5,5-tetramethyl-1,3,2-

dioxaborolane (3.1).

Cifiepin
3.1

The general procedure A was applied to 2-chlorothiophene (184 uL, 236 mg, 2
mmol, 1 equiv) and HBPin (348 (1L, 307 mg, 2.40 mmol, 1.20 equiv) for 15 minutes. The
product was isolated as colorless oil (476 mg, 97% yield). lH NMR(CDC13, 500 MHz): 6
7.37 (d, J= 3.7 Hz, 1 H), 6.95 (d, J= 3.7 Hz, 1 H), 1.31 (br s, 12 H, 4 CH3 ofBPin); 13.C
NMR {1H} (CDCI3, 75 MHz): 6 136.8 (C), 136.7 (CH), 127.6 (CH), 84.3 (2 C), 24.7 (4
CH3 of BPin); 11B NMR (CDCI3, 96 MHz): 6 28.8; FT -IR (neat) 17: 2980, 2932, 1530,
1433, 1352, 1334, 1282, 1271, 1142, 1035, 852, 804, 663 cm"; GC-MS (BI) m/z (%
relative intensity): W 244 (100), 229 (17), 201 (21), 184 (17) 158 (12); Anal. Calcd for
C10H14BC1028: C, 49.11; H, 5.77. Found: C, 49.12; H, 5.98.
Table 3.1, Entry 2. 2-(5-iodothiophen-2-yl)-4,4,5,5-tetramethyl-1,3,2-diox3borolane

(3.2).

s .
IUBPm

3.2

The general procedure A was applied to 2-iodothiophene (111 uL, 210 mg, 1
mol, 1 equiv) and HBPin (218 uL, 192 mg, 1.50 mmol, 1.50 equiv) for 1 h. The
product was isolated as a white solid (310 mg, 92% yield, mp 48-49 °C). 1H NMR

(CDCI3, 500 MHz): 6 7.27 (d, J= 3.5 Hz, 1 H), 7.25 (d, J= 3.5 Hz, 1 H), 1.31 (br s, 12

114

H, 4 CH3 of BPin); 13C NMR {1H} (CDCI3, 125 MHz): 6 138.5 (CH), 138.3 (CH), 84.3
(2 C), 81.5 (C), 24.7 (4 CH3 of BPin); nB NMR (CDCI3, 96 MHz): 6 28.7; FT-IR (neat)
17m“: 2978, 2932, 1522, 1418, 1314, 1267, 1142, 1064, 1018, 853, 663 cm"; GC-MS
(BI) m/z (% relative intensity): M 336 (100), 321 (13), 250 (6), 236 (14), 209 (12), 167
(43); Anal. Calcd for C10H14B102S: C, 35.75; H, 4.20. Found: C, 36.04; H, 4.24.

Table 3.1, Entry 3. 2-(5-methoxythiophen-Z-yl)-4,4,5,5-tetramethyl-l,3,2-

dioxaborolane (3.3).

MeOfiBPin
3.3

The general procedure A was applied to 2-methoxythiophene (202 uL, 228 mg, 2
mmol, 1 equiv) and HBPin (348 uL, 307 mg, 2.40 mmol, 1.20 equiv) for 1 h. The
product was isolated as colorless oil (395 mg, 82% yield). lH NMR(CDC13, 500 MHz): 6
7.31 (d, J= 3.8 Hz, 1 H), 6.28 (d, J= 3.8 Hz, 1 H), 3.89 (s, 3 H, OCH3), 1.31(br s, 12 H,
4 CH3 of BPin); 13C NMR {‘H} (CDCI3, 125 MHz): 8 172.8 (C), 136.5 (CH), 106.1
(CH), 83.8 (2 C), 60.4 (OCH3), 24.7 (4 CH3 of BPin); ”B NMR (CDCI3, 96 MHz): 8
29.0; FT-IR (neat) V: 3084, 2978, 2934, 2870, 1549, 1483, 1423, 1365, 1302, 1213,
1143, 989, 854, 781, 684, 661 cm"; GC-MS (E1) m/z (% relative intensity): M+ 240
(100), 225 (5), 197 (12), 180 (18); Anal. Calcd for CHH17BO3S: C, 55.02; H, 7.14.

Found: C, 54.72; H, 7.60.

115

Table 3.1, Entry 4. 1-(5-(4,4,5,5-tetramethyl-l,3,2-diox3borolan-2-yl)thiophen-2-

yl)ethanone (3.4).

M 06 3 BP'
3 W In

3.4

The general procedure A was applied to 2-acetylthiophene (108 uL, 126 mg, 1
mol, 1 equiv) and HBPin (175 uL, 154 mg, 1.20 mmol, 1.20 equiv) for 0.5 h. The
product was isolated as a white solid (213 mg, 85% yield, mp 64-66 °C). 1H NMR
(CDCI3, 500 MHz): 6 7.69 (d, J: 3.8 Hz, 1 H), 7.54 (d, J= 3.8 Hz, 1 H), 2.53 (s, 3 H,
COCH3), 1.31 (br s, 12 H, 4 CH3 of BPin); 13C NMR {'H} (CDCI3, 125 MHz): 8 190.6
(C=O), 149.4 (C), 137.2 (CH), 132.6 (CH), 84.6 (2 C), 27.4 (COCH3), 24.7 (4 CH3 of
BPin); 11B NMR (CDC13, 96 MHz): 6 29.2; FT-IR (neat) 17: 2980, 2934, 1669, 1520,
1348, 1288, 1267, 1142, 1020, 852, 667 cm"; GC-MS (EI) m/z (% relative intensity): M
252 (77), 237 (100), 209 (15), 195 (8), 179(5), 166 (33), 153 (14) 137 (12) 109 (6); Anal.
Calcd for C12H17BO3S: C, 57.16; H, 6.80. Found: C, 56.88; H, 7.06.

Table 3.1, Entry 5. Methyl 5-(4,4,5,5-tetramethyI-l,3,2-dioxaborolan-2-yl)thiophene-

2-c3rboxylate (3.5).

MeOZC S BPin
U

3.5

The general procedure A was applied to methyl-2-thiophenecarboxylate (116 uL,
142 mg, 1 mol, 1 equiv) and HBPin (192 uL, 218 mg, 1.50 mmol, 1.50 equiv) for 0.5 h.
The product was isolated as a white solid (252 mg, 94% yield, mp 114-117 °C). 1H NMR

(CDCI3, 500 MHz): 8 7.79 (d, J= 3.7 Hz, 1 H), 7.53 (d, J= 3.7 Hz, 1 H), 3.87 (s, 3 H,

116

C02CH3), 1.33 (br s, 12 H, 4 CH3 of BPin); 13C NMR {'11} (CDCI3, 125 MHz): 8 162.6
(C=O), 139.4 (C), 136.9 (CH), 133.9 (CH), 84.6 (2 C), 52.2 (COZCHg), 24.7 (4 CH; of
BPin); “B NMR (CDC13, 96 MHz): 8 29.1; FT-IR (neat) 9; 2970, 1719, 1527, 1354,
1248, 1145, 1097, 852, 832, 752, 665 cm}; GC-MS (EI) m/z (% relative intensity): M
268 (71), 253 (91), 237 (56), 182 (100); Anal. Calcd for C12H17BO4S: C, 53.75; H, 6.39.
Found: C, 53.44; H, 6.44.

Table 3.1, Entry 6. Trimethyl(5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-

yl)thiophen-2-yl)silane (3.6).

TMSWBPM
3.6

The general procedure A was applied to 2-trimethylsilylthiophene (312 mg, 2
mol, 1 equiv) and HBPin (435 11L, 384 mg, 3.00 mmol, 1.50 equiv) for 0.5 h. The
product was isolated as a white solid (523 mg, 93% yield, mp 61-62 °C). 1H NMR
(CDCI3, 500 MHz): 8 7.67 (d, J= 3.3 Hz, 1 H), 7.31 (d, J= 3.3 Hz, 1 H), 1.32 (br s, 12
H, 4 CH3 of BPin), 0.30 (s, 9 H, 3 CH3 of TMS); 13C NMR {'H} (CDCI3, 75 MHz): 8
148.4 (C), 137.8 (CH), 135.0 (CH), 84.0 (2 C), 24.8 (4 CH3 of BPin), —0.1 (3 CH3 of
TMS); “B NMR (CDCI3, 96 MHz): 8 29.6; FT-IR (neat) v; 3054, 2980, 2957, 1514,
1435, 1346, 1331, 1259, 1250, 1142, 1072, 981, 841, 821, 758, 699 cm"; GC-MS (El)
m/z (% relative intensity): M+ 282 (14), 267 (100), 239 (31), 167 (8); Anal. Calcd for
C13H23B0288i: C, 55.31; H, 8.21. Found: C, 54.85; H, 8.74; HRMS (BI): m/z 282.1285

[(M); Calcd for C13H23B02SSi: 282.1281].

117

Table 3.1, Entry 7. 2-(4-bromo-5-chlorothiophen-2-yl)-4,4,5,5-tetramethyl-1,3,2-
dioxaborolane (3.7).
Cl 3 BPin
V

Br
3.7

The general procedure A was applied to 2-chloro-3-bromothiophene (110 (AL, 197
mg, 1 mol, 1 equiv) and HBPin (192 ML, 218 mg, 1.50 mmol, 1.50 equiv) for 10
minutes. The product was isolated as a white solid (253 mg, 78% yield, mp 60-61°C). IH
NMR(CDC13, 500 MHz): 8 7.38 (s, 1 H), 1.30 (br s, 12 H, 4 CH3 of BPin); 13C NMR
{1H} (CDCI3, 125 MHz): 6 138.9 (CH), 133.2 (C), 112.0 (C), 84.6 (2 C), 24.7 (4 CH3 of
BPin); 11B NMR (CDCI3, 96 MHz): 6 28.5; FT-IR (neat) 17: 2980, 2932, 1523, 1425,
1340, 1267, 1142, 1041, 852, 661 cm"; GC-MS (E1) m/z (% relative intensity): M+ 324
(100), 322 (73), 309 (45), 281 (26), 264 (29), 243 (38); Anal. Calcd for CroHrgBBrClOzS:
C, 37.13; H, 4.05. Found: C, 37.20; H, 4.16.
Note: Attempted borylation of 2,5-dichloro-3-bromothiophene with borylation procedure
D also gave the same product where C-Cl bond was borylated and the single
monoborylated product was isolated in 73% yield (see attempted monoborylation of
tri-substituted thiophene). Only one of the two C-Cl bonds is activated with
chemoselectivity greater than 99%. The NMR data matched with the borylated product of

2-chloro-3-bromothiophene as described above.

118

Table 3.2. Monoborylation of 3-substituted thiophenes

Table 3.2, Entry 1. Borylation of 3-cyanothiophene (3.83 + 3.8b).

S BPin PinB 3
NC NC
47 53

3.88 3.8!)

The general procedure B was applied to 3-cyanothiophene (182 11L, 218 mg, 2.00
mmol, 2.00 equiv) and HBPin (145 uL, 128 mg, 1 mol, 1 equiv) for 1 h. The ratio of
two monoborylated products at the end of reaction was 47:53 by GC-FID. The
monoborylated product mixture was isolated as a white solid (126 mg, 54% yield). 1H
NMR (CDC13, 300 MHz): 6 (3.83) 8.13 (d, J= 1.2 Hz, 1 H), 7.75 (d, J= 1.2 Hz, 1 H),
1.33 (br s, 12 H, 4 CH3 of BPin), (3.8b) 7.62 (d, J= 4.9 Hz, 1 H), 7.38 (d, J= 4.9 Hz, 1
H), 1.36 (br s, 12 H, CH3 of BPin); 13C NMR {‘H} (CDCl3, 125 MHz): 8 (3.83) 140.8
(CH), 138.1 (CH), 114.7 (C), 111.9 (C), 85.1 (2 C), 24.7 (4 CH3 of BPin), (3.8b) 132.7
(CH), 131.3 (CH), 118.2 (C), 115.1 (C), 84.8 (2 C), 24.7 (4 CH3 of BPin); 11B NMR
(CDCI3, 96 MHz): 6 28.6; FT-IR (neat) 17: 2980, 2231, 1429, 1319, 1142, 1039, 850, 628
cm]; GC-MS (El) m/z (% relative intensity): (3.83) M+ 235 (7), 220 (100), 192 (9), 149
(37), 136 (15), (3.8b) M+1 236 (100), 220 (78), 194 (51), 178 (33), 149 (36), 136 (31);
Anal. Calcd for CHHMBNOZS: C, 56.19; H, 6.00; N, 5.96. Found: C, 55.74; H, 5.99; N,

6.00.

119

Table 3.2, Entry 2. Borylation of 3-chlorothiophene (3.93 + 3.9b).

3 BPin PinB 5
Cl Cl
78 22

3.98 3.9b

The general procedure B was applied to 3-chlorothiophene (186 uL, 237 mg, 2.00
mmol, 2.00 equiv) and HBPin (145 11L, 128 mg, 1 mmol, 1 equiv) for l h. The ratio of
two monoborylated products at the end of reaction was 78:22 by GC-FID. The
monoborylated product mixture was isolated as a white solid (160 mg, 66% yield). 1H
NMR(CDC13, 300 MHz): 6 (3.93) 7.43 (d, J = 1.0 Hz, 1 H), 7.35 (d, J = 1.0 Hz, 1 H),
1.32 (br s, 12 H, 4 CH3 of BPin), (3.9b) 7.51 (d, J= 5.0 Hz, 1 H), 7.01 (d, J= 5.0 Hz, 1
H), 1.34 (br s, 12 H, 4 CH3 of BPin); l3C NMR {'11} (CDCI3, 125 MHz): 8 (3.93) 136.9
(CH), 131.8 (C), 126.7 (CH), 84.4 (2 C), 24.7 (4 CH3 of BPin); “B NMR (CDCI3, 96
MHz): 6 29.0; FT-IR (neat) 17: 3107, 2980, 2932, 1522, 1421, 1356, 1336, 1142, 1026,
854, 665cm'l; GC-MS (EI) m/z (% relative intensity): M+ 244 (100), 246 (38), 231 (15),
229 (38), 209 (24), 158 (27); Anal. Calcd for CroHMBClOzS: C, 49.11; H, 5.77. Found:
C, 49.33; H, 5.81.

Table 3.2, Entry 3. Borylation of 3-bromothiophene (3.103 + 3.1%).

S BPin PinB 3
Br Br
89 1

1
3.1 08 3.1 0!)

The general procedure B was applied to 3-bromothiophene (190 11L, 326 mg, 2.00

mmol, 2.00 equiv) and HBPin (145 11L, 128 mg, 1 mmol, 1 equiv) for 1 h. The ratio of

120

two monoborylated products at the end of reaction was 89:11 by GC-F ID. The
monoborylated product mixture was isolated as a white solid (209 mg, 72% yield). lH
NMR(CDC13, 300 MHz): 8 (3.103) 7.49 (d, J= 1.2 Hz, 1 H), 7.46 (d, J= 1.2 Hz, 1 H),
1.32 (br s, 12 H, 4 CH3 of BPin), (3.10b) 7.48 (d, J= 5.0 Hz, 1 H), 7.08 (d, J= 5.0 Hz, 1
H), 1.34 (br s, 12 H, 4 CH3 of BPin); 13C NMR ('H} (CDCI3, 125 MHz): 8 (3.103) 139.3
(CH), 129.5 (CH), 111.2 (C), 84.4 (2 C), 24.7 (4 CH3 of BPin); “B NMR (CDCI3, 96
MHz): 8 29.0; FT-IR (neat) v: 2980, 1518, 1415, 1350, 1143, 1026, 852,665 cm"; GC-
MS (EI) m/z (% relative intensity): (3.103) M+ 289 (51), 290 (98), 288 (100), 275 (61 ),
273 (55), 247(18), 245 (21), 230 (19) 204 (41), (3.1%) M+ 289 (13), 290 (25), 288 (27),
275 (10), 273 (9), 209 (100), 189 (11), 167 (67); Anal. Calcd for C10H14BBrOZS: C,
41.56; H, 4.88. Found: C, 41.74; H, 4.88.

Table 3.2, Entry 4. Borylation of 3-methylthiophene (3.113 + 3.11b).

S BPin PinB S
gr )1
Me Me
89 1 1
3.11 3 3.1 1 b

The general procedure B was applied to 3-methylthiophene (194 11L, 196 mg,

2.00 mmol, 2.00 equiv) and HBPin (145 11L, 128 mg, 1 mol, 1 equiv) for 1 h. The ratio
of two monoborylated products at the end of reaction was 89:11 by GC-FID. The
monoborylated product mixture was isolated as colorless oil (150 mg, 67% yield). lH
NMR(CDC13, 300 MHz): 6 (3.113) 7.42 (d, J: 0.7 Hz, 1 H), 7.17 (t, J= 1.1 Hz, 1 H),
2.27 (d, J= 0.5 Hz, 1 H), 1.32 (br s, 12 H, 4 CH; of BPin), (3.11b) 7.46 (d, J= 4.6 Hz, 1
H). 6.95 (d, J = 4.6 Hz, 1 H), 2.47 (s, 1 H), 1.30 (br s, 12 H, 4 CH; of BPin); 13C NMR

{'H} (CDC13, 125 MHz): 8 (3.113) 139.4 (CH), 138.9 (C), 128.0 (CH), 83.9 (2 C), 24.7

121

(4 CH3 of BPin), 14.9 (CH3); llB NMR(CDC13, 96 MHz): 6 29.5; FT-IR (neat) v': 2978,
2930, 1550, 1441, 1371, 1327, 1302, 1271, 1143, 1028, 962, 854 665 cm"; GC-MS (El)
m/z (% relative intensity): (3.113) M+ 224 (100), 209 (27), 181 (18), 138 (44), (3.118) 1W
224 (100), 209 (68), 167 (64), 138 (54), 124 (61); Anal. Calcd for Cr anBOzS: C, 58.95;
H, 7.65. Found: C, 58.65; H, 8.09.

Table 3.2, Entry 5. 1-(5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yI)thiophen-3-

yl)ethanone (3.123).

S BPin
tr

MeOC

3.123

The general procedure A was applied to 3-acetylthiophene (126 mg, 1 mol, 1
equiv) and HBPin (174 uL, 154 mg, 1.20 mmol, 1.20 equiv) for 15 minutes. The product
was isolated as colorless oil (206 mg, 82% yield). 1H NMR(CDC13, 500 MHz): 6 8.26 (d,
J=1.1 Hz, 1 H), 8.00 (d,J= 1.1 Hz, 1 H), 2.50 (s, 3 H, COCH3)1.32 (br s, 12 H, 4 CH3
of BPin); 13C NMR {1H} (CDCI3, 125 MHz): 6 192.0 (C=O), 143.8 (C), 138.1 (CH),
137.0 (CH), 84.5 (2 C), 27.8 (COCH3), 24.8 (4 CH3 of BPin); “B NMR (CDCI3, 96
MHz): 6 29.2; FT-IR (neat) 17: 3098, 2980, 2934, 1680, 1530, 1448, 1381, 1373, 1340,.
1305, 1215, 1143, 1024, 850, 667 cm"; GC-MS (El) m/z (% relative intensity): M+ 252
(21), 237 (55), 209 (100), 195 (9), 153 (22), 137 (19); Anal. Calcd for C12H17BO3S: C,

57.16; H, 6.80. Found: C, 56.77; H, 7.19.

122

Table 3.2, Entry 6. Methyl 5-(4,4,5,5-tetramethyl—l,3,2-dioxaborolan-Z-yl)thiophene-

3-carboxylate (3.133).
S BPin
/

M9020

3.133

The general procedure A was applied to methyl 3-thiophenecarboxylate (121 (1L,
142 mg, 1 mol, 1 equiv) and HBPin (174 ML, 154 mg, 1.20 mmol, 1.20 equiv) for 1 h.
The product was isolated as a white solid (256 mg, 95% yield, mp 84-85 °C). 1H NMR
(CDC13, 500 MHz): 6 8.31 (d, J= 1.0 Hz, 1 H), 8.01 (d, J= 1.0 Hz, 1 H), 3.84 (s, 3 H,
C02CH3) 1.33 (br s, 12 H, CH3 of BPin); 13C NMR {1H} (CDCI3, 75 MHz): 8 163.1
(C=O), 138.8 (CH), 137.9 (CH), 134.9 (C), 84.4 (2 C), 51.6 (COzCH3), 24.7 (4 CH3 of
BPin); 11B NMR (CDCI3, 96 MHz): 6 29.4; FT-IR (neat) 9: 3107, 2980, 2951, 1722,
1537, 1458, 1431, 1388, 1373, 1336, 1307, 1224, 1143, 1024, 987, 852, 752, 667 cm";
GC-MS (EI) m/z (% relative intensity): M+ 268 (65), 253 (100), 237 (22), 225 (39), 211
(29), 193 (12), 182 (45), 169 (41), 137 (27); Anal. Calcd for C12H17BO4S: C, 53.75; H,
6.39. Found: C, 53.54; H, 6.66.
Table 3.2, Entry 7. Trimethyl(5-(4,4,5,5-tetramethyl-1,3,2-diox3borolan-2-

yl)thiophen-3-yl)silane (3.143).

3 BPin
W

TMS

3.143

123

The general procedure A was applied to 3-trimethylsilylthiophene (156 mg, 1
mol, 1 equiv) and HBPin (174 11L, 154 mg, 1.20 mmol, 1.20 equiv) for 30 minutes. The
product was isolated as a white solid (222 mg, 79% yield, mp 87-89 °C). 'H NMR
(CDCI3, 300 MHz): 6 7.71 (d, J= 1.0 Hz, 1 H), 7.69 (d, J= 1.0 Hz, 1 H), 1.33 (br s, 12
H, 4 CH3 of BPin), 0.24 (s, 9 H, 3 CH3 of TMS); ”C NMR {‘H} (CDCI3, 75 MHz): 8
142.4 (C), 141.9 (CH), 138.4 (CH), 83.8 (2 C), 24.6 (4 CH3 of BPin), —0.6 (3 CH3 of
TMS); “B NMR (CDC13, 96 MHz): 8 29.5; FT-IR (neat) v'; 2980, 2955, 1510, 1410,
1325, 1263, 1250, 1143, 1105, 1028, 902, 852, 839, 754, 667 cm"; GC-MS (EI) m/z (%
relative intensity): M+ 282 (7), 267 (100), 239 (2), 167 (7); Anal. Calcd for
C13H23BOZSS1: C, 55.31; H, 8.21. Found: C, 54.68; H, 8.47; HRMS (E1): m/z 282.1283
[(M*); Calcd for C13H23B028Si: 282.1281].

Table 3.2, Entry 8. Borylation of 3-p-tolylthiophene (3.153 + 3.15b).
S BPin PinB S
/ \

p-tolyl p—tolyl

97 3
3.158 3.1 5!)

The general procedure B was applied to 3-p-tolylthiophene (192 mg, 1.1 mmol,
1.1 equiv) and HBPin (145 11L, 128 mg, 1.00 mmol, 1.00 equiv) for 1 h. The ratio of two
monoborylated isomers at the end of reaction was 97:3 by GC-FID. The product was
isolated as colorless oil (223 mg, 74 % yield). IH NMR (CDCI3, 300 MHz): 6 7.91 (d, J =
1.2 Hz, 1 H), 7.68 (d, J = 1.2 Hz, 1 H), 7.48-7.52 (m, 2 H), 7.17-7.20 (m, 2 H), 2.35 (s, 3
H, CH3) 1.36 (br s, 12 H, 4 CH3 of BPin); ”C NMR {‘H} (CDC13, 75 MHz): 8 143.8 (C),
136.8 (C), 136.2 (CH), 132.9 (C), 129.5 (CH), 126.9 (CH), 126.4 (CH), 84.2 (2 C), 24.8

(4 CH3 of BPin), 21.1 (CH3); 11B NMR (CDCI3, 96 MHz): 6 29.4; FT-IR (neat) v”: 3090,

124

2978, 2928, 1547, 1441, 1379, 1371, 1329, 1311, 1269, 1143, 1026, 850, 819, 771, 667
cm"; GC-MS (El) m/z (% relative intensity): M+ 300 (100), 285 (12), 214 (12); Anal.
Calcd for CnHerOzS: C, 68.01; H, 7.05. Found: C, 68.54; H, 6.97; HRMS (BI): m/z
300.1360 [(M+); Calcd for CnHerOzS: 300.1355].

Table 3.3. Monoborylation of 2,5—di-substituted thiophenes

Table 3.3, Entry 1. 2-(2,5-Dichlorothiophen-3-yI)-4,4,5,5-tetramethyl-l,3,2-

dioxaborolane (3.16).

CI \3/ CI
PinB
3.16
The general procedure A was applied to 2-5-di-chlorothiophene (107 uL, 153 mg,
1 mol, 1 equiv) and HBPin (218 11L, 192 mg, 1.50 mmol, 1.50 equiv) for 20 h. The
product was isolated as a white solid (240 mg, 86% yield, mp 35-36 °C). 1H NMR
(CDCl3, 500 MHz): 8 6.94 (s, l H), 1.30 (br s, 12 H, 4 CH3 of BPin); ”C NMR ('H}
(CDCI3, 125 MHz): 6 137.1 (C), 131.1 (CH), 126.2 (C), 84.0 (2 C), 24.8 (4 CH3 of BPin);
”B NMR (CDCl3, 96 MHz): 8 28.5; FT-IR (neat) v: 2980, 1535, 1437, 1371, 1313,
1263, 1142, 1032, 966, 889, 848, 692 cm]; GC-MS (EI) m/z (% relative intensity): M"
278 (100), 280 (68), 263 (32), 265 (22), 243 M-35 (79), 245 (30), 201 (51); Anal. Calcd

for C10H13BC1202S: C, 43.05; H, 4.70. Found: C, 43.26; H, 4.74.

125

Table 3.3, Entry 2. 2-(2,5-Dibromothiophen-3-yI)-4,4,5,5-tetramethyl-1,3,2-

dioxaborolane (3.17).

Br 3 Br
\ /
PinB

3.17

The general procedure A was applied to 2-5-di-bromothiophene (113 11L, 142 mg,
1 mol, 1 equiv) and HBPin (218 01L, 192 mg, 1.50 mmol, 1.50 equiv) with 6 mol % [Ir]
catalyst loading for 36 h. Additional 3 mol % [Ir] catalyst and 1 equiv of HBPin was
added at this stage and the reaction was run for 12 more h at room temperature. The ratio
of the starting material to product after 48 h was 11:89. The product was isolated as a
white solid (206 mg, 56% yield, mp 72-73 °C). 1H NMR (CDCI3, 500 MHz): 6 7.09 (s, 1
H), 1.31 (br s, 12 H, 4 CH3 of BPin); ”C NMR {‘H} (C00,, 125 MHz): 8 135.8 (CH),
121.9 (C), 110.9 (C), 84.0 (2 C), 24.8 (4 CH3 of BPin); 11B NMR (CDCI3, 96 MHz): 6
28.5; FT-IR (neat) V: 2978, 1525, 1365, 1307, 1248, 1143, 991, 962, 883, 848, 690 cm'l;
GC-MS (El) m/z (% relative intensity): M 368 (100), 370 (51), 366 (52), 353 (18), 287
(56), 289 (59), 268 (28), 208 (77), 166 (69); Calcd for CtoHr3BBr202S: C, 32.65; H, 3.56.
Found: C, 32.92; H, 3.57.
Table 3.3, Entry 3. 2-(2,5-Dimethylthiophen-3-yl)-4,4,5,5-tetramethyl-l,3,2-

dioxaborolane (3.18).

\ /
PinB

3.18

126

The general procedure D was applied to 2-5-di-methylthiophene (228 1.1L, 224
mg, 2 mmol, 1 equiv) and neat HBPin (435 uL, 384 mg, 3.00 mmol, 1.50 equiv) for 16 h
at 150 °C. The product was isolated as a colorless semi solid (460 mg, 97% yield). lH
NMR(CDC13, 300 MHz): 6 6.81 (d, J= 1.2 Hz, 1 H), 2.59 (s, 3 H, CH3), 2.38 (d, J = 0.4
Hz, 3 H, CH3), 1.30 (br s, 12 H, 4 CH3 of BPin); ”C NMR {‘H} (CDCI3, 125 MHz): 8
150.8 (C), 136.1 (C), 130.7 (CH), 83.0 (2 C), 24.8 (4 CH; of BPin), 15.6 (CH3), 14.7
(CH3); llB NMR (CDCI3, 96 MHz): 6 29.3; FT-IR (neat) 9': 2978, 2924, 1493, 1394,
1304, 1265, 1145, 868, 700 cm"; GC-MS (El) m/z (% relative intensity): M+ 238 (100),
223 (8), 181 (37); Anal. Calcd for CtzHrgBOZS: C, 60.52; H, 8.04. Found: C, 60.62; H,
8.18.

Table 3.3, Entry 4. Borylation of 2-bromo-5-chlorothiophene (3.193 + 3.19b).

Cl 3 Br CI 3 Br
\ / U
PinB BPin
67 33
3.198 3.19b

The general procedure A was applied to 2-bromo-5-chlorothiophene (110 uL, 197
mg, 1 mmol, 1 equiv) and HBPin (290 11L, 256 mg, 2.00 mmol, 2.00 equiv) with 3% [Ir]
catalyst loading for 8 h. Additional 3 % [Ir] and 0.5 equiv of HBPin was added and the
reaction was run for 20 more b at room temperature. The ratio of the two monoborylated
products at the end of reaction was 67:33 by GC-FID. The monoborylated product
mixture was isolated as a white solid (281 mg, 87% yield). lH NMR(CDC13, 500 MHz):
5 (3.193) 7.10 (s, 1 H), 1.30 (br s, 12 H, 4 CH3 of BPin), (3.19b) 6.94 (s, 1 H), 1.30 (br s,
12 H, 4 CH3 of BPin); ”C NMR {'H} (CDCI3, 125 MHz): 8 (3.193) 139.6 (C), 134.9

(CH), 108.3 (C), 84.0 (2C), 24.8 (4 CH3 of BPin), (3.198) 132.0 (CH), 128.9 (C), 119.5

127

(C), 84.1 (2 C), 24.8 (4 CH3 of BPin); “B NMR (CDCI3, 96 MHz): 8 28.5; FT-IR (neat)
17: 2980, 1527, 1427, 1371, 1253, 1140, 1028, 962, 848, 693 cm"; GC-MS (E1) m/z (%
relative intensity): (3.193) M 324 (100), 322 (78), 289 (67), 287 (64), 208 (40), 166 (34),
(3.19b) M” 324 (89), 322 (69), 309 (23), 245 (41), 243 (99), 203 (43), 201 (100), 166
(50); Anal. Calcd for C10H13BBrClOZS: C, 37.13; H, 4.05. Found: C, 37.25; H, 4.05.
Note: The data for the pure major isomer 3.193 is described in the bromination section of
this supporting information.

Table 3.3, Entry 5. Borylation of 2-chloro-5-iodothiophene (3.203 + 3.20b).

CISI CISI

\ / W
PinB BPin
85 1 5
3.203 3.20b

The general procedure A was applied to 2-chloro-5-iodothiophene (122 mg, 0.5
mmol, 1 equiv) and HBPin (109 uL, 96 mg, 0.75 mmol, 1.50 equiv) for 20 h. The ratio of
two monoborylated products at the end of reaction was 85:15 by GC-FID. The
monoborylated product mixture was isolated as a white solid (165 mg, 89% yield). 1H
NMR (CDCI3, 300 MHz): 6 (3.203) 7.31 (s, 1 H), 1.30 (br s, 12 H, 4 CH; of BPin),
(3.208) 6.87 (s, 1 H), 1.31 (br s, 12 H, 4 CH3 of BPin); ”C NMR {‘H} (CDC13, 125
MHz): 6 (3.203) 143.4 (C), 142.3 (CH), 84.0 (2 C), 69.3 (C), 24.8 (4 CH3 of BPin),
(3.208) 132.8 (CH), 84.2 (2 C), 81.1 (C), 24.8 (4 CH3 of BPin); “B NMR (CDCI3, 96
MHz): 6 28.3; FT-IR (neat) 17: 2978, 1523, 1414, 1371, 1248, 1140, 1024, 966, 881, 848
690 cm"; GC-MS (El) m/z (% relative intensity): (3.203) M+ 370 (100), 355 (13), 335

(29), 270 (25), 208 (15), 166 (11), (3.20b) M+ 370 (100), 355 (10), 270 (24), 243 (13),

128

201 (32), 166 (21); Anal. Calcd for CroHnBIClOzS: C, 32.42; H, 3.54. Found: C, 32.58;

H, 3.38.

Table 3.3, Entry 6. Borylation of 2-chloro-S-methylthiophene (3.213 + 3.21b).

Cl 8 Me Cl 8 Me
\ , U
PinB BPin
70 30
3.213 3.211)

The general procedure A was applied to 2-chloro-5-methylthiophene (133 mg, 1
mol, 1 equiv) and HBPin (218 11L, 192 mg, 1.50 mmol, 1.50 equiv) for 18 h. The ratio
of two monoborylated products at the end of reaction was 70:30 by GC-FID. The
monoborylated product mixture was isolated as a colorless semi solid (221 mg, 86%
yield). lH NMR(CDC13, 300 MHz): 6 (3.213) 6.77 (q, J = 1.2 Hz, 1 H), 2.35 (d, J= 1.2
Hz, 3 H, CH3), 1.31 (br s, 12 H, 4 CH; of BPin), (3.21b) 6.95 (s, 1 H), 2.60 (s, 3 H, CH3),
1.28 (br s, 12 H, 4 CH3 of BPin); ”C NMR {'H} (CDC13, 125 MHz): 8 (3.213) 137.4 (C),
137.0 (C), 130.1 (CH), 83.6 (2 C), 24.8 (4 CH3 of BPin), 14.9 (CH3), (3.21b) 151.1 (C),
131.6 (CH), 125.4 (C), 83.4 (2 C), 24.8 (4 CH3 of BPin), 15.7 (CH3); llB NMR (CDCI3,
96 MHz): 6 29.1; FT-IR (neat) 17: 2980, 2926, 1556, 1475, 1390, 1371, 1309, 1257,
1143, 1026, 966, 898, 850, 696 cm"; GC-MS (E1) m/z (% relative intensity): (3.213) 258
M+ (100), 243 (17), 223 (51), 181 (36), 153 (37) (3.21b) 258 M (100), 243 (18), 223 (7),
201 (93), 172 (23); Anal. Calcd for CllHléBCIOZS: C, 51.10; H, 6.24. Found: C, 51.66;

H, 6.58; HRMS (E1): m/z 258.0653 [(M+); Calcd for C11H16BC102S: 258.06526].

129

Table 3.3, Entry 7. (5-Chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-

yl)thiophen-Z-yl)trimethylsilane (3.223).

CI 5 TMS
\/

PinB

3.223

The general procedure A was applied to 2-chloro-5-trimethylsilylthiophene (3 82
mg, 2 mol, 1 equiv) and HBPin (435 (1L, 384 mg, 3.00 mmol, 1.50 equiv) for 6 h. The
single monoborylated product was isolated as a solid (589 mg, 93% yield, mp 68-69 °C).
lH NMR(CDC13, 500 MHz): 6 7.26 (s, 1 H), 1.32 (br s, 12 H, 4 CH3 of BPin), 0.26 (s, 9
H, 3 CH3 of TMS); 13C NMR {1H} (CDCI3, 125 MHz): 6 144.7 (C), 139.42 (CH), 139.37
(C), 83.7 (2 C), 24.8 (4 CH3 of BPin), —0.24 (3 CH3 of TMS); “B NMR (CDC13, 96
MHz): 6 29.1; FT-IR (neat) 17': 2980, 1525, 1415, 1363, 1307, 1253, 1238, 1143, 993,
841, 758, 696 cm]; GC-MS (E1) m/z (% relative intensity) 316 (33), 301 (100), 281 (6),
201 (15): NF; Anal. Calcd for C13H22BC102SSi: C, 49.30; H, 7.00; Found: C, 49.16; H,
7.16.

Diborylation
Table 3.4. Diborylation of 2-substituted thiophenes
Table 3.4, Entry 1. 3,5-Bis(4,4,5,5-tetramethyl-l,3,2-dioxaborolan—2-yl)thiophene-2-

carbonitrile (3.25).

NC 3 BPin
\ /
PinB

3.25

130

Ta

dlll

The general procedure C was applied to 2-cyanoothiophene (94 11L, 109 mg, 1
mol, 1 equiv) and HBPin (435 uL, 384 mg, 3.00 mmol, 3.00 equiv) for l h. The single
diborylated product was isolated as a white solid (317 mg, 88% yield, mp 132-133 °C).
lH NMR(CDC13, 500 MHz): 6 7.87 (s, 1 H), 1.33 (br s, 12 H, CH3 of BPin), 1.31 (s, 12
H, 4 CH; of BPin); ”C NMR {'H} (CDCI3, 125 MHz): 8 143.1 (CH), 123.2 (C), 114.3
(C), 84.8 (2 C), 84.6 (2 C), 24.8 (4 CH3 of BPin), 24.7 (4 CH3 of BPin); “B NMR
(CDCI3, 96 MHz): 6 28.6; FT-IR (neat) 17: 2980, 2934, 2220, 1531, 1458, 1373, 1319,
1138, 1030, 966, 848, 667 cm"; GC-MS (El) m/z (% relative intensity): M" 361 (73), 346
(53), 320 (100), 303 (31), 275 (24), 262 (29); Anal. Calcd for Cr7H25B2NO4S: C, 56.55;
H, 6.98; Found: C, 56.45; H, 7.16.

Table 3.4, Entry 2. 2,2'-(5-Chlorothiophene-2,4-diyl)bis(4,4,5,5-tetramethyl-l,3,2-

dioxaborolane) (3.26).

Cl 3 BPin
\ /
PinB
3.26
The general procedure C was applied to 2-chlorothiophene (92 11L, 118 mg, 1
mol, 1 equiv) and HBPin (363 11L, 320 mg, 2.50 mmol, 2.50 equiv) for 12 h. The single
diborylated product was isolated as a white solid (315 mg, 85% yield, mp 130-131 °C).
lH NMR(CDC13, 500 MHz): 6 7.72 (s, 1 H), 1.30 (br s, 12 H, 4 CH3 of BPin), 1.29 (s, 12
H, 4 CH3 of BPin); ”C NMR {'H} (CDCl3, 125 MHz): 8 146.3 (C), 143.6 (CH), 84.2 (2
C), 83.8 (2 C), 24.8 (4 CH3 of BPin), 24.7 (4 CH3 of BPin); llB NMR(CDC13, 96 MHz):
6 29.0; FT-IR (neat) V: 2976, 2928, 1539, 1456, 1371, 1340, 1309, 1140, 1042, 964, 851,

665 cm'l; GC-MS (EI) m/z (% relative intensity): M+ 370 (100), 372 (40), 355 (46), 335

131

(85), 313 (21), 285 (39), 227 (52); Anal. Calcd for C16H25B2CIO4S: C, 51.87; H, 6.80;
Found: C, 51.69; H, 7.00.
Table 3.4, Entry 3. 2,2'-(5-Bromothiophene—2,4-diyl)bis(4,4,5,5-tetramethyl-1,3,2-

dioxaborolane) (3.27).

Br 3 BPin
\ /
PinB

3.27

The general procedure C was applied to 2-bromothiophene (97 11L, 163 mg, 1
mol, 1 equiv) and HBPin (363 uL, 320 mg, 2.50 mmol, 2.50 equiv) for 12 h. The single
diborylated product was isolated as a white solid (381 mg, 92% yield, mp 116-118 °C).
lH NMR(CDC13, 500 MHz): 6 7.69 (s, 1 H), 1.30 (br s, 12 H, 4 CH3 of BPin), 1.29 (s, 12
H, 4 CH; of BPin); ”C NMR {'H} (CDCI3, 125 MHz): 6 144.3 (CH), 129.3 (C), 84.2 (2
C), 83.8 (2 C), 24.8 (4 CH3 of BPin), 24.7 (4 CH3 of BPin); “B NMR (CDC13, 96 MHz):
6 28.9; FT-IR (neat) 17: 2978, 1537, 1452, 1327, 1140, 1026, 964, 850, 665 cm"; GC-MS
(El) m/z (% relative intensity): M 414 (100), 416 (97), 401 (22), 335 (71); Anal. Calcd
for C15stBzBrO4S: C, 46.31; H, 6.07; Found: C, 46.39; H, 6.06.
Table 3.4, Entry 4. 2,2'-(5-Methylthiophene—2,4-diyl)bis(4,4,5,5-tetramethyl-1,3,2-

dioxaborolane) (3.28).

Me 3 BPin
\ /
PinB

3.28

132

The general procedure C was applied to 2-methylthiophene (97 11L, 98 mg, 1
mol, 1 equiv) and HBPin (435 ML, 384 mg, 3.00 mmol, 3.00 equiv) for 72 h. The ratio
of the two isomeric monoborylated products at the end of reaction was 98.5:1.5 by
GC-FID (The GC-FID retention time of the minor diborylated isomer was different from
the retention time of the single diborylated product of 3-methylthiophene). The product
was isolated as a white solid (316 mg, 90% yield, mp 127-129 °C). lH NMR(CDC13, 500
MHz): 6 7.81 (s, 1 H), 2.68 (s, 3 H, CH3), 1.29 (br s, 12 H, 4 CH3 of BPin), 1.28 (s, 12 H,
4 CH3 of BPin); 13C NMR {1H} (CDC13, 125 MHz): 6 159.6 (C), 144.9 (CH), 83.8 (2 C),
83.2 (2 C), 24.9 (4 CH3 of BPin), 24.7 (4 CH3 of BPin), 15.9 (CH3); “B NMR (CDCI3, 96
MHz): 6 29.5; FT-IR (neat) 1'": 2976, 1541, 1475, 1323, 1138, 1012, 844 cm"; GC-MS
(El) m/z (% relative intensity): M 350 (87), 335 (32), 293 (100), 264 (45), 250 (38);
Anal. Calcd for C17H23B204S: C, 58.32; H, 8.06; Found: C, 57.96; H, 7.81.

Table 3.4, Entry 5. 2,2'-(5-Methoxythiophene-2,4-diyl)bis(4,4,5,5-tetramethyl-1,3,2-

dioxaborolane) (3.29).

M30 5 BPin
\ /
PinB

3.29
The general procedure C was applied to 2-methoxythiophene (101 11L, 114 mg, 1
mol, 1 equiv) and HBPin (435 ML, 384 mg, 3.00 mmol, 3.00 equiv) for 48 h. The ratio
of the two isomeric monoborylated products at the end of reaction was 98.6:1.4 by
GC-FID (The GC-F ID retention time of the minor diborylated isomer was different from

the retention time of the single diborylated product of 3-methoxythiophene). The product

was isolated as a white solid (324 mg, 89% yield, mp 110-112 °C). 1H NMR(CDC13, 500

133

MHz): 6 7.68 (s, l H), 3.98 (s, 3 H, OCH3), 1.282 (br s, 12 H, 4 CH3 of BPin), 1.280 (s,
12 H, 4 CH3 of BPin); ”C NMR (1H) (CDC13, 125 MHz): 6 181.5 (C), 143.8 (CH), 83.7
(2 C), 83.2 (2 C), 61.8 (OCH3), 24.8 (4 CH; of BPin), 24.7 (4 CH3 of BPin); llB NMR
(CDCI3,96 MHz): 6 29.3; FT-IR (neat) 17: 2978, 1549, 1481, 1334, 1140, 1022, 968, 852,
663 cm"; GC-MS (EI) m/z (% relative intensity): M 366 (100), 352 (10), 324 (5), 282
(11), 250 (13); Anal. Calcd for CnHngzOsS: C, 55.77; H, 7.71; Found: C, 55.41; H,
7.56.

Table 3.5. Diborylation of 3-substituted thiophenes

Table 3.5, Entry 1. 2,5-Bis(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)thiophene-3-

carbonitrile (3.32).

PinB S BPin
U

NC

3.32

The general procedure C was applied to 3-cyanothiophene (91 11L, 109 mg, 1
mol, 1 equiv) and HBPin (363 ML, 320 mg, 2.50 mmol, 2.50 equiv) for 0.5 h. The
single diborylated product was isolated as a white solid (306 mg, 85% yield, mp 139 °C).
lH NMR(CDC13, 500 MHz): 6 7.80 (s, 1 H), 1.34 (br s, 12 H, 4 CH3 of BPin), 1.31 (s, 12
H, 4 CH3 of BPin); ”C NMR {‘H} (CDC13, 125 MHz): 8 140.3 (CH), 118.8 (C), 115.2
(C), 85.1 (2 C), 84.8 (2 C), 24.7 (8 CH3 of 2 BPin); 1'B NMR (CDC13, 96 MHz): 6 28.8;
FT-IR (neat) 17: 2980, 2936, 2230, 1525, 1373, 1269, 1138, 1055, 962, 850, 667 cm“;
GC-MS (EI) m/z (% relative intensity): W 361 (70), 346 (45), 331 (28), 320 (100), 304

(80), 275 (39), 262 (51); Anal. Calcd for C17H25B2N04S: C, 56.55; H, 6.98; Found: C,

134

55.78; H, 6.96; HRMS (FAB): m/z 362.1778 [(MH); Calcd for C17H26B2N048:
362.1768].
Table 3.5, Entry 2. 2,2'-(3-Chlorothiophene-2,5-diyl)bis(4,4,5,5-tetramethyl-1,3,2-

dioxaborolane) (3.33).

S

PinB BPin
U

Cl

3.33

The general procedure C was applied to 3-chlorothiophene (93 uL, 118 mg, 1
mol, 1 equiv) and HBPin (363 11L, 320 mg, 2.50 mmol, 2.50 equiv) for 1 h. The single
diborylated product was isolated as a white solid (337 mg, 91% yield, mp 112-114 °C).
1H NMR(CDC13, 500 MHz): 6 7.45 (s, 1 H), 1.32 (br s, 12 H, 4 CH3 of BPin), 1.30 (s, 12
H, 4 CH3 of BPin); ”C NMR (‘H} (CDCI3, 125 MHz): 8 138.3 (CH), 134.7 (C), 84.5 (2
C), 84.3 (2 C), 24.73 (4 CH3 of BPin), 24.72 (4 CH3 of BPin); 11B NMR (CDCI3, 96
MHz): 6 29.1; FT-IR (neat) V: 2980, 1516, 1383, 1348, 1307, 1140, 1041, 958, 853, 669
cm"; GC-MS (El) m/z (% relative intensity): W 370 (57), 355 (38), 335 (100), 285 (40);
Anal. Calcd for C16H25B2CIO4S: C, 51.87; H, 6.80; Found: C, 51.86; H, 6.88.

Table 3.5, Entry 3. 2,2'-(3-Bromothiophene-2,5-diyl)bis(4,4,5,5—tetramethyl-1,3,2-

dioxaborolane) (3.34).

S

PinB BPin
34

Br

3.34

135

The general procedure C was applied to 3-bromothiophene (95 uL, 163 mg, 1
mol, 1 equiv) and HBPin (363 11L, 320 mg, 2.50 mmol, 2.50 equiv) for 1 h. The single
diborylated product was isolated as a white solid (396 mg, 95% yield, mp 96—98 °C). lH
NMR (CDC13, 500 MHz): 6 7.52 (s, 1 H), 1.32 (br s, 12 H, 4 CH3 of BPin), 1.30 (s, 12 H,
4 CH3 of BPin); ”C NMR {'H} (CDCI3, 125 MHz): 8 141.2 (CH), 119.9 (C), 84.5 (2 C),
84.3 (2 C), 24.73 (4 CH3 of BPin), 24.71 (4 CH3 of BPin); llB NMR(CDC13, 96 MHz): 6
28.9; FT-IR (neat) V: 2978, 1510, 1344, 1304, 1269, 1140, 1039, 958, 853, 667 cm‘l;
GC-MS (E1) m/z (% relative intensity): M+ 415 (33), 416 (51), 414 (52), 401 (15), 399
(11), 335 (100), 249 (20), 193 (31); Anal. Calcd for C16H25B2Br048: C, 46.31; H, 6.07;
Found: C, 46.32; H, 6.16.

Table 3.5, Entry 4. 2,2'-(3-Methylthiophene-2,5-diyl)bis(4,4,5,5-tetramethyl-1,3,2-

dioxaborolane) (3.35).

S

PinB BPin
U

Me

3.35

The general procedure C was applied to 3-methylthiophene (97 uL, 98 mg, 1
mol, 1 equiv) and HBPin (435 11L, 384 mg, 3.00 mmol, 3.00 equiv) for 6 h. The
product was isolated as a white solid (268 mg, 77% yield, mp 128-129 °C). 1H NMR
(CDCI3, 500 MHz): 6 7.43 (s, 1 H), 2.43 (s, 3 H, CH3), 1.303 (br s, 12 H, 4 CH; of BPin),
1.302 (s, 12 H, 4 CH3 of BPin); ”C NMR {‘H} (CDCl3, 125 MHz): 8 149.3 (C), 140.6
(CH), 84.0 (2 C), 83.6 (2 C), 24.8 (4 CH3 of BPin), 24.7 (4 CH3 of BPin), 15.6 (CH3); “8
NMR (CDCI3, 96 MHz): 6 29.2; FT-IR (neat) 17: 2978, 2932, 1537, 1387, 1373, 1332,

1311, 1290, 1267, 1140, 1060, 962, 854, 680, 669 cm'l; GC-MS (EI) m/z (% relative

136

intensity): M+ 350 (100), 335 (26), 292 (22), 264 (96) 250 (29); Anal. Calcd for
CnHnganS: C, 58.32; H, 8.06; Found: C, 58.34; H, 8.45.
Table 3.5, Entry 5. 2,2'-(3-p-Tolylthiophene-2,5-diyl)bis(4,4,5,5-tetramethy|-1,3,2-
dioxaborolane) (3.36).
PinB S BPin
\ /
ptolyl
3.36
The general procedure C was applied to 3-p-tolylthiophene (174 mg, 1 mol, 1
equiv) and HBPin (333 11L, 294 mg, 2.30 mmol, 2.30 equiv) for 16 hr. The product was
isolated as colorless oil (260 mg, 61% yield). lH NMR (CDCI3, 300 MHz): 6 7.73 (s, 1
H), 7.42-7.45 (m, 2 H), 7.12-7.15 (m, 2 H), 2.36 (s, 3 H, CH3), 1.32 (br s, 12 H, 4 CH3 of
BPin), 1.27 (br s, 12 H, 4 CH3 of BPin); ”C NMR {‘H} (CDCI3, 125 MHz): 8 152.2 (C),
139.6 (CH), 136.7 (C), 133.8 (C), 128.9 (2 CH), 128.4 (2 CH), 84.1 (2 C), 83.9 (2 C),
24.7 (4 CH; of BPin), 24.5 (4 CH3 of BPin), 21.2 (CH3); ”B NMR (CDCI3, 96 MHz): 8
29.8; FT-IR (neat) V: 2978, 2932, 1537, 1473, 1373, 1331, 1309, 1261, 1140, 1037, 958,
854, 819, 669 cm'l; GC-MS (EI) m/z (% relative intensity): M 426 (100), 340 (9), 310
(9); HRMS (FAB): m/z 426.2213 [(M+); Calcd for C23H32B204S: 426.2207].

Attempted borylation of tri-substituted thiophene.

Borylation of 2-5-di-chloro-3-bromo-thiophene.

Cl 3 Cl Cl 3 BPin
W ___. 1r
Br Br

3.40 3.7

137

The general procedure D was applied to 2-5-di-chloro-3-bromo—thiophene (3.40)
(232 mg, 1 mol, 1 equiv) and neat HBPin (218 11L, 192 mg, 1.50 mmol, 1.50 equiv) for
2 h at 150 °C. The product 3.7 was isolated as a colorless solid (233 mg, 73% yield). The
spectroscopic data of this product matched with the data of borylated product obtained
from 2-chloro-3-bromo-thiophene as described earlier.
Bromination
a. 2-(4-Bromo-2,5-dimethylthiophen-3-yI)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane

(3.41).

Me 3 Me Me 3 Me

\ / __. \ /
PinB PinB Br
3.18 3.41

2-(2,5-dimethylthiophen-3-y1)-4,4,5,5-tetramethyl-1 ,3 ,2-dioxaborolane (3.18)
(238 mg, 1 mol, 1 equiv) was dissolved in 2 mL of CHCl3 in a 20 mL scintillation vial
equipped with a magnetic stirring bar. Bromine (160 mg, 1 mol, 1 equiv, dissolved in 2
mL of CHC13) was added drop-wise during two minutes. The reaction was then quenched
with water. The product was extracted with CHzClz (3 x 20 mL) and dried over MgSO4.
Column chromatography (hexane/CHzClz 1:1, R; 0.7) furnished the desired product as a
white solid (260 mg, 82%, mp 55-56 °C). 1H NMR (CDC13, 300 MHz): 6 2.54 (s, 3 H,
CH3), 2.29 (s, 3 H, CH3), 1.32 (br s, 12 H, 4 CH3 of BPin); ”C NMR {1H} (CDCI3, 125
MHz): 6 147.9 (C), 131.2 (C), 113.1 (C), 83.5 (2 C), 24.8 (4 CH3 of BPin), 16.2 (CH3),
14.5 (CH3); 11B NMR (CDCI3, 96 MHz): 6 29.5; FT-IR (neat) 17': 2978, 2922, 1537, 1377,

1315, 1234, 1143, 852 cm"; GC-MS (BI) m/z (% relative intensity): M 317 (46), 318

138

(84), 316 (81), 303 (11) 301 (10), 261 (100), 259 (99), 237 927), 195 (38), 180 (41);
Anal. Calcd for CrzngBBrOZS: C, 45.46; H, 5.72. Found: C, 45.54; H, 5.91.
General Procedure E (Substitution of TMS with Br)

TMS group was replaced with Bromine by employing the literature conditions
used for aromatic bromination.8 Substrate (1 mmol, 1 equiv) was added to a 20 mL
scintillation vial equipped with a magnetic stirring bar. N-bromosuccinamide (1 mol, 1
equiv) was added in to the vial. Acetonitrile (3-5 mL) was also added to the vial. The
reaction mixture was stirred at room temperature and was monitored by GC-FID/MS.
After the completion of the reaction, the volatile materials were removed on a rotary
evaporator and the crude product was passed through a short silica plug to afford the

brominated product.

b. 2-(5-Bromo-2-chlorothiophen-3-yl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane
(3.193).
CI 3 TMS CI 3 Br
\ / —__. \ /
PinB PinB
3.223 3.193

The general procedure E was applied to (5-chloro-4-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolan-2-yl)thiophen-2-yl)trimethylsilane 3.223 (317 mg, 1 mmol) for 12 h. The
product was isolated as a white solid (295 mg, 91%, mp 51-53 °C). 1H NMR (CDCI3, 300
MHz): 6 7.10 (s, 1 H), 1.30 (br s, 12 H, CH3 of BPin); 13C NMR {'H} (CDCI3, 125
MHz): 6 139.6 (C), 134.9 (CH), 108.3 (C), 84.1 (2 C), 24.8 (4 CH3 of BPin); 11B NMR
(CDC13, 96 MHz): 6 28.5; FT-IR (neat) 17: 2978, 1530, 1427, 1373, 1311, 1253, 1142,

1028, 962, 848, 883, 848, 692 cm"; GC-MS (El) m/z (% relative intensity): M 323 (48),

139

324 (100), 322 (81), 309 (21), 307 (14), 289 (38), 287 (36) 208 (23), 166 (22); Anal.
Calcd for CloHt3BBrClOZS: C, 37.13; H, 4.05; Found: C, 37.25; H, 4.19.

c. 5-Bromo-2-chloro-3-m-tolylthiopbene (3.44).

CI 3 TMS Cl 3 Br
\ / —. \ /
Me Me
3.43 3.44

The general procedure E was applied to (5-chloro-4-m-tolylthiophen-Z-
yl)trimethylsilane (3.43) (280 mg, 1 mmol) for 12 h. The product was isolated as a
colorless liquid (261 mg, 91%). ‘H NMR(CDC13, 300 MHz): 8 7.29—7.31 (m, 3 H),
7.15-7.18 (m, 1 H), 7.02 (s, 1 H), 2.38 (s, 3 H, CH3); l3C NMR {'H} (CDCI3, 75 MHz): 6
139.3 (C), 138.2 (C), 133.1 (C), 131.2 (CH), 129.1 (CH), 128.8 (CH), 128.4 (CH), 125.5
(CH), 124.0 (C), 108.3 (C), 21.4 (CH3); FT-IR (neat) V: 3042, 2920, 2858, 1604, 1487,
1028, 972, 831, 789, 779, 700 cm"; GC-MS (EI) m/z (% relative intensity): M+ 287 (63),
288 (100), 290 (29), 287 (63), 251 (5), 171 (19); Anal. Calcd for CrngBrClS: C, 45.94;
H, 2.80; Found: C, 45.96; H, 2.79.

One-Pot borylation/Suzuki coupling of substituted thiophenes

a. 2-Methyl-5-(3-(trifluoromethyl)phenyl)thiophene (3.45).

Me 3
\ / CF3

3.45

140

The general borylation procedure A was applied to 2-methylthiophene (484 11L,
491 mg, 5 mol, 1 equiv) and HBPin (870 11L, 768 mg, 6.00 mmol, 1.20 equiv) in a
Schlenk flask for 0.5 h. The reaction mixture was pumped down under high vacuum for
0.5 h to remove the volatile materials. Pd(PPh3)4 (116 mg, 0.10 mol, 2 mol%),
3-bromo-benzotrifluoride (837 11L, 1350 mg, 6.00 mmol, 1.2 equiv), and DME (6 mL)
were added to the Schlenk flask inside the glove box. The Schlenk flask was then brought
out of the glove box and attached to a Schlenk line. K3P04-nHzO (1592 mg, 1.50 equiv)
was added under N2 counter flow to the Schlenk flask. The flask was stoppered and the
mixture was heated at 80 °C for 8 h. The flask was cooled down to room temperature and
20 mL of water were added to the reaction mixture. The reaction mixture was extracted
with ether (3 x 20 mL). The combined ether extractions were washed with brine (20 mL),
followed by water (10 mL), dried over MgSO4 before being concentrated under reduced
pressure on a rotary evaporator. Column chromatography (hexanes, R; 0.5) furnished the
product as white semi solid (1026 mg, 85% yield). 1H NMR (CDCI3, 500 MHz): 6 7.77
(t, J= 0.8 Hz, 1 H), 7.68 (d, J= 7.6 Hz, 1 H), 7.42-7.48 (m, 2 H), 7.15 (d, J= 3.5 Hz, 1
H), 673-6.75 (m, 1 H), 2.51 (s, 3 H, CH3); ”C NMR {‘H} (CDCI3, 125 MHz): 8 140.7
(C), 140.1 (C), 135.5 (C), 131.2 (q, ch-F = 32.6 Hz, C), 129.3 (CH), 128.5 (CH), 126.4
(CH), 124.1 (q, lJc.r:= 273 Hz, CF 3), 124.0 (CH), 123.4 (q, 3Jen: = 3.6 Hz, CH), 122.0 (q,
3Jed: = 3.6 Hz, CH), 15.4 (CH3); FT-IR (neat) 17: 3073, 2922, 2865, 1497, 1340, 1325,
1165, 1126, 1074, 790, 694 cm]; GC-MS (El) m/z (% relative intensity): M+ 242 (100),

223 (4), 173 (6); Anal. Calcd for C12H9F3S: C, 59.49; H, 3.74; Found: C, 59.38; H, 3.56.

141

b. (5-Chloro-4-m-tolylthiophen-2-yl)trimethylsilane (3.43).

CI 3 TMS
\/

Me
3.43

The general borylation procedure A was applied to 2-chloro-5-
trimethylsilylthiophene (382 mg, 2 mol, 1 equiv) and HBPin (435 11L, 384 mg, 3.00
mmol, 1.50 equiv) in a Schlenk flask for 10 h. The reaction mixture was pumped down
under high vacuum for 1 h to remove the volatile materials. Pd(PPh3)4 (46 mg, 2 mol %),
3-bromo-toluene (291 11L, 410 mg, 2.40 mmol, 1.2 equiv), and DME (3 mL) were added
to the Schlenk flask inside the glove box. The Schlenk flask was then brought out of the
glove box and attached to a Schlenk line. K3P04-nH20 (637 mg, 1.50 equiv) was added
under N2 counter flow to the Schlenk flask. The flask was stoppered and the mixture was
heated at 80 °C for 6 h. The flask was cooled down to room temperature and 10 mL of
water were added to the reaction mixture. The reaction mixture was extracted with ether
(3 x 10 mL). The combined ether extractions were washed with brine (10 mL), followed
by water (10 mL), dried over MgSO4 before being concentrated under reduced pressure
on a rotary evaporator. Column chromatography (hexanes, R] 0.5) furnished the product
as a colorless liquid (369 mg, 66% yield). 1H NMR (CDC13, 300 MHz): 6 7.27-7.37 (m, 3
H), 7.13-7.16 (m, 1 H), 7.12 (s, 1 H), 2.39 (s, 3 H, CH3), 0.31 (s, 9 H, 3 CH3 of TMS);
13C NMR {1H} (CDCI3, 75 MHz): 6 139.6 (C), 138.2 (C), 138.0 (C), 135.3 (CH), 134.3
(C), 129.3 (C), 129.1 (CH), 128.29 (CH), 128.27 (CH), 125.6 (CH), 21.5 (CH3), —0.3 (3

CH3 of TMS); FT—IR (neat) V: 3040, 2957, 2922, 1606, 1408, 1252, 993, 839, 781, 756,

142

700, 630 cm"; GC-MS (E1) m/z (% relative intensity): M+ 280 (49), 282 (19), 266 (100),

267 (48); Anal. Calcd for CMHnClSSi: C, 59.86; H, 6.10; Found: C, 59.56; H, 6.21.

143

BIBLIOGRAPHY

(l) Gronowitz, S. Thiophene and its derivatives; Wiley: New York, 1985.

(2) Miyaura, N.; Suzuki, A. Chemical Reviews 1995, 95, 2457-2483.

(3) Mikhaaeilov, B. M.; Bubnov, 6. N.; Mikhaaeilov, B. M. Organoboron
compounds in organic synthesis; Rev. English ed.; Harwood Academic: Chur,
Switzerland ; New York, N.Y., USA, 1984.

(4) Sundararaman, A.; Venkatasubbaiah, K.; Victor, M.; Zakharov, L. N.;
Rheingold, A. L.; Jakle, F. Journal Of The American Chemical Society 2006, 128,
16554-16565.

(5) Wakamiya, A.; Mori, K.; Yamaguchi, S. Angewandte
Chemie-International Edition 2007, 46, 4273-4276.

(6) Wakamiya, A.; Taniguchi, T.; Yamaguchi, S. Angewandte
Chemie-International Edition 2006, 45, 3170-3173.

(7) Kabalka, G. W.; Akula, M. R.; Zhang, J. H. Nuclear Medicine And
Biology 2002, 29, 841-843.

(8) Ebdrup, S.; Jacobsen, P.; Farrington, A. D.; Vedso, P. Bioorganic &
Medicinal Chemistry 2005, 13, 2305-2312.

(9) Liversedge, I. A.; Higgins, S. J.; Giles, M.; Heeney, M.; McCulloch, I.
Tetrahedron Letters 2006, 47, 5143-5146.

(10) Neumann, T.; Dienes, Y.; Baumgartner, T. Organic Letters 2006, 8,
495-497.

(11) Krause; Pomeranz Berichte Der Deutschen Chemischen Gesellschaft
1932, 65, 777.

144

(12) Johnson, J. R.; Van Campen, M. G.; Grurnmitt, 0. Journal of the
American Chemical Society 1938, 60, l 1 1-1 15.

(13) Lawesson, S.-O. Arkivfoer Kemi 1957, II, 387-395.

(14) Ishiyama, T.; Murata, M.; Miyaura, N. Journal Of Organic Chemistry
1995, 60, 7508-7510.

(15) Christophersen, C.; Begtrup, M.; Ebdrup, S.; Petersen, H.; Vedso, P.
Journal Of Organic Chemistry 2003, 68, 9513-9516.

(16) Zhu, W.; Ma, D. W. Organic Letters 2006, 8, 261-263.

(17) Billingsley, K. L.; Barder, T. E.; Buchwald, S. L. Angewandte
Chemie-lnternational Edition 2007. 46, 5359-5363.

(18) Iverson, C. N.; Smith, M. R. Journal Of The American Chemical Society
1999, 121, 7696-7697.

(19) Cho, J. Y.; Iverson, C. N.; Smith, M. R. Journal Of The American
Chemical Society 2000, 122, 12868-12869.

(20) Cho, J. Y.; Tse, M. K.; Holmes, D.; Maleczka, R. E.; Smith, M. R. Science
2002, 295, 305-308.

(21) Tse, M. K.; Cho, J. Y.; Smith, M. R. Organic Letters 2001, 3, 2831-2833.

(22) Ishiyama, T.; Takagi, J.; Ishida, K.; Miyaura, N.; Anastasi, N. R.; Hartwig,
J. F. Journal Of The American Chemical Society 2002, 124, 390-391.

(23) Ishiyama, T.; Takagi, J.; Hartwig, J. F.; Miyaura, N. Angewandte
Chemie-International Edition 2002, 41, 3056-3058.

(24) Holleman, A. F. Chemical Reviews 1924, 1, 187-230.

(25) Gilman, H.; Bebb, R. L. Journal Of The American Chemical Society 1939,
61, 109-112.

145

(26) Wittig, G.; Pockels, U.; Droge, H. Berichte Der Deutschen Chemischen
Gesellschaft 1938, 71, 1903-1912.

(27) Takagi, J.; Sato, K.; Hartwig. J. F .; Ishiyama, T.; Miyaura, N. Tetrahedron
Letters 2002, 43, 5649-5651.

(28) Chotana, G.; Holmes, D.; Maleczka, R. E.; Smith, M. R. In Abstracts of
Papers of the American Chemical Society 2005; Vol. 230, p U3200-U3201.

(29) Hiroto, S.; Hisaki, I.; Shinokubo, H.; Osuka, A. Angewandte
Chemie-International Edition 2005, 44. 6763-6766.

(30) Hata, H.; Shinokubo, H.: Osuka, A. Journal of the American Chemical
Society 2005, 12 7, 8264-8265.

(31) Paul, S.; Chotana, G. A.; Holmes, D.; Reichle, R. C.; Maleczka, R. E.;
Smith, M. R. Journal Of The American Chemical Society 2006, 128, 15552-15553.

(32) Ishiyama, T.; Sato, K.; Nishio, Y.; Saiki, T.; Miyaura, N. Chemical
Communications 2005, 5065-5067.

(33) Shimada, S.; Batsanov, A. S.; Howard, J. A. K.; Marder, T. B.
Angewandte Chemie-International Edition 2001, 40, 2168-2171.

(34) Kuivila, H. G.; Benjamin, L. E.; Price, A. D.; Polevy, J. H.; Murphy, C. J.
Journal Of Organic Chemistry 1962, 27, 825-&.

(35) Szumigala, R. H.; Devine, P. N.; Gauthier, D. R.; Volante. R. P. Journal
of Organic Chemistry 2004, 69, 566-569.

(36) Carreno, M. C.; Ruano, J. L. G.; Sanz, G.; Toledo, M. A.; Urbano, A.
Journal Of Organic Chemistry 1995, 60, 5328-5331.

(37) Uson, R.; Oro, L. A.; Cabeza, J. A. Inorganic Syntheses 1985, 23, 126-30.

(38) Merola, J. S.; Kacmarcik, R. T. Organometallics 1989, 8, 778-784.

146

(39) Barton, T. J.; Hussmann, G. P. Journal of Organic Chemistry 1985, 50,
5881-5882.

(40) Liska, R. Heterocycles 2001, 55, 1475-1486.

(41) Wu, X. M.; Riekc, R. D. Journal of Organic Chemistry 1995, 60,
6658-6659.

(42) Wu, R. L.; Schumm, J. 3.; Pearson, D. L.; Tour, J. M. Journal Of Organic
Chemistry 1996, 61, 6906-6921.

(43) Boller, T. M.; Murphy, J. M.; Hapke, M.; Ishiyama, T.; Miyaura, N.;
Hartwig, J. F. Journal Of The American Chemical Society 2005, 12 7, 14263-14278.

147

CHAPTER 4
Bisoxazoline Ligands in Iridium Catalyzed Aromatic C-H Activation/ Borylation

Introduction

Selective functionalization of hydrocarbons represents one of the most
challenging problems in homogeneous and heterogeneous catalysis. Recently transition
metal catalyzed selective C—H activation-functionalization into valuable functional
groups such as C—O, C—N, C—Halogen bonds has emerged as a useful tool for this
purpose.l In 1999, Iverson and Smith reported the first thermal catalytic aromatic C-H
activation borylation.2 Since then, iridium catalyzed aromatic borylation has emerged as
the most convenient methodology for the regioselective functionalization of aromatic and
heteroaromatic hydrocarbons.3"9 Several common functional groups such as halogens,
ester, amide, nitrile, etc. are tolerated in this methodology. However, the most striking
feature of this new tool available to the synthetic chemist is that the regioselectivities are
governed by sterics.3'5’7‘” Hence, C—H borylations complement electrophillic aromatic

0 and directed ortho metalations.”22 Excellent selectivity is generally

substitutions2
observed in 1,3—di-substituted arenes, which are borylated at the 5-position (Scheme 4.1).
This unique feature allows for the synthesis of new aromatic building blocks, which were

previously either unknown or difficult to synthesize.6‘7"9

Scheme 4.1. Regioselective iridium catalyzed aromatic borylation.

X Y HBPin/BzPinz, X Y
0 [Ir] precatalyst, ligand.

BP'n
x, v = Cl, Br, Me, OMe, CN, 0023, CONRZ, CF3 etc '

 

148

Since the first report of this reaction by our group in 1999, the main focus of
research in this field has been to improve the selectivity (for aromatic C—H bond
activation vs. aromatic C-Halogen or benzylic C—H bond activation) and activity of the
catalyst system. Several ligands have been employed for this purpose. These include
phosphines such as dmpe or dppe,5 bpy/dtbpy,ll pyridine-imine,23 tris(pyrazolyl)boarte,24
carbenes,” and salicylaldimine.26 However no attempt has been made to improve the
regioselectivities when mixtures of regioisomers are obtained.

Borylations of 1,3- and symmetric 1,2-di-subsituted benzenes are the most
selective since both substrate classes have C-H sites whose flanking carbon-substituents
are hydrogen. Borylation of symmetric 1,4-substituted benzene also results in a single
regioisomer. However, borylations of unsymmetric 1,4-/1,2-di-substituted benzenes, and
2,5-di-substituted 5-membered heterocycles are more varied in their outcomes.

Good selectivity in borylation of unsymmetric 1,4-substituted benzenes can be
observed when the steric demands of the two substituents are quite different. For
example, when one of the two substituents in 1,4-substituted benzene is either F or CN,
high selectivity for borylation ortho to these substituents is feasiblei”7 In case of CN, we
have reported that although greater than 99% selectivity is possible when the second
substituent is large such as ester, amide, iodo, or trifluoromethyl; the selectivity decreases
when the second substituent has steric demand smaller such as to bromo or methyl.
Selectivities are also decreased in going from 1,4-di-substituted arene to
2,5-di-substituted 5-membered heterocycles (with identical substituents) due to the
opening of bond angle.7 We became interested to determine if it is possible to improve

the differentiation between the two substituents on the arene based on their sterics.

149

Results and Discussion

4-Chloro benzonitrile was chosen as a test substrate as its borylation using dtbpy
ligand gives an 80:20 mixture of two regioisomers as shown in Scheme 4.2.7 Since
regioselectivities in iridium-catalyzed borylation are governed by sterics, we conjectured
that increasing the steric bulk on the ligand closer to the iridium metal center might
improve the selectivity. Borylation using 6,6‘-di-methyl-bipyridyl ligand 4.1 was very
slow and the selectivity was almost identical to that for dtbpy. Probably the presence of
two methyl groups has halted the catalytic activity. Reducing the steric bulk to only one
Me group in 6‘-methyl-bipyridyl 4.2 also did not improve the selectivity under these

conditions.
Scheme 4.2. Regioselectivity in borylation of 4-Chloro benzonitrile.

1 equiv HBPin

 

 

 

4 Cl—QCN 3 mol% [Ir] catalyst, r.t. : Cl-Q—CN + ClO—CN
BPin PinB
2.2a 2.2b
Ligand 2.23 2.2b Time
'Bu 'Bu
\ / \ / 1.23 80 20 48 h complete
N N
\ / \ / 1.22 80 20 48 h complete
N N
\ / \ / 4.1 81 19 48 h, ~ 3% conversion
N N
Me Me
\ / \ / 4.2 77 23 48 h, ~ 10% conversion
N N
Me

150

The observed no effect in regioselectivities upon modifying the bpy based ligand
can be understood by examining the proposed active catalyst in this reaction. The
proposed active catalysts in the iridium catalyzed aromatic borylation are 5-coordinate,

l6 electron, bi-dentate ligated iridium tris-boryl complexes such as 4.3 shown in Figure

Bn
t-Bu . H BPin
/ , BPin O /N\l BP'
\ N\'lr.mein ”08180618 I’lr<‘BP'ln
B \/ 'N’ ‘BPin O N 'n
1- U ';
Bn
4-3 4.4

Figure 4.1. Proposed iridium catalysts for aromatic borylation.

The incoming arene substrate approaches from the bottom of the proposed
complex. From Figure 4.1, it is clear that the presence of methyl groups on the 6-position
of bipyridine derived ligand will only increase the steric bulk in the plane of bpy ligand
and will not assist in differentiating between the two substituents on the incoming arene
substrate. During our early studies on different ligands for aromatic borylation, we
noticed that di-imine type ligands, derived from the condensation of bi-napthyl-di-amine
and appropriate ketone, were effective for aromatic borylation at elevated temperatures.
Considering the apparent similarity in bpy and di-ketimine type ligands, we looked for
other ligands that contain the di-imine core but on which the steric bulk can be varied
above and/or below the plane of the ligand. Substituted bis-oxazoline ligands fulfill both
of these requirements. The 2—substituent in a bis-oxazoline type ligand will be above or
below the plane of ligand as it is on an sp3 hybridized carbon. As shown in Figure 4.1,

One of the 2-substituent on the bis-oxazoline ligand in the proposed active catalyst 4.4

151

should be pointing towards the incoming substrate, which might result in better
differentiation between the two substituents on the arene ring.

Although bis-oxazoline derived ligands have extensively been employed in
several types of reactions, they have not been tested in aromatic borylation. We decided

to investigate borylation of aromatic substrates using these ligands (Figure 4.2).

'Bu 'Bu 0 O 0W0
‘ — ENHNl [EH2] L1. .1;
BLT tBu

\ ,1 k, / PhHZC‘“ CH2Ph

1 .23 4.5 4.6 4.7

Figure 4.2. Bidentate di-imine based ligands used for aromatic borylation.

Borylation of 3-chlorobenzotrifluoride was attempted with 2,2'-bis[(4S)-4-benzyl-
2-oxazoline] (4.5). To our delight, the reaction was complete in 48 h at room temperature

using 3 mol % 4.5/[Ir(OMe)COD]2, and the borylated product was isolated in 82% yield

 

 

 

(Figure 4.3).
1.5 mol% [Ir(OMe)(COD)]2 F3C Cl
F3C Cl . 3 mol% 4.5 .
+ BQPIHQ > 82% yield
THF, r.t., 48 h
BPin
1.5 mol% [Ir(OMe)(COD)]2 F3C CF3
F30 CF3 . 3 mol% 4.6
+ 0.5 B2P1n2 > Full
THF, r.t., 48 h conversion
BPin in 48 h
1.5 lTlOlo/o [Ir(OMe)(COD)]2 F3C Cl
F30 C' . 3 mol% 4.7 .
+ 82P1n2 > No conversron
THF. r.t. after 24 h at r.t.

25% conversion
after 96 h at 100 °C

Figure 4.3. Aromatic borylation with bisoxazoline ligands.

152

Borylation was also possible with unsubstituted 2,2’-bis(2-oxazoline) (4.6). The
reaction time for heteroaromatic substrates was even less than that for aromatic
substrates. Increasing the carbon backbone in 2,2-isopropylidene—bis(4-tert-butyl-2-
oxazoline) (4.7) was not helpful as no catalytic borylation of 3—chlorobenzotrifluoride
was observed at room temperature. This indicated the importance of appropriate bite
angle for better catalytic activity. It is worthwhile to mention that in the above mentioned
reactions, the catalyst was not pre-generated by first mixing [Ir(OMe)(COD)]z with
HBPin, which may have resulted in low activity. Still, these results were encouraging, as
only bpy based ligands were previously known to catalyze aromatic borylation at ambient
temperatures.

Borylation of 4-chlorobenzonitrile was attempted and we were pleased to observe
that the regioselectivity was improved from 80:20 with 1.23 to 93:7 using 4.5.
Unsubstituted bisoxazoline ligand 4.6 gave selectivity of 84:16 under these conditions. It
seems that the presence of benzyl groups on the 2-position in 4.5 (vs. 4.6) is helpful in
differentiating the two substituents on the arene substrate.

We next examined borylation of other substrates where mixtures of regioisomers
were observed. The results are presented in Table 4.1. For reference the regioselectivities

using dtbpy ligand are also included.

153

Table 4.1. Borylation regioselectivities for 4.5 vs. dtbpy (1.23).a

A

 

 

P d t 4.5 1.23
Entry Substrate to ”C S b Ratio 3 : b Ratio 3 : b
a %yield, Time (h), %yield, Time (h),
Boron equiv Boron equiv
NC 0 Me NC 0 Me NC 0 Me -9 -
1 >99.1 85.15
PinB BPin 1'5 "5
2.253 2.258
Me Me Me
I l I
2 CN N Me NC N Me NC N Me 97:3b 85:15
W U U 66. (72)c 80, (16)
_ 3 1.5
PinB BPin
2.243 2.248
BPin
Br PinB Br Br
3 | \ l \ | \ 93:7b 67;33
, , , 85. (6) 81, (18)
NC N NC N NC N 1.5 2
2.27:. 2.27b
Br PinB Br Br
4 | \ | \ l \ 75:25a 87:13a
/ / / 79. (64)e —'. (16)
N Cl N Cl PinB N CI 1.5 1.5
4.88 4.88
PinB BPin
93:70 80:20
59 NC—O-Cl NC CI NC CI 60, (36) 76,(36)
0.25 0.25
2.23 2.28
PinB BPin
. h - h
59 F—QCI FOO FGCI 983416? 9232-51?
0.25 0.25
4.93 4.9b
7 O 0 8P. 0 > 99.4:06i 97.5:25i
/ / '” / 93, (1) 82, (0.5)
1.2 1.2
BPin
4.10A 4.103

 

aUnless otherwise noted, all reaction were carried out at room temperature with 3 mol% [Ir]/4.5 catalyst
loading and 1.2-1.5 equiv of HBPin. Yields are based on substrate. Ratios were determined by GC-FID in
crude reaction mixture upon completeion of reaction. t’Regioisomer assignment is based on ref. 7.
cReaction was run by pre generating the catalystusing 0.2 equiv HBPin, 3 mol% [ir(OMe)(COD)]2, and 6
mol% 4.5. 1 equiv of nglnz was used as the boron source. About 80% conversion was observed after 48
h at r.t.. after which additional 1.5 mol% [ir(OMe)(COD)]2, 3 mol% 4.5, and 1 equiv HBPin were added.
Reaction was complete after 72 h.dSee experimental section for regioismer assgnment by 2D NMR.
°Reaction started with 3 mol% [Ir(OMe)(COD]2, 3 mol% 4.5 and 1.5 equiv HBPin. After 30 h, additional 1.5
mol% [Ir(OMe)(COD)]2 was added and the reaction was complete alter 64 h. 'Reaction went to full
conversion, however no attempt was made to isolate the product. 9Yields are based on HBPin.
hRegioisomer assgnment of major isomer is based on 13C NMR. iRegioismer assgnment is based on ref.

12 and 10.

154

Borylation of unsymmetric 2-cyano-5-methyl filran was found to be highly
selective with greater than 99% regioselectivity for functionalization adjacent to smaller
cyano group. This selectivity was much better than that for 1.23, which was 85:15.7
Although borylation of 2-cyano-5-methyl furan with 4.5 was complete in less than 2 h,
borylation of more electron rich substrate, 2-Cyano-l,5-di-methyl-pyrrole, with this
ligand was very sluggish at room temperature. Here 9 mol% [Ir]/4.5 was required for full
conversion in 64 h. Despite its low reactivity, 4.5 was more selective (97:3) as compare
to 1.23 (85:15).7

For 2-cyano-4-brom0pyridine, where the two substituents are para to each other,
the regioselectivity was found to be 93:7 using 4.5. This selectivity was much better than
that for dtbpy, which was 67:33.7 The selectivity for this substrate using 4.6 was 78:22.
This indicates that the presence of benzyl groups on the bisoxazoline ligand results in
better steric differentiation between the bromo and cyano substituents in the substrate.
Similar selectivities for borylation of 4-chlorobenzonitrile and 2-cyano-4-bromopyridine
using 4.5 indicate a slight electronic preference for borylation at the 4-position of
pyridine.

It has been reported that the borylation of unsubstituted pyridine takes place at 3-
and 4-positions with statistical 67:33 selectivity.l2 The absence of any borylation at the
2-position is considered to be due to the possible adduct formation between pyridine and
borane (however the llB NMR indicates no interaction between HBPin and pyridine). As
a consequence, borylation of 3-substituted or 2,3-di-substituted pyridine should
selectively take place at the 5-position. Surprisingly, borylation of

2-Chloro-3-bromopyridine with [Ir]/dtbpy catalyst system gave a mixture of two

155

regioisomers. While the major isomer was the 5-borylated product, 2D NMR analysis
showed that the minor isomer was 6-borylated product. The result was surprising since
iridium catalyzed borylation on the 2-position of pyridine, when 3- and 4-positions are
available for C—H borylation, is unprecedented.27 With 4.5 the selectivity was even better
for the 2-position and the monoborylated product mixture (75:25) was isolated in 79%
yield. The formation of the 5-borylated product as the major isomer, even though the
2-position is more electronically favored (in the absence of any steric hindrance via
adduct formation) hints the participation of more than one catalytically active species.
lsomeric purities of the monoborylated products for entries 6 and 7 were increased up to
99.4% using 4.5.

Monoborylation of l-methylpyrazole with dtbpy gave a mixture of 5- and
4-borylated regioisomers with 90:10 selectivity (Figure 4.4). Surprisingly, the
regioselectivity using 4.5 was also identical. Considering that bulky benzyl groups in 4.5
may be causing hindrance for borylation next to the NMe group, we tested the

unsubstituted 4.6 for this substrate. Indeed the selectivity was improved to 97:3 with 4.9.

156

Me Me

.N - ,N
NJBPIn big—2

 

1.5 mol% [Ir(OMe)(COD)]2 BPin
3 mol% dtbpy (1.23) ‘ 4.113 4.11b
ether, r.t., 5 h, 67% T 90 : 10

1.5 mol% [Ir(OMe)(COD)]2

Me
N
, 3 mol% 4.5
N 7 ' e 90 -
\ / + 1'5 HBPm ether, r.t., 18 h ’ 10

 

3 mol% [Ir(OMe)(COD)]2
6 mol% 4.6 :
THF, r.t., 10 h, 59% 97 ‘ 3

 

 

Figure 4.4. Regioselectivities for monoborylation of 1-methylpyrazole.

Monoborylation of 3-substituted thiophenes also give mixtures of 2- or
5-monoborylated regioisomers when the 3-substituent is sterically less bulky (e.g. Me,
Cl, Br, CN). We therefore also studied these substrates to see if any improvement in
regioselectivity is possible with ligand 4.5 (Scheme 4.3). Our results for these substrates
are shown in Table 4.2.

For 3-cyanothiophene, the selectivity with dtbpy (1.23) was 47:53. This was not
the sterically preferred out come, and was an exception to the general observation that the
regioselectivities in Ir catalyzed borylation are governed by sterics. The combination of
electronic activation and very small size of the cyano group may be the reason for the
slight preference for borylation on the 2-position in this case. Using 4.5, the
regioselectivity was improved to 38:62. It seems that the bisoxazoline ligand 4.5 is more
selective for borylation ortho to the cyano group. At the same time, we thought that

Presence of bulky benzyl groups in 4.5 might be shifting the borylation away from the

157

2-position to the 5-position. Hence borylation using unsubstituted ligand 4.6 was

attempted, and indeed the selectivity was improved to 14:86 in favor of the 2-position.

Scheme 4.3. Monoborylation of 3-substituted thiophenes with 4.5.

 

1 equiv HBPin,
2 equiv S 1.5 mol% [Ir(OMe)(COD)]g, A? S BPin PinB S
w 3 mol% 4.5, W + m
R ether, r.t. 1h R R
3.xa 3.xb

Table 4.2. Comparison of regioselectivities for monoborylation of 3-substituted

thiophenes with 4.5 and 1.23 according to scheme 4.3.3

 

 

Products 4-5 1-23
Entry Substrate 3 b 3.xa : 3.xb 3.xa : 3.xb
%yield o/oy19ld
18 S S BPin PinB S 38:62 47:53
3\ /l \ / \ / 52 54
NC NC NC
3.88 3.8b
28 S S BPin PinB 3 86:14 78:22
5\ /7 \ / m 66 66
CI Cl Cl
3.98 3.9b
3 S S BPin PinB 3 94:6 89:11
5\ /l W m 63 72
Br Br Br
3101: 3.108
4 S S BPin PinB 3 93:7 89:11
S\ /l W m 68 67
Me Me Me
3.118 3.118

‘

“All reactions were carried out under conditions described in Scheme 4.3. Regioisomeric ratios
were determined by GC-FID. Regioisomeric assigments are based on 1H NMR. bRegioselectivity
Using 4.6 was 14:86 with 59% yield. cRatio determined by 1H NMR.

 

158

When the 3-substituent is Cl, Br, or Me, the major monoborylated isomer is the
5-borylated isomer with 1.23, consistent with sterically directed borylation. For these
substrates the regioselectivities were further slightly improved with 4.5.

2,5-substituted thiophenes also give a mixture of regioisomers when the 2- and
5-substituents are not identical (Scheme 4.4). The two regioisomers can easily be
identified by the lH NMR chemical shifts of the methine protons in the borylated
products. The major product is the isomer where borylation takes place next to the
sterically less demanding substituent. Our results for some of these substrates are shown

in Table 4.3.

159

Scheme 4.4. Monoborylation of 2,5-di-substituted thiophenes with 4.5.

1.5-2 equiv HBPin,

 

R1 S R2 1.5 mol% [lI(OMe)(COD)]2, ‘ R1 S R2 R1 3 R2
ether, r.t. PinB BPin
3 b

Table 4.3. Borylation of 2.5-substituted thiophenes according to scheme 4.4.

 

 

 

4.5 1.23
Pr d t 3:b 32b
Entry Substrate 0 “CS b % [Ir], Time (h) % [Ir], Time (h)
3 Boron equiv Boron equiv
%yield %yield
1 Cl 3 Me CI 3 Me CI 3 Me 85:15 70:30
1.5 1.5
PinB BPin 82 86
3.218 3.218
2 CI 3 Br CI 3 Br Cl 3 Br 72:28 67:33
1.5 2
PinB BPin 87 87
3.198 3.19b
3 CI 3 l Cl 3 l CI 3 I 92:8 85:15
U U U we» 3......
1.5 1.5
PinB BPin 89 89
3.208 3.20b
4 NC 3 Br NC 3 Br CN 3 Br >98:2 _a
PinB BPin 90
2.288 2.26b
s s “ —
CI CI CI CI 3. (6)
5 .-
W W 1.5 31150)
34 .
Me PinB 86
3.16
6 Br 8 Br Br 3 Br _ 3.(5) 9,618)
\ / \ / 195’ 2.5
Me PinB 56
3.17

aStoichiometric i.e. ~3% conversion by GC-FID was observed when the borylation was
attempted with 1.23 in TH F.

160

For 2-chloro-5-methyl-thiophene, the selectivity was improved from 70:30 with
dtbpy to 85:15 with 4.5. Since Me and Br are of similar size, we expected a similar
increase for 2-Chloro-S-bromo-thiophene. However the use of 4.5 caused only slight
increase in selectivity for this substrate. Presumably electronic factors may also have
contributed in improvement of selectivity in the case of 2-chloro-S-methyl-thiophene. A
more significant improvement in regioselectivity was also observed for
2-chloro-5-iodo-thiophene.

Despite the slight increase in selectivity for 2-chloro-5-bromo-thiophene, we
noticed that the reaction was complete in only 3 h with 3 mol% [Ir]/4.5 as compare to 28
h with 6 mol% [Ir]/dtbpy. Longer reaction time with dtbpy ligand is probably due to the
activation of weak C-Halogen bond in this case which results in catalyst deactivation.
This result prompted us to test borylation of 2-cyano-5-bromo-thiophene, a substrate
whose catalytic borylation was not feasible with dtbpy ligand.7 Indeed the catalytic
borylation of 2-Cyano-5—bromo-thiophene was found to be possible with 4.5 and the
borylated product was isolated in 90% yield. Similarly, use of 4.5 resulted in reduced
reaction times/catalyst loadings for borylation of 2,5-di-bromo and 2,5-di-chloro

thiophenes (Entries 5 and 6).

161

 

Scheme 4.5. Monoborylation of 1,3-di-fluorobenzene with ligands 1.23, 4.5, and 4.6.

 

1 equiv HBPin, BF‘”
, F F 1.5 mol% [Ir(OMe)(COD)]g, F F F F F F
4 equw . a: + +
3 mol% ligand, .
ether, r.t. BP'”
BPin
2.158 2.15b 2.150

Table 4.4. GC-FID ratios of monoborylated products of 1,3-di-fluorobenzene according

to scheme 4.5.

 

Regioisomers

 

 

Entry Ligand Time (h) 2.153 2.15b 2.15c
1 1.23 16 48 31 21
2 4.5 36 22 21 57
3 4.6 36 5 12 83

 

Regioisomeric assignments were made by comparing the GC-FID retention
times of the products in the crude reaction mixture with those for authentic
samples.

Fluorine has a very small steric demand, allowing boryltaion ortho to F
substituents in arenes. Monoborylation of 1,3-di-fluorobenzene was examined with
ligands 1.23, 4.5 and 4.6 (Scheme 4.5). The observed regioisomer distribution is shown
in Table 4.4. The major monoborylated product with 1.23 was the 5-borylated isomer, in
accordance with the sterically directed aromatic borylation. However, the major
regioisomer with 4.6 was 2.15c, indicating the preference for bisoxazoline type ligands to
borylate ortho to the fluoro group. Interestingly, the presence of benzyl groups in 4.5

directed borylation away from the fluorine substituents.

162

Scheme 4.6. Monoborylation of 1,2-di-fluorobenzene with ligands 1.23, 4.5, and 4.6.

 

1 equiv HBPin,
, F 1.5 mol% [Ir(OMe)(COD)]z, F F
4 equw I) 3 mol% ligand, F D +
F ether, r.t. F BPin F
BPin
4.123 4.12b

Table 4.5. GC-FID ratios of monoborylated products of 1,2-di-fluorobenzene according

to scheme 4.6.

 

Regioisomers

 

 

Entry Ligand Time (h) 4.123 4.1 2b
1 1.23 16 37 63
2 4.5 36 18 82
3a 4.6 36 9 91

 

Regioisomeric assignments was made by comparing the GC-FID
retention time of the products in the crude reaction mixture with
that for an authentic sample of 4.123. alProduct mixture from a
reaction in THF for 48 h at room temperature using 3 mol% [lr]/4.6,
1 equiv HBPin, and 2 equiv of arene substrate was isolated in 31%
yield.

For monoborylation of 1,2-difluorobenzene (Scheme 4.6), all three ligands tested
here were more selective for borylation ortho to the fluoro substituent. The best
selectivity was observed with 4.6. The origin for the preference of borylation ortho to F
vs. H is not clear at this point. The results described here are preliminary, and hence,
detail work including regioisomeric distribution with other ligands such as dmpe/dppe,
investigation of other fluorinated aromatics along with isolated yields needs to be carried

out in order to develop a better understanding (of borylation of fluorinated substrates).

163

Conclusions

In conclusion, bisoxazoline type ligands are effective in iridium-catalyzed
borylation. Heteroaromatic substrates and activated aromatics can easily be borylated at
room temperature. Several cases were noticed where bisoxazoline derived ligands 4.5 and
4.6 gave better regioselectivity as compare to dtbpy. 4.5 was also more effective than
dtbpy for borylation of 2,5-di-halo substituted thiophenes. Generally, the presence of
bulky group on the 2-position of bisoxazoline ligand resulted in improved steric
differentiation of the substituents in the substrate. However the exact origin of difference
in borylation regioselectivities observed with bisoxazoline type ligands vs. dtbpy is not

clear at this point.

164

 

Experimental Details and Spectroscopic Data
Materials

All substrates were purified before use. Solid substrates were sublimed under
vacuum and liquid substrates were purified by distillation. Bis(n4-l,5-Cyclooctadiene)-di-
,u-methoxy-diiridiuma) [Ir(OMe)(COD)]z was prepared per the literature procedure.28
Pinacolborane (HBPin) was generously supplied by BASF and was distilled before use.
Ether and tetrahydrofuran (THF) were obtained from a dry still packed with activated
alumina and degassed before use. Silica gel (230—400 Mesh) was purchased from
EMD".
General Borylation Procedures

General Procedure A

In a glove box, a 20 mL scintillation vial equipped with a magnetic stirring bar,
was charged with 2,2’-bis[(4S)-4-benzyl-2-oxazoline] (9.6 mg, 0.03 mmol, 3 mol%)
(4.5). Ether (1 mL) was added to the scintillation vial in order to dissolve the ligand.
[Ir(OMe)(COD)]z (10 mg, 0.015 mmol, 3 mol% Ir) was weighed in a test tube. HBPin
(218 ML, 192 mg, 1.50 mmol, 1.50 equiv) or BzPinz (256 mg, 1.00 mmol, 1 equiv), and
ether (1 mL) were added to the [Ir(OMe)(COD)]z containing test tube. The resulting
solution was transferred to the 20 mL scintillation vial. Additional ether (1 mL) was used
to wash the test tube and the washings were transferred to the scintillation vial. Substrate
(1 mmol, 1 equiv) was then added to the scintillation vial and the reaction mixture was
stirred at room temperature. The reaction was monitored by GC-FID/MS. After
completion of the reaction, the volatile materials were removed on a rotary evaporator.
The crude material was dissolved in CHzClz and passed through a short plug of silica to

afford the corresponding borylated product.

165

 

General Procedure B (Borane as limiting reactant)

In a glove box, a 20 mL scintillation vial equipped with a magnetic stirring bar,
was charged with 2,2'-bis[(4S)-4-benzyl-2-oxazoline] (9.6 mg, 0.03 mmol, 3 mol%).
(4.5). Ether (1 mL) was added to the scintillation vial in order to dissolve the ligand.
[Ir(OMe)(COD)]z (10 mg, 0.015 mmol, 3 mol% Ir) was weighed in a test tube. HBPin
(145 ML, 128 mg, 1 mmol, 1 equiv) and ether (1 mL) were added to the [Ir(OMe)(COD)]z
containing test tube. The resulting solution was transferred to the 20 mL scintillation vial.
Additional ether (1 mL) was used to wash the test tube and the washings were transferred
to the scintillation vial. Substrate (2.00 mmol, 2.00 equiv) was then added to the
scintillation vial and the reaction mixture was stirred at room temperature. The reaction
was monitored by GC-FlD/MS. After completion of the reaction, the volatile materials
were removed on a rotary evaporator. The crude material was dissolved in CHzClz.
Unreacted starting material was recovered by eluting with hexanes through a short plug
of silica. Eluting with CHzClz afforded the corresponding borylated product.

General Procedure C

The general procedure A was applied using 2,2’-bis(2-oxazoline) (4.6) as the
ligand.

General Procedure D

The general procedure A was applied using dtbpy (1.23) as the ligand and
hexanes as the solvent.

General Procedure E
The general procedure B was applied using dtbpy as the ligand and hexanes as the

solvent.

166

 

Table 4.1, Entry 1. S-methyl-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-Z-yl)furan-2-

carbonitrile (2.253).

NCOMe
\/

PinB
2.258

The general procedure A was applied to 2-cyano-5-methy1furan (105 ILL, 107 mg,
1 mol, 1 equiv) and HBPin (218 11L, 192 mg, 1.50 mmol, 1.50 equiv) for 2 h. Only one
regioisomer was observed by GC-FID. The borylated product was isolated as a white
solid (225 mg, 96% yield, mp 89 °C) with >99% isomeric purity by 1H NMR.
Regiochemical assignment is based on ref. 7. 1H NMR(CDC13, 300 MHz): 6 6.24 (q, J =
1.0 Hz, 1 H), 2.31 (d, J= 1.0 Hz, 3 H, CH3), 1.30 (br s, 12 H, 4 CH; of BPin); 13C NMR
{1H} (CDCI3, 75 MHz): 6 157.7 (C), 130.5 (C), 112.0 (C), 111.5 (CH), 84.4 (2 C), 24.7
(CH3, 4 CH3 of BPin), 13.5 (CH3); llB NIVR (CDCl3, 96 MHz): 6 28.9; FT-IR (neat) 17:
2984, 2936, 2224, 1541, 1406, 1373, 1331, 1300, 1147, 1041, 854, 817, 709 cm“; GC-
MS (EI) m/z (% relative intensity): M+1 234 (100), 233 (98), 218 (23), 203 (16), 190 (41),
175 (23); HRMS (FAB): m/z 234.1305 [(M”); Calcd for C12H17BNO3: 234.1302].

Borylation with Procedure D with 1.5 equiv HBPin for 0.5 h gave two

regioisomers in ratio 85:15 with 95% (221 mg) yield.7

167

 

Table 4.1, Entry 2. Borylation of 2-cy3no-l,S-di-methylpyrrole.

Me Me
NC N Me NC N Me
H U
PinB BPin
97 3
2.243 2.24b

Borylation of 2-cyano-1,5-di-methylpyrrole (120 mg, 1 mol, 1 equiv) with
BzPinz (254 mg, 1.00 mmol, 2.00 equiv of Boron) was started after pre-generating the
catalyst using 3 mol% [Ir(OMe)(COD)]z, HBPin (26 mg, 0.20 mmol, 0.20 equiv), and 6
mol% of 4.5. After 48 h at room temperature, about 80% conversion of the starting
material was observed. Additional 3 mol% [Ir]/4.5 and 1 equiv of HBPin was added and
the reaction was run for 24 more h at room temperature. The ratio of two monoborylated
regioisomers at the end of reaction was 97:3 by GC-FID. Regiochemical assignment is
based on ref. 7. The borylated product was isolated as a white solid (163 mg, 66% yield,
mp 130-131 °C). 1H NMR (CDCI3, 300 MHz): 6 (2.243) 6.22 (d, J= 0.7 Hz, 1 H), 3.62
(s, 3 H, NCH3), 2.21 (d, J = 0.7 Hz, 3 H, CH3), 1.29 (br s, 12 H, 4 CH3 of BPin); 13C
NMR {1H} (CDCI3, 125 MHz): 6 (2.243) 135.6 (C), 114.5 (CH), 114.3 (C), 110.3 (C),
83.6 (2 C), 32.4 (NCH3), 24.8 (CH3, 4 CH3 of BPin), 12.2 (CH3); 11B NMR (CDCI3, 96
MHz): 6 28.9; FT-IR (neat) V: 2978, 2215, 1562, 1500, 1408, 1311, 1260, 1142, 1016,
707 cm'l; GC-MS (EI) m/z (% relative intensity): M 246 (100), 231 (35), 189 (32), 160
(25), 146 (58); HRMS (E1): m/z 246.1539 [(M); Calcd for C13H19BN202: 246.1540].

Borylation with Procedure D with 1.5 equiv HBPin for 16 h gave two

regioisomers in ratio 85:15 with 80% yield.7

168

 

Table 4.], Entry 3. Borylation of 2-cyano-5-bromopyridine (2.273 + 2.27b).

BPin
PinB \ Br \ Br
I 3 l ,
NC N NC N
93 7
2.273 2.27b

The general procedure A was applied to 2-cyano-5-bromopyridine (183 mg, 1
mol, 1 equiv) and HBPin (218 uL, 192 mg, 1.50 mmol, 1.50 equiv) for 6 h. The ratio of
two monoborylated regioisomers at the end of reaction was 93:7 by GC-FID.
Regiochemical assignment is based on ref. 7. Kugelrohr distillation gave mixture of
monoborylated products as a white solid (263 mg, 85% yield). 1H NMR (CDCI3, 300
MHz): 6 (2.273) 8.76 (d, J= 2.4 Hz, 1 H), 8.28 (d, J= 2.4 Hz, 1 H), 1.37 (br s, 12 H, CH3
of BPin), (2.278) 8.76 (s, 1 H), 7.85 (s, 1 H), 1.36 (br s, 12 H, CH3 of BPin); ”C NMR
{'H} (CDCI3, 75 MHz): 6 (2.273) 153.6 (CH), 145.8 (CH), 136.1 (C), 124.4 (C), 116.6
(C, nitrile), 85.7 (2 C), 24.8 (CH3, 4 CH; of BPin), (2.27b) 153.1 (CH), 134.5 (CH),
131.4 (C), 130.1 (C), 116.7 (C, nitrile), 85.6 (2 C), 24.8 (CH3, 4 CH3 of BPin); ”B NMR
(CDC13, 96 MHz): 6 29.5; FT-IR (neat) V: 3048, 2979, 2244, 1566, 1539, 1416, 1383,
1342, 1318, 1269, 1142, 1069, 1026, 964, 872, 847, 771 cm"; GC-MS (El) m/z (%
relative intensity): (2.273) 308 M (41), 310 (M2+ 37), 293 (95), 267 (96), 250 (65), 229
(34), 209 (42), (2.27b) 308 M+ (7), 293 (33), 267 (17), 229 (100), 187 (91); Anal. Calcd
for CrthaBBerOzz C, 46.65; H, 4.57; N, 9.07. Found: C, 46.52; H, 4.48; N, 8.76.

The ratio of the two regioisomers with Procedure C for 6 h was 78:22 with 78%
yield.

The ratio of the two regioisomers with Procedure D with 2 equiv HBPin for 18 h

was 67:33 with 81% yield.7

169

 

Table 4.1, Entry 4. Borylation of 2-chloro-3-bromopyridine (4.83 + 4.8b).

PinB \ Br \ Br
I / I /

N CI PinB N CI
75 25
4.83 4.8b

The general procedure A was applied to 2-chloro-3-bromopyridine (192 mg, 1
mol, 1 equiv) and HBPin (218 11L, 192 mg, 1.50 mmol, 1.50 equiv) with 3% [Ir]/4.5
catalyst loading for 30 h. At that stage, additional 1.5 mol% [Ir(OMe)(COD)]z was added
and the reaction was stirred for 34 more hour. The ratio of the two monoborylated
regioisomers at the end of reaction (total 64 h) was 75:25 by GC-FID. Kugelrohr
distillation gave mixture of monoborylated products as a white solid (252 mg, 79%
yield). NMR spectroscopy (gHMQC and gHMBC) was used to assign the regiochemistry
of the minor isomer as described in the following section. IH NMR (CDCI3, 300 MHz): 6
(4.83) 8.57 (d, J = 2 Hz, 1 H), 8.22 (d, J = 2 Hz, 1 H), 1.29 (br s, 12 H, 4 CH3 of BPin),
(4.8b) 7.86 (d, J= 7.8 Hz, 1 H), 7.54 (d, J= 7.8 Hz, 1 H), 1.31 (s, 12 H, 4 CH3 of BPin);
”C NMR {1H} (CDC13, 125 MHz): 8 (4.8a) 153.4 (CH), 153.2 (C), 147.9 (CH), 120.1
(C), 84.7 (2 C), 24.7 (CH3, 4 CH; of BPin), (4.8b) 151.3 (C), 140.9 (CH), 130.0 (CH),
122.7 (C), 85.0 (2 C), 24.7 (CH3, 4 CH3 of BPin); “B NMR (CDCl,, 96 MHz): 8 29.4;
FT-IR (neat) V: 3040, 2980, 2932, 1576, 1344, 1142, 1037, 844, 733, 675 cm"; GC-MS
(E1) m/z (% relative intensity): (4.83) 318 M+1 (85), 317 M (24), 319 M+2 (45), 304 (47),
302 (37), 276 (9), 262 (16), (4.8b) 319 M“2 (80), M+ 317 (66), 304 (33), 302 (28), 284
(21), 282 (17), 263 (87), 261 (67), 238 (10), 220 (38), 218 (34); Anal. Calcd for
CHHMBBrClNOz: C, 41.49; H, 4.43; N, 4.40. Found: C, 41.63; H, 4.51; N, 8.22.

The ratio of two regioisomers with Procedure D for 16 h was 87: 1 3.

170

C6 C4

 

 

 

 

 

 

 

 

 

 

C4’ .
C5
C2
. C3
‘ C3
C2
. l l
n j
__I (99013
Hd 7.8“: O
a E
1.6-.1 ' O
F; . 0
HC I 7.8-g
-; O o
3.0“;
_= c 0
J 2‘
1 "’5 o o
Hb
8.4“; O O
8 6- a 0
Ha ’
8 8- -
: I Y Y I T I T Y Y Y T Y Y " V I Y I Y Y I Y I Y Y V Y T T T T—T Y I I I T Y T Y I—rj 1' Y I I T 7 TT
165 160 155 150 145 140 135 130 125 120 115
'1 (99')

Figure 4.5. gHMBC spectrum of product mixture of 4.83 and 4.8b.

Regiochemical assignment of 4.83 and 4.8b.

4 4~ BPin
' 5 3 Br 5‘ 3‘ Br Br
PinB \ \ \
l / 2 6‘ l / 2‘ l
6 - ’
N CI PinB N Cl N CI
75 25 not detected
4.83 4.8b 4.8c

1H NMR of the product mixture showed that the value of the coupling constant J
between the two protons of the major regioisomer is 2.0 Hz. This data unambiguously
assign the major isomer as 4.83. The value of the coupling constant J between the two
protons of the minor regioisomer is 7.8 Hz This can either be for the 4-borylated (4.8c)

or 6-borylated (4.8b) product. Quaternary carbon atoms, C3 and C3‘, attached to Br in

171

major and minor isomer respectively can easily be identified as they appear most up-field
(Figure 5). Similarly, carbon atoms, C2 and C2‘, attached to C1 in major and minor
isomer respectively can also be easily identified as they are the deshielded quaternary
carbons above 150 ppm. Carbon C2‘ showed a strong 3-bond cross peak in the gHMBC
spectrum to proton Hc, to which carbon C3‘ also showed a week 2-bond cross peak. This
can only be true if proton He is on carbon C4‘, thereby ruling out the possibility of
4-borylated product, and hence unambiguously assigning the regiochemistry of the minor
isomer as being 6-borylated product. The minor regioisomer also does not show any
methine (CH) carbon above 150 ppm in the '3 C NMR spectrum, which should be the case
for the carbon C6 of 4.8c. The chemical shifts of the remaining carbons and their
corresponding cross-peaks in the gHMBC spectrum are also in accordance of this

assignment.

Table 4.1, Entry 5. Borylation of 4-chlorobenzonitrile (2.23 + 2.2b).

Cl CI
BPin
BPin
ON ON

93 7
2.23 2.2b

General procedure B was applied to 4-chlorobenzonitrile (550 mg, 4.00 mmol,
4.00 equiv) and HBPin (145 uL, 128 mg, 1 mol, 1 equiv) for 36 h. The ratio of two
monoborylated regioisomers at the end of reaction was 93:7 by GC-FID. Regiochemical
assignment is based on ref. 7. Kugelrohr distillation furnished the borylated product
mixture as a white solid (158 mg, 60% yield). IH NMR(CDC13, 300 MHz): 6 (2.23) 7.80

(d, J= 2.2 Hz, 1H), 7.57 (d, J: 8.3 Hz, 1H), 7.45 (dd, J= 8.3, 2.2 Hz, 1H), 1.33 (br s,

172

12H, 4 CH3 of BPin), (2.2b) 7.94 (d, J= 2.2 Hz, 1H), 7.56 (dd, J= 8.3, 2.2 Hz, 1H), 7.41
(d, J= 8.3 Hz, 1H), 1.32 (br s, 12H, 4 CH3 of BPin); ”C NMR {'H} (CDC13, 75 MHz): 8
(2.23) 138.5 (C), 135.8 (CH), 134.5 (CH), 131.2 (CH), 118.0 (C nitrile), 115.3 (C), 85.0
(2 C), 24.6 (CH3, 4 CH; of BPin), (2.2b) 144.5 (C), 140.1 (CH), 134.6 (CH), 130.2 (CH),
117.8 (C nitrile), 110.2 (C), 84.7 (2 C), 24.6 (CH3, 4 CH3 of BPin); “B NMR (CDCI3, 96
MHz): 6 29.6; FT-IR (neat) V: 2982, 2228, 1587, 1554, 1479, 1402, 1373, 1333, 1271,
1215, 1169, 1144, 1103, 1065, 1042, 965, 870, 847, 831 cm"; GC-MS (E1) m/z (%
relative intensity): (2.23) 263 M+ (24), 248 (65), 222 (100), 205 (31), 164(32), 137 (11),
(2.2b) 263 M” (1), 248 (27), 228 (100), 186 (60), 164 (15), 142 (6); Anal. Calcd for
C13H15BC1N02: C, 59.25; H, 5.74; N, 5.32. Found: C, 58.90; H, 5.74; N, 5.10.

The ratio of two regioisomers with Procedure C was 84:16.

The ratio of two regioisomers with Procedure E was 80:207 with 76% yield.
Table 4.1, Entry 6. 2-(5-chloro-2-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-

dioxaborolane (4.93).

CI Cl
BPin
BPin
F F
99.4 .6
4.93 4.9b

General procedure B was applied to 4-fluorochlorobenzene (350 1.1L, 522 mg,
4.00 mmol, 4.00 equiv) and HBPin (145 11L, 128 mg, 1 mol, 1 equiv) for 6 h. The ratio
of two monoborylated regioisomers at the end of reaction was 99.4:0.6 by GC-FID.
Regiochemical assignment of the major product is based on the C—F coupling

information in the '3 C NMR (with the help of the fact that the boron bearing carbon is not

173

 

observed due to broadening from and coupling with boron). The GC-F ID peak area for
4.9b was decreased in going from ligand 1.23 to 4.5. The borylated product was isolated
as a white solid (213 mg, 83% yield, mp 75-76 °C). 'H NMR (CDCI3, 500 MHz): 8
(4.93) 7.66 (dd, J = 4.9, 2.9 Hz, 1H), 7.32-7.36 (m, 1 H), 6.96 (t, J = 8.3 Hz, 1H), 1.33 (br
s, 12H, 4 CH; of BPin); ”C NMR {‘H} (CDCI3, 75 MHz): 8 (4.93) 165.5 (d, 1J0; = 252
Hz, C), 136.2 (d, 3Jc-F = 8.1 Hz, CH), 133.0 (d, 3Jc-r = 9.1 Hz, CH), 128.9 (s, C), 116.8
(d, 2Jc.r: = 26.2 Hz, CH), 84.2 (2 C), 24.8 (CH3, 4 CH3 of BPin); 11B NMR (CDCI3, 96
MHz): 8 29.6; ”F NMR(CDC13,282 MHz): 8 —105.8; FT—IR (neat) v': 2982, 1610, 1485,
1408, 1338, 1267, 1221, 1143, 1099, 1070, 964, 875, 850, 821, 682, 640 cm'l; GC-MS
(E1) m/z (% relative intensity): (4.93) 256 M (80), 241 (100), 213 (17), 196 (73), 179
(20), 152 (74); Anal. Calcd for CrzHrsBClFozz C, 56.19; H, 5.89. Found: C, 56.26; H,
5.89.
The ratio of two regioisomers with Procedure E was 97.2:2.8 with 68% yield.

Table 4.1, Entry 7. 2-(benzofuran-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

(4.108).

O O
BPin

99.4 0.6
4.108 4.1 01)

The general procedure A was applied to benzofuran (108 11L, 118 mg, 1 mol, 1
equiv) and HBPin (175 ILL, 154 mg, 1.20 mmol, 1.20 equiv) for 1 h. The ratio of two
monoborylated regioisomers at the end of reaction was 99.4:0.6 by GC-FID.
Regiochemical assignment is based on ref. 12 and 10. The GC-FID peak area for 4.10b

was decreased in going from ligand 1.23 to 4.5. The borylated product was isolated as a

174

white solid (227 mg, 93% yield, mp 86—87 °C). 'H NMR(CDC13, 300 MHz): 8 7.58-7.62
(m, 1 H), 7.55 (dd, J= 8.3, 0.7 Hz, 1 H), 7.38 (d, J= 1.0 Hz, 1 H), 7.28-7.34 (m, 1 H),
7.20 (dt, J= 7.8 Hz, 1.0 Hz, 1 H), 1.36 (s, 12 H, CH3 of BPin); ”C NMR {'H} (CDCI3,
75 MHz): 8 157.5 (C), 127.5 (C), 125.9 (CH), 122.7 (CH), 121.8 (CH), 119.5 (CH),
111.9 (CH), 84.6 (2 C), 24.7 (4 CH3 of BPin); “B NMR (CDCI3, 96 MHz): 8 28.1; FT-IR
(neat) v: 3065, 2991, 2978, 2936, 1566, 1361, 1327, 1138, 1068, 962, 852, 831, 819,
756, 748, 692 cm"; GC-MS (E1) m/z (% relative intensity): M+ 244 (52), 245 (9), 243
(14), 229 (11), 201 (100), 159 (16), 158 (17), 144 (19); Anal. Calcd for C14H17BO3: C,
68.89; H, 7.02. Found: C, 68.82; H, 7.35.

Borylation with Procedure D gave two regioisomers in ratio 97.5:2.5 with 82%
yi e1 d.l°"2‘23

1-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole 94.113).

Me Me
N - N
. BPin .
N N
\\ /l \\ /Z
BPin
97 3
4.113 4.11 b

The general procedure C was applied to l-methylpyrazole (82 mg, 1 mol, 1
equiv) and HBPin (218 11L, 192 mg, 1.50 mmol, 1.50 equiv) with 6% [Ir] catalyst loading
for 10 h. The ratio of two monoborylated regioisomers at the end of reaction was 97:3 by
GC-FID. Regiochemical assignment is based on coupling information in the 1H NMR.
Kugelrohr distillation afforded the borylated product was isolated as a white solid (122
mg, 59% yield, mp 62-63 °C). 1H NMR (CDCI3, 300 MHz): 6 (4.113) 7.46 (d, J = 2.0

Hz, 1 H), 6.69 (d, J= 2.0 Hz, 1 H), 4.06 (s, 3 H, CH3), 1.31 (br s, 12 H, 4 CH3 of BPin);

175

13C NMR {'H} (CDCI3, 75 MHz): 6 (4.113) 138.3 (CH), 115.8 (CH), 84.1 (2 C), 39.3
(CH3), 24.8 (CH3, 4 CH3 of BPin); “B NMR (CDC13, 96 MHz): 8 27.7; FT-IR (neat) v“:
2982, 1529, 1350, 1331, 1288, 1250, 1143, 1105, 1012, 854, 798, 704 cm'l; GC-MS (EI)
m/z (% relative intensity): M”l 209 (100), 193 (2), 165 (3), 122 (6); HRMS (EI): m/z
209.1464 [(M“); Calcd for CergBNZOZ: 209.1461].

Borylation with Procedure A with 3 equiv HBPin and 6 mol% [Ir] catalyst for 18
h gave two regioisomers in ratio 89:1 1.

Borylation with Procedure D with 1.5 equiv HBPin for 5 h gave two regioisomers
in ratio 90:10 with 67% yield.

Table 4.2, Entry 1. Borylation of 3-cyanothiophene (3.83 + 3.8b).

S BPin PinB 3
NC NC
38 62

3.83 3.8b

The general procedure B was applied to 3-cyanothiophene (182 ML, 218 mg, 2.00
mmol, 2.00 equiv) and HBPin (145 ILL, 128 mg, 1 mol, 1 equiv) for 1 h. The ratio of
two monoborylated regioisomers at the end of reaction was 38:62 by GC-FID. The
monoborylated product mixture was isolated as a white solid (145 mg, 62% yield). 1H
NMR (CDC13, 300 MHz): 6 (3.83) 7.62 (d, J = 4.9 Hz, 1 H), 7.38 (d, J = 4.9 Hz, 1 H),
1.36 (br s, 12 H, 4 CH3 of BPin), (3.8b) 8.13 (d, J = 1.2 Hz, 1 H), 7.75 (d, J = 1.2 Hz, 1
H), 1.33 (br s, 12 H, 4 CH3 of BPin); 13C NMR {1H} (CDCI3, 125 MHz): 6 (3.83) 132.7
(CH), 131.4 (CH), 118.3 (C), 115.2 (C), 84.9 (2 C), 24.7 (4 CH3 of BPin), (3.8b) 140.8
(CH), 138.1 (CH), 114.7 (C), 111.9 (C), 85.1 (2 C), 24.7 (4 CH3 of BPin); “B NMR

(CDCI3, 96 MHz): 6 28.6; FT-IR (neat) V: 2980, 2231, 1429, 1319, 1142, 1039, 850, 628

176

 

 

cm'l; GC-MS (E1) m/z (% relative intensity): (3.8a) 1V1+1 236 (100), 220 (78), 194 (51),
178 (33), 149 (36), 136 (31), (3.8b) M 235 (7), 220 (100), 192 (9), 149 (37), 136 (15);
Anal. Calcd for CHHMBNOZS: C, 56.19; H, 6.0; N, 5.96. Found: C, 55.74; H, 5.99; N,
6.0.

The ratio of two regioisomers with Procedure C was 14:86 with 59% yield.

The ratio of two regioisomers with Procedure E was 47 :53 with 54% yield.

Table 4.2, Entry 2. Borylation of 3-chlorothiophene (3.93 + 3.9b).

S BPin PinB 3
yr m
Cl CI
86 14
3.93 3.9b

The general procedure B was applied to 3-chlorothiophene (186 ILL, 237 mg, 2.00
mmol, 2.00 equiv) and HBPin (145 (1L, 128 mg, 1 mol, 1 equiv) for 1 h. The ratio of
two monoborylated regioisomers at the end of reaction was 86:14 by lH NMR. The
monoborylated product mixture was isolated as a white solid (161 mg, 66% yield). 1H
NMR (CDC13, 300 MHz): 6 (3.93) 7.43 (d, J = 1.0 Hz, 1 H), 7.35 (d, J = 1.0 Hz, 1 H),
1.32 (br s, 12 H, 4 CH3 of BPin), (3.9b) 7.51 (d, J= 5.0 Hz, 1 H), 7.01 (d, J= 5.0 Hz, 1
H), 1.34 (br s, 12 H, 4 CH; of BPin); ”C NMR {'H} (CDCl3, 125 MHz): 8 (3.9a) 136.9
(CH), 131.8 (C), 126.7 (CH), 84.4 (2 C), 24.7 (4 CH3 of BPin); 11B NMR (CDCI3, 96
MHz): 6 29.0; FT -IR (neat) V: 3107, 2980, 2932, 1522, 1421, 1356, 1336, 1142, 1026,
854, 665cm"; GC-MS (EI) m/z (% relative intensity): M+ 244 (100), 246 (38), 231 (15),
229 (38), 209 (24), 158 (27); Anal. Calcd for C10H14BC1028: C, 49.11; H, 5.77. Found:
C, 49.33; H, 5.81.

The ratio of two regioisomers with Procedure E was 78:22 with 66% yield.

177

Table 4.2, Entry 3. Borylation of 3-bromothiophene (3.103 + 3.10b).

S BPin PinB S
y] m
Br Br
94 6
3.108 3.108

The general procedure B was applied to 3-bromothiophene (190 ILL, 326 mg, 2.00
mmol, 2.00 equiv) and HBPin (145 ML, 128 mg, 1 mol, 1 equiv) for 1 h. The ratio of
two monoborylated regioisomers at the end of reaction was 94:6 by GC-FID. The
monoborylated product mixture was isolated as a white solid (182 mg, 63% yield). 1H
NMR (CDCI3, 300 MHz): 6 (3.103) 7.49 (d, J = 1.2 Hz, 1 H), 7.46 (d, J = 1.2 Hz, 1 H),
1.32 (br s, 12 H, 4 CH3 of BPin), (3.10b) 7.48 (d, J= 5.0 Hz, 1 H), 7.08 (d, J= 5.0 Hz, 1
H), 1.34 (br s, 12 H, 4 CH; of BPin); ”C NMR {‘H} (CDCI3, 125 MHz): 8 (3.108) 139.3
(CH), 129.5 (CH), 111.2 (C), 84.4 (2 C), 24.7 (4 CH3 of BPin); llB NMR (CDCI3, 96
MHz): 6 29.0; FT-IR (neat) V: 2980, 1518, 1415, 1350, 1143, 1026, 852, 665 cm"; GC-
MS (EI) m/z (% relative intensity): (3.103) W 289 (51), 290 (98), 288 (100), 275 (61),
273 (55), 247 ( 18), 245 (21), 230 (19) 204 (41), (3.10b) M+ 289 (13), 290 (25), 288 (27),
275 (10), 273 (9), 209 (100), 189 (11), 167 (67); Anal. Calcd for CroHraBBr02S: C,
41.56; H, 4.88. Found: C, 41.74; H, 4.88.

The ratio of two regioisomers with Procedure E was 89:11 with 72% yield.

Table 4.2, Entry 4. Borylation of 3-methylthiophene (3.113 + 3.11b).

S BPin PinB 5
yr :6

Me Me

93 7
3.118 3.11b

178

 

The general procedure B was applied to 3-methylthiophene (194 ML, 196 mg,
2.00 mmol, 2.00 equiv) and HBPin (145 11L, 128 mg, 1 mol, 1 equiv) for 1 h. The ratio
of two monoborylated regioisomers at the end of reaction was 93:7 by GC-FID. The
monoborylated product mixture was isolated as a white solid (153 mg, 68% yield). 1H
NMR (CDC13, 300 MHz): 6 (3.103) 7.42 (d, J= 0.7 Hz, 1 H), 7.17 (t, J= 1.1 Hz, 1 H),
2.27 (d J= 0.5 Hz, 1 H), 1.32 (br s, 12 H, 4 CH3 of BPin), (3.10b) 7.46 (d, J= 4.6 Hz, 1
H), 6.95 (d, J = 4.6 Hz, 1 H), 2.47 (s, 1 H), 1.30 (br s, 12 H, 4 CH3 of BPin); l3C NMR
{1H} (CDCI3, 125 MHz): 6 (3.103) 139.4 (CH), 138.9 (C), 128.0 (CH), 83.9 (2 C), 24.7
(4 CH3 of BPin), 14.9 (CH3); llB NMR(CDC13, 96 MHz): 6 29.5; FT-IR (neat) V: 2978,
2930, 1550, 1441, 1371, 1327, 1302, 1271, 1143, 1028, 962, 854 665 cm"; GC-MS (El)
m/z (% relative intensity): (3.103) M+ 224 (100), 209 (27), 181 (18), 138 (44), (3.10b) M+
224 (100), 209 (68), 167 (64), 138 (54), 124 (61); Anal. Calcd for CanBOzS: C, 58.95;
H, 7.65. Found: C, 58.65; H, 8.09.

The ratio of two regioisomers with Procedure E was 89:11 with 67% yield.

Table 4.3, Entry 1. Borylation of 2-chloro-S-methylthiophene (3.213 + 3.21b).

Cl 3 Me Cl 3 Me
PinB BPin
85 15
3.21:: 3.21b

The general procedure A was applied to 2-chloro-5-methylthiophene (133 mg, 1
mol, 1 equiv) and HBPin (218 uL, 192 mg, 1.50 mmol, 1.50 equiv) for 36 h. The ratio
of two monoborylated regioisomers at the end of reaction was 85 :15 by GC-FID. The
monoborylated product mixture was isolated as a colorless semi solid (210 mg, 82%

yield). 1H NMR (CDC13, 300 MHz): 8 (3.213) 6.77 (q, J = 1.2 Hz, 1 H), 2.35 (d, J = 1.2

179

 

Hz, 3 H, CH3), 1.31 (br s, 12 H, 4 CH3 of BPin), (3.21b) 6.95 (s, 1 H), 2.60 (s, 3 H, CH3),
1.28 (br s, 12 H, 4 CH; of BPin); ”C NMR {'I-i} (CDC13, 125 MHz): 8 (3.218) 137.4 (C),
137.0 (C), 130.1 (CH), 83.6 (2 C), 24.8 (4 CH3 of BPin), 14.9 (CH3), (3.21b) 151.1 (C),
131.6 (CH), 125.4 (C), 83.4 (2 C), 24.8 (4 CH3 of BPin), 15.7 (CH3); 11B NMR (CDC13,
96 MHz): 6 29.1; FT-IR (neat) V: 2980, 2926, 1556, 1475, 1390, 1371, 1309, 1257,
1143, 1026, 966, 898, 850, 696 cm"; GC-MS (BI) m/z (% relative intensity): (3.213) 258
M+(100), 243 (17), 223 (51), 181 (36), 153 (37) (3.21b) 258 M+(100), 243 (18), 223 (7),
201 (93), 172 (23); Anal. Calcd for CunBClOZS: C, 51.10; H, 6.24. Found: C, 51.66;
H, 6.58; HRMS (E1): m/z 258.0653 [(W); Calcd for CrrHr6BC102S: 258.06526].
The ratio of two regioisomers with Procedure D was 70:30 with 86% yield.

Table 4.3, Entry 2. Borylation of 2-bromo-5-chlorothiophene (3.193 + 3.19b).

Cl 3 Br CI 3 Br
w W
PinB BPin
72 28
3.198 3.1%

The general procedure A was applied to 2-bromo-5-chlorothiophene (110 11L, 197
mg, 1 mol, 1 equiv) and HBPin (218 ILL, 192 mg, 1.50 mmol, 1.50 equiv) for 3 h. The
ratio of two monoborylated regioisomers at the end of reaction was 72:28 by GC-FID.
The monoborylated product mixture was isolated as a white solid (281 mg, 87% yield).
lH NMR (CDC13, 500 MHz): 6 (3.193)) 7.10 (s, 1 H), 1.30 (br s, 12 H, 4 CH3 of BPin),
(3.198) 6.94 (s, 1 H), 1.30 (br s, 12 H, 4 CH3 of BPin); ”C NMR {‘H} (CDC13, 125
MHz): 6 (3.193) 139.6 (C), 134.9 (CH), 108.3 (C), 84.0 (2C), 24.8 (4 CH3 of BPin),
(3.198) 132.0 (CH), 128.9 (C), 119.5 (C), 84.1 (2 C), 24.8 (4 CH3 of BPin); “B NMR

(CDC13, 96 MHz): 6 28.5; FT-IR (neat) V: 2980, 1527, 1427, 1371, 1253, 1140, 1028,

180

 

962, 848, 693 cm"; GC-MS (El) m/z (% relative intensity): (3.193) M 324 (100), 322
(78), 289 (67), 287 (64), 208 (40), 166 (34), (3.19b) NE 324 (89), 322 (69), 309 (23), 245
(41), 243 (99), 203 (43), 201 (100), 166 (50); Anal. Calcd for C10H13BBrClOZS: C, 37.13;
H, 4.05. Found: C, 37.25; H, 4.05.

Borylation of 2-bromo-5-chlorothiophene using Procedure D was not complete
after 8 h at 3% [Ir] catalyst loading. Additional 3 % [Ir] and 0.5 equiv of HBPin was
added and the reaction was run for 20 more h at room temperature. The ratio of two
monoborylated regioisomers at the end of reaction was 67:33 by GC-FID. The product
was isolated in 87% (281 mg) yield.

Table 4.3, Entry 3. Borylation of 2-chloro—5-iodothiophene (3.203 + 3.20b).

Cl 3 1 CI 3 I
\ / W

PinB BPin
92 8
3.208 3.208

The general procedure A was applied to 2-chloro-5-iodothiophene (245 mg, 1
mol, 1 equiv) and HBPin (218 (AL, 192 mg, 1.50 mmol, 1.50 equiv) for 16 h. The ratio
of two monoborylated regioisomers at the end of reaction was 92:8 by GC-F ID. The
monoborylated product mixture was isolated as a white solid (330 mg, 89% yield). 1H
NMR (CDC13, 300 MHz): 6 (3.203) 7.31 (s, 1 H), 1.30 (br s, 12 H, 4 CH3 of BPin),
(3.208) 6.87 (s, 1 H), 1.31 (br s, 12 H, 4 CH3 of BPin); ”C NMR {‘H} (CDCI3, 125
MHz): 6 (3.203) 143.4 (C), 142.3 (CH), 84.0 (2 C), 69.3 (C), 24.8 (4 CH3 of BPin),
(3.208) 132.8 (CH), 84.2 (2 C), 81.1 (C), 24.8 (4 CH3 of BPin); “B NMR (CDCI3, 96
MHz): 6 28.3; FT-IR (neat) V: 2978, 1523, 1414, 1371, 1248, 1140, 1024, 966, 881, 848

690 cm"; GC-MS (EI) m/z (% relative intensity): (3.203) 1Wr 370 (100), 355 (13), 335

181

 

(29), 270 (25), 208 (15), 166 (11), (3.20b) M+ 370 (100), 355 (10), 270 (24), 243 (13),
201 (32), 166 (21); Anal. Calcd for C10H13BICIOZS: C, 32.42; H, 3.54. Found: C, 32.58;
H, 3.38.

The ratio of two regioisomers with Procedure D was 85: 15 with 89% yield.
Table 4.3, Entry 4. 5-bromo-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-

yl)thiophene-2-carbonitrile (2.263).

NCSBr
\/

PinB

>98
2.263

The general procedure A was applied to 2-bromo-5-cyanothiophene (111 (AL, 188
mg, 1 mol, 1 equiv) and HBPin (218 ILL, 192 mg, 2.00 mmol, 1.50 equiv) with 3% [Ir]
catalyst loading for 8 h. Additional 3 % [Ir] catalyst and 0.5 equiv of HBPin was added at
this stage and the reaction was run for 8 more h at room temperature. The borylated
product was isolated as a white solid (284 mg, 90% yield, mp 98-100 °C) with >98%
isomeric purity by GC-FID. 'H NMR (CDC13, 500 MHz): 6 7.30 (s, 1 H), 1.30 (br s, 12
H, CH3 of BPin); 13C NMR {1H} (CDCI3, 125 MHz): 6 136.0 (CH), 119.1 (C), 118.8 (C),
113.1 (C), 84.9 (2 C), 24.7 (CH3, 4 CH3 of BPin); “B NMR (CDC13, 96 MHz): 8 28.0;
FT-IR (neat) V: 2980, 2218, 1520, 1408, 1332, 1255, 1143, 1132, 964, 891, 846, 696 cm'
1; GC-MS (El) m/z (% relative intensity): M+ 315 (100), 313 (97), 314 (59), 300 (32), 298
(30), 272 (85), 257 (47), 255 (48), 229 (22), 192 (76); Anal. Calcd for CnHigBBrNOZS:
C, 42.07; H, 4.17; N, 4.46. Found: C, 42.32; H, 4.11; N, 4.50.

It was not possible to borylate this substrate using Procedure D.7

182

 

Table 4.3, Entry 5. 2—(2,5-dichlorothiophen-3-yI)-4,4,5,5-tetramethyl-l,3,2-

dioxaborolane.

Cl 3 Cl
\ /
PinB

3.16

The general procedure A was applied to 2-5-dichlorothiophene (107 11L, 153 mg,
1 mol, 1 equiv) and HBPin (218 ML, 192 mg, 1.50 mmol, 1.50 equiv) for 6 h. The
product was isolated as a white solid (233 mg, 84% yield, mp 35-36 °C). 1H NMR
(CDCI3, 500 MHz): 8 6.94 (s, 1 H), 1.30 (br s, 12 H, 4 CH3 of BPin); ”C NMR {'H}
(CDCI3, 125 MHz): 6 137.1 (C), 131.1 (CH), 126.2 (C), 84.0 (2 C), 24.8 (4 CH; of BPin);
”B NMR (CDCI3, 96 MHz): 8 28.5; FT-IR (neat) v: 2980, 1535, 1437, 1371, 1313,
1263, 1142, 1032, 966, 889, 848, 692 cm"; GC-MS (El) m/z (% relative intensity): M
278 (100), 280 (68), 263 (32), 265 (22), 243 M-35 (79), 245 (30), 201 (51); Anal. Calcd
for CroHnBClezS: C, 43.05; H, 4.70. Found: C, 43.26; H, 4.74.

Borylation of 2,5-dichlorothiophene using Procedure D took 20 h for full
conversion at 3% [Ir] catalyst loading. The product was isolated in 86% (240 mg)
isolated yield.

Table 4.3, Entry 6. 2-(2,5-dibromothiophen—3-yI)-4,4,5,5-tetr3methyl-1,3,2-

dioxaborolane.

Br 3 Br
\ /
PinB

3.17

183

 

The general procedure A was applied to 2-5-dibromothiophene (113 ML, 142 mg,
1 mol, 1 equiv) and HBPin (218 ML, 192 mg, 1.50 mmol, 1.50 equiv) for 6 h. The
product was isolated as a white solid (331 mg, 90% yield, mp 72-73 °C). 1H NMR
(CDCI3, 500 MHz): 6 7.09 (s, 1 H), 1.31 (br s, 12 H, 4 CH3 of BPin); 13C NMR {1H}
(CDCI3, 125 MHz): 6 135.8 (CH), 121.9 (C), 110.9 (C), 84.0 (2 C), 24.8 (4 CH; of BPin);
1'B NMR (CDCI3, 96 MHz): 6 28.5; FT-IR (neat) V: 2978, 1525, 1365, 1307, 1248,
1143, 991, 962, 883, 848, 690 cm'l; GC-MS (El) m/z (% relative intensity): 1W 368
(100), 370 (51), 366 (52), 353 (18), 287 (56), 289 (59), 268 (28), 208 (77), 166 (69);
Calcd for C10H13BBrzOZS: C, 32.65; H, 3.56. Found: C, 32.92; H, 3.57.

Borylation of 2,5-bromothiophene using Procedure D was not complete after 36 h
at 6% [Ir] catalyst loading. Additional 3 % [Ir] and 1 equiv of HBPin was added and the
reaction was run for 12 more h at room temperature. The ratio of the starting material to
product after 48 h was 11:89. The product was isolated in 56% (206 mg) yield.

Table 4.4. Borylation of 1,3-di-fluorobenzene (2.153 + 2.15b + 2.15c).

BPin

F F F. : :F F, i .F
; BPin
BPin
22 21 57
2.153 2.15b 2.15c

The general procedure B was applied to 1,3-di-fluorobenzene (394 11L, 456 mg, 4
mol, 4 equiv) and HBPin ( 145 11L, 128 mg, 1.00 mmol, 1.00 equiv) for 36 h. The ratio
of three monoborylated regioisomers at the end of reaction was 22:21 :57 by GC-FID.29

The ratio of the two regioisomers with Procedure C was 5:12:83.

The ratio of the three regioisomers with Procedure E was 48:31 :21.

184

 

Table 4.5. Borylation of 1,2-di-fluorobenzene (4.123 + 4.12b).

F0 Klfij/ BPin
BPin
18 82
4.128 4.128

The general procedure B was applied to 1,2-di-fluorobenzene (394 uL, 456 mg, 4
mol, 4 equiv) and HBPin (145 uL, 128 mg, 1.00 mmol, 1.00 equiv) for 36 h. The ratio
of two monoborylated regioisomers at the end of reaction was 18:82 by GC-F ID.
Regiochemical assignment is based on comparison with the GC-FID retention times of
the two isomers, 8.15 and 8.48 minute for 4.123 and 4.12b respectively, with that of an
authentic sample of 4.123 prepared from the Pd catalyzed borylation of
4-bromo-1,2-di-fluorobenzene as described below.

The ratio of the two regioisomers with Procedure C was 9:91.

The ratio of the two regioisomers with Procedure E was 37:63.

Preparation of authentic sample of 2-(3,4-difluorophenyI)-4,4,5,5-tetramethyl-1,3,2-
dioxaborolane (4.123).

In a glove box, a 100 mL schlenk flask, equipped with a magnetic stirring bar,
was charged with Pd2(dba)3 (14 mg, 0.015 mol, 3 mol% Pd) and
tricyclohexylphosphine (PCy3, 20 mg, 0.072 mmol, 7.2 mol%). Dioxane (6 mL) was
added and the resulting mixture was stirred for 30 minutes at room temperature. BzPinz
(280 mg, 1.1 mmol), KOAc (147 mg, 1.5 mmol), and 4-bromo-1,2-di-fluorobenzene(193
mg, 1 mmol) were added successively. The schlenk flask was brought to a schlenk line. A

condenser was attached, and the flask was flushed with nitrogen. The reaction mixture

185

 

was stirred at 80 °C for 2 h. The mixture was treated with water (10 mL), and the product
was extracted with ether, washed with brine, and dried over MgSO4. Crude material was
eluted with CHzClz through a plug of silica gel to afford the desired product (157 mg,
65% yield) as light yellow oil; GC-FID retention time 8.15 minute; 'H NMR (CDC13, 300
MHz): 6 7.47-7.59 (m, 2 H), 7.07-7.16 (m, 1 H), 1.31 (s, 12 H, 4 CH; of BPin); 13C NMR
{‘H} (CDC13, 75 MHz): 8 ”C NMR {'H} (CDCI3, 75 MHz): 8 152.8 (dd, 'Jc_F = 252 Hz,
3J0; = 12.1 Hz, C), 149.7 (dd, lJc.p= 248 Hz, 3Jc-p = 12.1 Hz, C), 131.3 (m, CH), 123.2
(d, chm = 15.1 Hz, CH), 116.9 (d, 2Jc-r: = 16.1 Hz, CH), 84.0 (2 C), 24.8 (4 CH3 of BPin);
“B NMR (CDCI3, 96 MHz): 8 31.1; ”F NMR (CDC13, 282 MHz): 8 —133.9 (m), —139.5
(m); FT-IR (neat) V: 2980, 1614, 1520, 1417, 1361, 1273, 1197, 1145, 1116, 964, 920,
854, 763, 677 cm"; GC-MS (El) m/z (% relative intensity): M 240 (7), 225 (100), 197
(7), 154 (28); Anal. Calcd for C12H15BF202: C, 60.04; H, 6.30. Found: C, 60.06; H, 6.21;

HRMS (EI): m/z 240.1132 [(M); Calcd for CrzHrsBFgozz 240.1133].

186

 

BIBLIOGRAPHY

(1) Dick, A. R.; Sanford, M. S. Tetrahedron 2006, 62, 2439-2463.

(2) Iverson, C. N.; Smith, M. R. Journal Of The American Chemical Society
1999, 121, 7696-7697.

(3) Cho, J. Y.; Iverson, C. N.; Smith, M. R. Journal Of The American
Chemical Society 2000, 122, 12868-12869.

(4) Tse, M. K.; Cho, J. Y.; Smith, M. R. Organic Letters 2001, 3, 2831-2833.

(5) Cho, J. Y.; Tse, M. K.; Holmes, D.; Maleczka, R. E.; Smith, M. R. Science
2002, 295, 305-308.

(6) Maleczka, R. E.; Shi, F.; Holmes, D.; Smith, M. R. Journal Of The
American Chemical Society 2003, 125, 7792-7793.

(7) Chotana, G. A.; Rak, M. A.; Smith, M. R. Journal Of The American
Chemical Society 2005, 12 7, 10539-10544.

(8) Holmes, D.; Chotana, G. A.; Maleczka, R. E.; Smith, M. R. Organic
Letters 2006, 8, 1407-1410.

(9) Shi, F.; Smith, M. R.; Maleczka, R. E. Organic Letters 2006, 8,
1411-1414.

(10) Paul, S.; Chotana, G. A.; Holmes, D.; Reichle, R. C.; Maleczka, R. E.;
Smith, M. R. Journal Of The American Chemical Society 2006, 128, 15552-15553.

(1 l) Ishiyama, T.; Takagi, J.; Ishida, K.; Miyaura, N.; Anastasi, N. R.; Hartwig,
J. F. Journal Of The American Chemical Society 2002, 124, 390-391.

(12) Takagi, J.; Sato, K.; Hartwig, J. F.; Ishiyama, T.; Miyaura, N. Tetrahedron
Letters 2002, 43, 5649-5651.

187

(13) Ishiyama, T.; Takagi, J.; Hartwig, J. F.; Miyaura, N. Angewandte
Chemie-International Edition 2002, 41, 3056-3058.

(14) I Ishiyama, T.; Takagi, J.; Yonekawa. Y.; Hartwig, J. F.; Miyaura, N.
Advanced Synthesis & Catalysis 2003, 345, 1103-1106.

(15) Ishiyama, T.; Nobuta, Y.; Hartwig, J. F.; Miyaura, N. Chemical
Communications 2003, 2924-2925.

(16) Boiler, T. M.; Murphy, J. M.; Hapke, M.; Ishiyama, T.; Miyaura, N.;
Hartwig, J. F. Journal Of The American Chemical Society 2005, 127, 14263-14278.

(17) Murphy. J. M.; Tzschucke, C. C.; Hartwig, J. F. Organic Letters 2007, 9,
757-760.

(18) Tzschucke, C. C.; Murphy, J. M.; Hartwig, J. F. Organic Letters 2007, 9,
761-764.

(19) Murphy, J. M.; Liao, X.; Hartwig, J. F. Journal of the American Chemical
Society 2007, 129, 15434-15435.

(20) Holleman, A. F. Chemical Reviews 1924, 1, 187-230.

(21) Wittig, G.; Pockels, U.; Droge, H. Berichte Der Deutschen Chemischen
Gesellschaft 1938, 71, l903-l912.

(22) Gilman, H.; Bebb, R. L. Journal Of The American Chemical Society 1939,
61, 109-112.

(23) Tagata, T.; Nishida, M. Advanced Synthesis & Catalysis 2004, 346,
1655-1660.

(24) Murata, M.; Odajima, H.; Watanabe, S.; Masuda, Y. Bulletin Of The
Chemical Society Of Japan 2006, 79, 1980-1982.

(25) Frey, G. D.; Rentzsch, C. F.; von Preysing, D.; Scherg, T.; Muhlhofer, M.;
Herdtweck, E.; Herrmann, W. A. Journal Of Organometallic Chemistry 2006, 691, 5725-
5738.

188

(26) Yinghuai, Z.; Yan, K. C.; Jizhong, L.; Hwei, C. S.; Hon, Y. C.; Emi, A.;
Zhenshun, S.; Winata, M.; Hosmane, N. S.; Maguire, J. A. Journal Of Organometallic
Chemistry 2007, 692, 4244-4250.

(27) Mkhalid, I. A. 1.; Coventry, D. N.; Albesa-Jove, D.; Batsanov, A. S.;
Howard, J. A. K.; Perutz, R. N.; Marder, T. B. Angewandte C hemie-International Edition
2006, 45, 489-491.

(28) Uson, R.; Oro, L. A.; Cabeza, J. A. Inorganic Syntheses 1985, 23, 126-30.

(29) For regiochemical assignments and spectroscopic data see Chapter 2.

189

CHAPTERS
One-Pot Borylation/Amination Reactions:
Synthesis of Arylamine Boronate Esters from Halogenated Arenes
Introduction
Metal-catalyzed halide substitution reactions have enhanced the synthetic
utility of halogenated aromatic compounds. Noteworthy examples include C-—C,"2 C—N,
and C—O3'5 bond-forming reactions, which are predominantly Pd-mediated processes.6
Because the scope of these transformations is tied to commercial availability of
halogenated compounds, processes that enable functionalization at non-halogen sites can
augment the substrate pool. In this regard, 1r catalyzed borylation reactions are
particularly intriguing because C—H bonds in halogenated aromatic systems can be
converted selectively to C—B bonds.7°'0 We, and others, have shown that this selectivity
enables one-pot elaborations of aryl halides to phenols, when the boronic ester is
oxidized,H or to biaryls and polyaromatics when the nascent arylboronate ester is
subjected to subsequent Pd mediated C—C coupling.7"o‘l2
These results suggest that other metal catalyzed transformations of crude
arylboronate esters produced from Ir-catalyzed aromatic borylations might be possible. In
this chapter we describe a one-pot borylation/amination protocol where aryl halides can
be converted to C-borylated anilines. In addition to requiring that the Pd catalyzed
reaction operates without interference from Ir species that remain after borylation,
realization of the tandem catalytic process hinges on the successful differentiation

between C—N and C—C couplings with an aryl halide when amines and boronic esters are

present in the reaction milieu.

190

 

Cross-couplings of aryl boron reagents or amines with aryl halides constitute two
of the most important reactions for aryl halides. These reactions are typically facilitated
by Pd catalysts in the presence of stoichiometric quantities of base. Given the similar
reaction conditions for C—C and C—N couplings, attempted catalytic amination of the
halogenated arylboronate ester in Scheme 5.1 could produce an aryl amine if C—N
coupling is favored, polyaromatic products if C—C coupling dominates, or a mixture of

these products if C—N and C—C formation is competitive.

Scheme 5.1. Possible outcomes for a one-pot borylation/amination sequence.

 

 

x x B(OR)2
+ HB(OR)2 Ir catalyst 4,
_. H2
Z Z
R‘RZN B(OR)2
A C—N coupling R‘RZNH,
F Pd catalyst,
2 base
?

 

 

 

C— C_ coupling _

3

Z
In terms of literature precedent, the prospects for selective amination according to
Scheme 5.1 were bleak. As well as we are aware, there are no examples where C—B
bonds survive during Pd—catalyzed amination conditions. Moreover, there are numerous

1 -l6 . .
3 and esters'7 are accompllshed 1n

examples where cross couplings of arylboronic acids
the presence of primary and secondary amines. However, our examinations of one-pot
aromatic borylation/C—C coupling of arenes offered a ray of hope for the amination

pathway in Scheme 5.1. Specifically, we found that Suzuki-Miyaura cross-couplings of

pinacolate esters of arylboronic acids were typically slower than reactions of the

191

 

arylboronic acids themselves.18 Moreover, the rates of C—C couplings for pinacol
boronate esters further diminish when the reactions are carried out under anhydrous
conditions. Since virtually all examples of B—C/C—X cross-couplings of substrates with
amine functionality involve boronic acids or boronate esters in the presence of either
water or hydroxide, we reasoned that the combination of an aprotic base and an
anhydrous, aprotic solvent offered the best Chance for realizing C—N in lieu of C—C
couphng.
Results and Discussion

After an initial attempt of the one-pot reaction sequence failed, we explored
aminations of the purified borylation product of 3-chlorotoluene. To our delight, selective
C—N coupling was found using anhydrous K3P04 as the base according to Eq I.
Returning to the one-pot sequence, we examined the effects of the Ir and Pd precatalysts,
base, and solvent on yields for the “one-pot” sequence in Scheme 5.2. The results are

tabulated in Table 5.].

Me 1.3 equiv PhNHz, Me
1 mol% szdbag,
3 mol% PtBu3,
BPin 1.4 equiv anhydrous K3PO4, BPin
DME, 100 °C, 18 h

 

Cl PhHN (5.1)

5.1
79% yield

192

 

 

 

Scheme 5.2. One-pot borylation/amination of 3-chlorotoluene.

 

 

 

Me 2-0 equiv HBPin. Me I 1.3 equiv PhNHz, Me
2 mol % [Ir], # Pd precatalyst, A
CI 2 mol % Ir ligandf Cl PtBu3, base, 7 PhHN
heat L BPin solvent, 100 °C, 8pm
36 h
Table 5.1. Effects of Ir and Pd precatalyst, base, and solvent on one-pot

borylation/amination of 3-chlorotoluene according to scheme 5.2.

 

 

Entry lr precatalyst Ir Borylation Pd Base Solvent GC-
Ligand Conditions Precatalyst yield”

1 (lnd)lr(COD) dmpe l50 °C, szdba3 K3PO4 DME 93
18 h

2 (lnd)lr(COD) dppe 150 °C, szdba3 [(31304 DME 89
18 h

3 (lnd)lr(COD) dtbpy 100 °C, szdba3 [(31304 DME 87
18 h

4 [Ir(OMe)(COD)]z dtbpy 80 °C. szdba3 K3P04 DME 87
24 h

5 (lnd)lr(COD) dmpe 150 °C, szdba3 K3PO4:nH20 DME 0
18 h

6 (lnd)lr(COD) dmpe 150 °C, szdba3 C52C03 DME 88
18 h

7 (lnd)lr(COD) dmpe 150 °C, szdba3 NaOtBu DME 18
18 h

8 (lnd)lr(COD) dmpe 150 °C, szdba3 KOtBu DME 10
18 h

9 (lnd)lr(COD) dmpe 150 °C. szdba3 K3 P04 Dioxane 85
18 h

10 (lnd)lr(COD) dmpe l50 °C, szdba3 [(31304 Toluene 84
IS h

ll (lnd)lr(COD) dmpe 150 °C, Pd(OAc)2 K3p04 DME 56
18 h

 

aGC-yields based upon starting arene as an average of three runs.

193

Entries 1—4 examine the effects of the Ir source and the Ir ligand. While room
temperature borylations are prohibitively slow for 3-chlorotoluene, the borylations could
be carried out at 80 °C when the Ir ligand was 4,4'-di-tert-butyl-2,2'-bipyridyl (dtbpy).
The best yields of the borylated aryl amine were obtained when borylations were carried
out using the (lnd)lr(COD)/1,2-bis(dimethylphosphino)ethane (dmpe) Ir
precatalyst/ligand formulation. In all cases, conversion of 3-Chlorotoluene to the
intermediate boronate ester was complete. Hence, the variations in yields for entries 1-4
likely arise from the efficiencies of the amination step.

Entries 1 and 5-8 illustrate the effects of the base on the amination step. K3P04
and CszCO3 are both effective, whereas NaOtBu and KOtBu gave very low yields of the
amino boronate ester. Entry 5 shows the deleterious effects of water as the amino
boronate ester is not detected when K3POa-nHzO is the base. In contrast to NaOtBu and
KOtBu, where predominance of the intermediate boronate ester indicates that conversion
to the amino boronate is simply slow, with K3P04°nHzO the intermediate boronate ester
is completely consumed. Entries 1, 9, and 10 show that the amination step is moderately
sensitive to variations in the solvent, with DME giving superior results. Lastly, entries 1
and 1 1 illustrate the effect of the Pd precatalyst with szdba3 being superior to Pd(OAC)2,
the principle difference being significant generation of the deborylated aryl amine for the
latter Pd precatalyst.

Armed with the results from Table 5.1, we examined the scope of the
borylation/amination sequence for various 3-substituted halobenzenes for which
borylation at the 5-position predominates. The general conditions in Scheme 5.3 were

used and the results are listed in Table 5.2.

194

 

Scheme 5.3. Preparation of 1,3,5-arylamino boronate esters by one-pot

borylation/amination of arylhalides.

C

1.3 equiv R‘RZNH,
1 mol% Pd2(dba)3, Z
3-4 mol% PR3,

2.0 equiv HBPin,
2 mol% (lnd)lr(COD), ‘

 

 

2 mol% dmpe/dppe? 1.5 equiv K3PO4A' PhHN
100-150 °C, 4-18 h BPin DME, 100 °C, BPin
17-23 h
Ligand = 3 mol% PtBu3 5.2
NM92
. Q Q
CYQP

Table 5.2. Preparation of 1,3,5-arylamino boronate esters according to scheme 5.3.

 

Entry 2 X Borylation Conditions Amination Conditions Product %yield

 

 

 

 

Ligand Temp Time Amine Ligand Time
(h) (h)
1 Me Cl dmpe 150 °C 8 PhNH2 5.2 19 5.1 75
2 Me Cl dmpe 150 °C 16 morpholine 5.2 22 5.4 73
3 Me CI dmpe 150 °C 17 PhNMeH 5.3 16 5.5 83
4 Me Cl dmpe 150 °C 17 BupNH 5.2 23 5.6 50
5 Me Br dmpe 150 °C 8 PhNH2 5.2 19 5.1 63
6 002Me Cl dppe 100 °C 17 PhNH2 5.2 16 5.7 47
7 CF3 CI dppe 100 °C 4 PhNH2 5.3 18 5.8 71
8"“ CF3 Cl dppe 100 °C 4 mlorpholine 5.3 17 5.9 49
9 CF3 CI dmpe 150 °C 4 PhNMeH 5.2 23 5.10 65
1o OMe CI dmpe 150 °C 12 PhNH2 5.3 17 5.1 1 63
11 NM32 Cl dmpe 150 °C 18 PhNH2 5.3 17 5.12 73

 

aSuzuki product ~ 20% was also observed by GC-Fl D.

195

The isolated yields for the reactions in Table 5.2, based on the starting aryl halide,
range from 47-83% with an average yield of 64%. This average corresponds to an 80%
yield for the individual steps, assuming that the borylation and amination yields are
identical. When the pure aryl boronate ester derived from borylation of
3-chlorotolene was isolated and subsequently aminated with aniline, the product in entry
1 was isolated in 60% overall yield based on 3-chlorotoluene, compared to the 75% yield
obtained for the one-pot reaction. Thus, higher isolated yields are realized in the one-pot
tandem reactions where isolation and purification of the intermediate aryl halide boronate
esters are avoided.'9

Entries 1-4, examine the effect of varying the amine on aminations of the
borylation product of 3-chlorotoluene. The yields for aniline, morpholine, and
N-methylaniline are excellent, while amination with dibutylamine gave a significantly
lower yield of the 3—amino boronate ester. Entries 1, 6, 7, 10, and 11 show the effect of
varying the Z substituent in Scheme 3. Electron withdrawing substituents give lower
yields of the 3-amino boronate esters. Since electron withdrawing substituents on aryl
boronic acids accelerate Suzuki-Miyaura cross-couplings, competition from this side
reaction may contribute to the lower yields for electron deficient aryl chlorides.
Consistent with this notion, small quantities of aminated biaryls that arise from
Suzuki-Miyaura coupling can be detected in the crude reaction mixture for entry 8.

Examples of 2 and 4-substituted halogenated benzenes that react with a high
degree of regioselectivity are more limited. Nevertheless, the results from one-pot
borylation/amination reactions using these substrates suggest that extensions beyond the

regiochemistries in Table 5.2 are possible.

196

 

Table 5.3. One-pot borylation/amination of ortho and para-substituted chlorobenzenes.a

 

 

Entry Aryl halide Product % yield
Cl Cl PhHN

1 Cl PhHN BPin CI BPin 46
19 : 1
5.148 5.141)

BPin BPin

2b CI—Q—Cl PhHN CI Cl NHPh 0

5,153 5.15!)

~ 10% GC-yield. Two regioisomers observed
in 7:1 ratio by GC-FID.

BPin

3 r1308. define. .5
7

5.16

 

aSee experimental details for specific reaction conditions. bThe intermediate
boronate ester was isolated.

Because unsymmetrical o-disubstituted benzenes typically exhibit poor borylation
regioselectivities, the only 2-substituted halogenated benzene examined is
o-dichlorobenzene. Regioselective borylation at the 4-position affords an intermediate
boronate ester where the chloride positions are chemically distinct. Thus, synthetic utility
depends on high regioselectivity in the amination step. Fortunately, the BPin group exerts
a directing effect that, regardless of its origins (i.e. steric or electronic), responds to
variations in the Pd phosphine ligand. While good regioselectivity is found for Pth
(2: 1) and 2-dicyclohexylphosphino-2'—dimethylamino—1,1'-biphenyl (6: l),
2-(dicyclohexyl phosphino)bipheny1 (5.13) gave superior results affording a 19:1 ratio of

two regioisomers by GC-F ID. 2D NMR spectroscopy (gHMBC) showed that the major

197

product was the one where amination took place on the chloride para to the BPin group
(see experimental details). With the exception of regioselective amination at the
2-position of 2,3-dichloropyridine,20 regioselectivities of this type have not been
previously reported.

p-Dichlorobenzene similarly affords a single monoborylated product where the
chloride positions are also chemically distinct. For this substrate, a two-fold excess of
arene is required to minimize diborylation. Consequently, the intermediate boronate ester
was isolated. In contrast to the one pot reaction for o-dichlorobenzene, subsequent
amination of this boronate ester with aniline was less efficient, less regioselective, and
deborylation was also observed. Attempts to isolate the pure amino boronate esters were
unsuccessful.

When the 4-subtituent in 4-substituted chlorobenzenes is sufficiently large,
borylation at the 2-position predominates. For example, 4-(trifluoromethyl)-
chlorobenzene affords a 95:5 ratio of 2 and 3-monoborylated products respectively. The
major regioisomer can easily be identified from the C—F coupling information in the '3 C
NMR (with the help of the fact that the boron bearing carbon is not observed due to
broadening from and coupling with boron). Subsequent amination of the crude reaction
mixture with aniline and isolation gives isomerically pure 2-borylated amine. As was the
case for p-dichlorobenzene, approximately 20% of the intermediate boronate ester suffers
deborylation, suggesting that this may be a general problem for aminations of chlorides

ortho to BPin groups.

198

Conclusions

In summary, one pot borylation/amination provides an efficient protocol for
preparing the 1.3 ,S-arylamino boronate esters from 3-substituted aryl halides. The one pot
sequence can be extended to ortho and para— substituted chlorobenzenes. In the case of
dichlorobenzenes, a highly regioselective substitution has been observed para to the BPin
group in the boronate ester derived from the borylation of o-dichlorobenzene. The key
feature that enables the one-pot sequence is preference of C—N over C—C coupling when
a primary or secondary amine. a pinacolate boron ester, and an aryl halide are subjected
to Pd coupling conditions where anhydrous K3PO,, is the requisite base?”24 We are

presently evaluating the generality and pursuing applications of this selectivity .25

199

 

 

 

Experimental Details and Spectroscopic Data
Materials

All commercially available chemicals were used as received or purified as
described. Aryl halides were refluxed over CaHz, distilled, and degassed. Aniline,
N-methylaniline, dibutylamine, and morpholine were refluxed over KOH, distilled, and
degassed. Methyl-3-chlorobenzoate was stirred over 4A molecular sieves and then passed
through activated alumina before use. Pinacolborane (HBPin) was stirred over PPh3
overnight, vacuum transferred into an air free flask and brought into the glove box.
4,4'-Di-tert-butyl-2,2'—bipyridine (dtbpy) was sublimed before use. (nS-Indenyl)
(cyclooctadiene)iridium {(lnd)lr(COD)} and bis(n4-1,5-Cyclooctadiene)-di-u-methoxy-
diiridium(I) [Ir(OMe)(COD)]2 were prepared per literature procedures.26‘27 Anhydrous
potassium phosphate was obtained by heating hydrated potassium phosphate at 150 °C
under vacuum for 7 days. Ethylene glycol dimethyl ether (DME) and n-hexane were
refluxed over sodium, distilled, and degassed. Silica gel (60 A, 230-400 Mesh) was used
for column chromatography.
General Procedure

In a dry box, aryl halide (2 mmol, 1 equiv), HBPin (580 ML, 512 mg, 4.00 mmol,
2.00 equiv), (Ind)Ir(COD) (17 mg, 0.04 mmol, 2.0 mol%) and dmpe (6 mg, 0.04 mmol, 2
mol%) or dppe (16 mg, 0.04 mmol, 2 mol%) were transferred into a thick-walled air-free
flask equipped with a magnetic stirring bar. The flask was sealed, removed from the
glove box, and stirred at 150 °C (dmpe) or 100 °C (dppe) until the reaction was judged
complete by GC-FID. The reaction mixture was allowed to cool to room temperature and

subsequently placed under vacuum for 1-2 h. The thick walled flask was brought into the

200

 

dry box and anhydrous K3POa (594 mg, 2.8 mmol, 1.4 equiv), szdba3 (18 mg, 0.02
mmol, 1 mol %), PtBu; (12 mg, 0.06 mmol, 3 mol%), 2-dicyclohexylphosphino-Z'-(N,N-
di-methylamino)biphenyl (32 mg. 0.08 mmol, 4 mol%) or
2-(dicyclohexylphosphino)biphenyl (28 mg, 0.08 mmol, 4 mol%), amine (2.4-2.6 mmol,
1.2-1.3 equiv) and DME (3mL) were added. The flask was then sealed, removed from the
dry box and stirred at 100 °C until the reaction was judged complete by GC-FID. After
completion, the reaction mixture was extracted three times with ether. The combined
organics were washed with brine followed by water, dried over MgSOa, and concentrated
under reduced pressure. The crude material was then subjected to column
chromatography.

Table 5.2, Entry 1. N-Phenyl-3-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolane—2-

yI)-aniline (5.1).

Me

Ph
BPin

5.1

The general procedure was applied to 3-chlorotoluene (253 mg, 2 mmol). The
borylation step was carried out neat with HBPin (580 (1L, 512 mg, 4.00 mmol, 2.00
equiv) and dmpe (6 mg, 0.04 mmol, 2 mol%) at 150 °C for 8 h. The amination step was
then carried out using PtBu3 ( 12 mg, 0.06 mmol, 3 mol%) and aniline (224 mg, 2.40
mmol, 1.20 equiv) at 100 °C for 19 h. Column chromatography (hexanes/CHzClz 2:3)
furnished the desired product (463 mg, 75% yield, mp 100 °C) as a light yellow oil,
which solidified on standing. 'H NMR (C6D6, 500 MHz) 8 7.64 (br s, 2 H), 7.07-7.03 (m,

2 H), 6.92-6.89 (m, 2 H), 6.86 (br s, l H), 6.77-6.74 (m, 1 H), 5.05 (br s, 1 H), 2.11 (s, 3

201

H), 1.13 (br s, 12 H, 4 CH3 of BPin); ”C NMR {‘11} (C6D6, 125 MHz) 8 144.0 (C), 143.0
(C), 138.4 (C), 129.5 (CH), 129.2 (CH), 122.5 (CH), 122.2 (CH), 120.7 (CH), 117.8
(CH), 83.7 (C), 24.94 (4 CH3 of BPin), 21.34 (CH3); “B NMR (C6D6, 96 Hz) 8 29.1;
,FT-IR (NaCl) 9': 3393, 3365 (sh), 3036, 2979, 2926, 2867, 1590, 1518, 1497, 1470,
l410,1368,1312,1271,1237,1215,1167,1144,1117,1031,1019,967,911,853,745,
712, 698, 668 cm’1 GC-MS (El) m/z (% relative intensity): M+ 309 (100), 294 (2), 250
(3), 236 (7), 209 (27), 193 (14), 167 (11), 147 (5). Anal. Calcd for CtonaBOZN: C,
73.80; H, 7.82; N, 4.53. Found: C, 73.82; H, 7.94; N, 4.43.

Table 5.2, Entry 2. 3-(N-morpholino)-5-(4,4,5,5-tetr3methyl-1,3,2-dioxaborolane-2-

yl)-toluene (5.2).

Me
O N
\_/
BPin

5.4

The general procedure was applied to 3-chlorotoluene (253 mg, 2 mmol). The
borylation step was carried out neat with HBPin (580 11L, 512 mg, 4.00 mmol, 2.00
equiv) and dmpe (6 mg, 0.04 mol, 2 mol%) at 150 °C for 16 h. The amination step was
then carried out using Pth (12 mg, 0.06 mol, 3 mol%) and morpholine (209 mg, 2.4
mmol, 1.2 equiv) at 100 °C for 22 h. Column chromatography (hexanes/EtOAc 2:1)
furnished the desired product (445 mg, 73.4% yield) as a light yellow oil. 1H NMR (C613,,
500 MHz) 6 7.64 (s, 1 H), 7.54 (d, J = 2.4 Hz, 1 H), 6.68 (s, 1H), 3.51 (t, J = 4.8 Hz, 4
H), 2.74 (t, J = 4.8 Hz, 4 H), 2.22 (d, J = 0.4 Hz, 3 H), 1.16 (br s, 12 H, 4 CH3 of BPin);
13C NMR {‘H} (C6D6, 125 MHz) 6 151.5 (C), 138.0 (C), 128.3 (CH), 120.1 (CH), 120.0

(CH), 83.6 (C), 67.0 (CH2), 49.6 (CH2), 25.0 (4 CH3 of BPin), 21.7 (CH3); “B NMR 8

202

28.8. FT-IR (NaCl) V: 2977, 2921, 2855, 2820, 1590, 1470, 1441, 1387, 1372, 1316,
1271, 1242, 1188, 1165, 1146, 1123, 1013, 967, 853, 708 cm]; GC MS (EI) rn/z (%
relative intensity): M+ 303 (100), 288 (4), 272 (6), 258 (5), 245 (41), 203 (7), 187(6), 172
(10), 159 (35), 145 (70), 131 (8), 117 (27), 91 (13), 65 (7), 57 (10); Anal. Calcd for
C17H26BN03: C, 67.34; H, 8.64; N, 4.62. Found: C, 67.28; H, 8.56; N, 4.55.

Table 5.2, Entry 3. N-Methyl-N-phenyl-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-

dioxaborolane—Z-yl)-3niline (5.5).

Me
Me\
N
Ph’
BPin

5.5

The general procedure was applied to 3-chlorotoluene (127 mg, 1 mmol). The
borylation step was carried out neat with HBPin (290 uL, 256 mg, 2.00 mmol, 2.00
equiv) and dmpe (3 mg, 0.02 mol, 2 mol%) at 150 °C for 17 h. The amination step was
then carried out using 2-dicyclohexylphosphino-2’-(N,N-di-methy1amino)biphenyl (16
mg, 0.04 mol, 4 mol%) and N-methylaniline (139 mg, 1.30 mmol, 1.30 equiv) at 100
°C for 16 h. Column chromatography (hexanes/ether 4: 1) furnished the desired product
(270 mg, 83.4% yield) as a light yellow oil which solidified on standing. Analytically
pure material was obtained by sublimation (140 °C at 0.05 mm Hg), mp 69-71 °C. IH
NMR (C6D6, 300 MHz) 6 7.82 (d, J = 2.0 Hz, 1 H), 7.73 (d, J = 0.7 Hz, 1 H), 7.12-7.05
(m, 2 H), 7.00 (m, 1 H), 6.95-6.90 (m, 2 H), 6.82-6.76 (m, 1 H), 2.94 (s, 3 H), 2.07 (m, 3
H), 1.11 (br s, 12 H, 4 CH; of BPin); ”C NMR {‘H} (C6D6, 125 MHz) 8 149.8 (C), 149.2
(C), 138.5 (C), 130.4 (CH), 129.4 (CH), 126.4 (CH), 125.8 (CH), 120.6 (CH), 119.5

(CH), 83.7 (C), 40.2 (CH3), 25.0 (4 CH3 of BPin), 21.3 (CH3); “B NMR 8 26.4; FT-IR

203

 

 

(neat) V: 3038, 2978, 2928, 1599, 1585, 1498, 1435, 1383, 1370, 1315, 1250, 1192,
1146, 1117, 1094, 966, 905, 853, 752, 712, 698 cm"; GC MS (EI) m/z (% relative
intensity): M+ 323 (100), 222 (7). Anal. Calcd for C20H26BNO2: C, 74.32; H, 8.11; N,
4.33. Found: C, 74.42; H, 7.81; N, 4.27.

Table 5.2, Entry 4. N-N-Di-n-butyI-S-methyl-5-(4,4,5,5-tetramethyl-l,3,2-

dioxaborolane—Z-yD-aniline (5.6).

Me
Bu\
IN
Bu
BPin

5.6

The general procedure was applied to 3-chlorotoluene (127 mg, 1 mmol). The
borylation step was carried out neat with HBPin (290 uL, 256 mg, 2.00 mmol, 2.00
equiv) and dmpe (3 mg, 0.02 mol, 2 mol%) at 150 °C for 17 h. The amination step was
then carried out using PtBu3 (6 mg, 0.03 mol, 3 mol%) and dibutylamine (155 mg,
1.20 mmol, 1.2 equiv) at 100 °C for 23 h. Column chromatography (hexanes/ether 12:1)
furnished the desired product (174 mg, 50.2% yield) as a light yellow oil. 1H NMR
(C6D6, 500 MHz) 6 7.51-7.49 (m, 2 H), 6.74 (br s, 1 H), 3.14-3.10 (t, J = 7.8 Hz, 4 H),
2.28 (s, 3 H), 1.43-1.49 (m, 4 H), l.18-1.11 {m, 16 H; methyls in BPin and methylenes in
8utyls (-CH2-CH2-CH3)2 }, 0.81-0.78 (t, J = 7.8 Hz, 6 H); ”C NMR {‘H} (C613,, 125
MHz) 6 148.5 (C), 138.0 (C), 124.4 (CH), 117.0 (CH), 116.8 (CH), 83.4 (C), 50.9 (CH2),
29.9 (CH2), 25.0 (4 CH3 of BPin), 22.0 (CH3), 20.6 (CH2), 14.1 (CH3); 11B NMR 6 37.2;
FT-IR (neat) V: 2959, 2932, 2874, 1591, 1443, 1402, 1370, 1310, 1273, 1190, 1146, 853,
710 cm"; GC-MS (EI) m/z (% relative intensity): M+ 345 (20), 302 (100), 260 (32). Anal.

Calcd for C21H36BNO2: C, 73.04; H, 10.51; N, 4.06. Found: C, 72.91; H, 10.91; N, 3.82.

204

 

Table 5.2, Entry 5. N-PhenyI-3-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolane-2-

yI)-aniline (5.1).

Me

Ph’
BPin

5.1

The general procedure was applied to 3-bromotoluene (342 mg, 2 mmol). The
borylation step was carried out neat with HBPin (580 11L, 512 mg, 4.00 mmol, 2.00
equiv) and dmpe (6 mg, 0.04 mol, 2 mol%) at 150 °C for 8 h. The amination step was
then carried out using PtBu3 (12 mg, 0.06 mol, 3 mol%) and aniline (224 mg, 2.40
mmol, 1.20 equiv) at 100 °C for 19 h. Column chromatography (hexanes/CH2CI2 2:3)
furnished the desired product (3 89 mg, 63% yield) as light yellow oil.
Table 5.2, Entry 6. Methyl-3-(phenyIamino)-5-(4,4,5,5-tetr3methyl-l,3,2-

dioxaborolane-2-yI)-benzoate (5.7).

002869

Ph
BPin

5.7
The general procedure was applied to methyl-3-chlorobenzoate (341 mg, 2
mmol). The borylation step was carried out neat with HBPin (580 11L, 512.0 mg, 4.00
mmol, 2.00 equiv) and dppe (16 mg, 0.04 mol, 2 mol%) at 100 °C for 17 h. The
amination step was then carried out using PtBu3 (12 mg, 0.06 mol, 3 mol%) and aniline
(224 mg, 2.4 mmol, 2.4 equiv) at 100 °C for 16 h. Column chromatography

(CH2Cl2/ether 30:1) furnished the desired product (335 mg, 47.4%, yield, mp 154-155

205

 

°C) as a creamy solid. lH NMR(CDC13, 500 MHz) 6 7.99 (dd, J = 1.6, 1.0 Hz, 1 H), 7.84
(dd, J = 2.6, 1.6 Hz, 1 H), 7.61 (dd, J = 2.6, 1.0 Hz, 1 H), 7.29-7.25 (m, 2 H), 7.07-7.05
(m, 2 H), 6.96-6.93 (tt, J= 7.3, 1.2, 1.1 Hz, 1 H), 5.77 (br s, 1 H), 3.87 (s, 3 H), 1.32 (br
s, 12 H, 4 CH3 of BPin); ”C NMR {1H} (CDCI3, 125 MHz) 8 167.13 (C), 143.0 (C),
142.6 (C), 130.8 (C), 129.5 (CH), 128.2 (CH), 128.1 (CH), 121.5 (CH), 120.6 (CH),
118.1 (CH), 84.1 (C), 52.0 (CH3), 24.8 (4 CH3 of BPin); 11B NMR (C6D6, 96 Hz) 6 27.8;
FT-IR (KBr) V: 3368, 3042, 3019, 2992, 2977, 2952, 1701, 1593, 1534, 1499, 1466,
1437, 1426, 1418, 1379, 1325, 1308, 1289, 1260, 1219, 1167, 1146, 1123, 1030, 1011,
992, 970, 940, 884, 851, 774, 754, 704, 696, 671, 585 cm'l; GC-MS (EI) m/z (% relative
intensity): M+ 353 (100), 338(3), 322(4), 253 (17), 236 (12), 220 (6), 194 (39), 167 (22),
77 (13), 59 (10). Anal. Calcd for C20H24BO4N: C, 68.01; H, 6.85; N, 3.97. Found: C,
68.21; H, 6.86; N, 3.93.

Table 5.2, Entry 7. N-PhenyI-3-(trifluoromethyl)-5-(4,4,5,5-tetramethyl-1,3,2-

dioxaborolane-Z-yl)-3niline (5.8).

CF3

Ph’
BPin

5.8
The general procedure was applied to 3-chloro-benzotrifluoride (361 mg, 2
mmol). The borylation step was carried out neat with HBPin (400 mg, 3.10 mmol, 1.55
equiv) and dppe (16 mg, 0.04 mol, 2 mol%) at 100 °C for 4 h. The amination step was
then carried out using 2-dicyclohexylphosphino-2'-(N,N-di-methylamino)biphenyl (32
mg, 0.08 mol, 4 mol%) and aniline (224 mg, 2.40 mmol, 1.2 equiv) at 100 °C for 18 h.

Column chromatography (hexanes/CH2CI2 2:3) furnished the desired product (518 mg,

206

 

 

 

71% yield, mp 83-85 °C) as a light yellow solid. 1H NMR (C6D6, 500 MHz) 6_ 8.03 (d, J
= 0.9 Hz, 1 H), 7.74 (d, J = 2.3 Hz, 1 H), 7.14-7.13 (m, 1 H), 7.02-6.99 (m, 2 H),
6.84-6.82 (m, 2 H), 6.79-6.76 (m, 1 H), 4.96 (br s, 1 H), 1.06 (br s, 12 H, 4 CH3 of BPin);
”C NMR {'H} (C3),, 125 MHz) 8 144.0 (C), 142.2 (C), 131.5 (q, 2J.;.F = 32.1 Hz, C),
129.7 (CH), 126.4 (CH), 125.0 (q, 'Jc.p = 272 Hz, CF 3), 123.3 (q, 3Jc.r: = 3.6 Hz, CH),
122.3 (CH), 118.9 (CH), 116.3 (q, 3Jc.p = 3.6 Hz, CH), 84.2 (C), 24.8 (4 CH3 of BPin);
”B NMR (C613,, 96 Hz) 8 29.9; ”F NMR (€an, 282 MHz) 8 -62.7; FT-IR (NaCl) V:
3397, 3362, 3040, 2980, 2932, 2870, 1595, 1520, 1497, 1520, 1497, 1470, 1447, 1414,
1389, 1331, 1300, 1273, 1240, 1215, 1167, 1142, 1125, 1100, 1080, 1030, 996, 970, 953,
876, 851, 828, 760, 745, 710, 696, 689, 666 cm"; GC-MS (EI) m/z (% relative intensity):
M+ 363 (100), 348 (5), 344 (4), 281 (5), 277 (11), 263 (45), 242 (5), 216 (14), 193 (9),
174 (7), 167 (9), 85 (9), 77 (13), 59 (10). Anal. Calcd for C19H21BF3N 02: C, 62.83; H,
5.83; N, 3.86. Found: C, 62.65; H, 5.55; N, 3.78; HRMS (E1): m/z 363.1607 [(M”); Calcd
for C19H21BF3NO2: 363.1617].

Table 5.2, Entry 8. 3-(N-morpholino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborol3ne-2-

yl)-benzotrifluoride (5.9).

CF3
O N
\_/
BPin
5.9

The general procedure was applied to 3-chloro-benzotrifluoride (361 mg, 2
mmol). The borylation step was carried out neat with HBPin (400 mg, 3.10 mmol, 1.55
equiv) and dppe (16 mg, 0.04 mol, 2 mol%) at 100 °C for 18 h. The amination step was

then carried out using 2-dicyclohexylphosphino-2'-(N,N-di-methylamino)biphenyl (36

207

mg, 0.08 mol, 4 mol%) and morpholine (209 mg, 2.4 mmol, 1.2 equiv) at 100 °C for 17
h. Column chromatography (CH2Cl2/Ether 30:1) filrnished the desired product (349.1 mg,
48.9% yield, mp 72 °C) as a light yellow waxy solid. 1H NMR (C6D6, 500 MHz) 6 7.98
(s, l H), 7.58 (d, J= 2.4 Hz, 1 H), 7.06 (s, 1 H), 3.36 (t, J = 4.8 Hz, 4 H), 2.52 (t, J= 4.8
HZ, 4 H), 1.12 (4 CH3 of BPin); l3C NMR {‘H} (C6D6, 125 MHz) 6 151.4 (C), 131.3 (q,
2Jc4= = 31 Hz, C), 125.4 (q, 'Jc-r= = 272 Hz, CF3), 125.2 (CH), 122.4 (q, 3J0]: = 3.6 Hz,
CH), 114.5 (q, 3Jc-r: = 3.1 Hz, CH), 84.2 (C), 66.6 (CH2), 48.4 (CH2), 24.9 (4 CH3 of
BPin); ”F NMR (C6D6, 282 MHz) 8 -62.3; “B NMR (C6D6, 96 Hz) 8 28.1; FT-IR
(NaCl) V: 2980, 2928, 2896, 2859, 2832, 1601, 1470, 1441, 1402, 1325, 1294, 1271,
1167, 1146, 1123, 994, 974, 961, 878, 847, 706, 687 cm"; GC MS (EI) m/z (% relative
intensity): M 357 (100), 342 (7), 299 (25), 284 (33), 256 (10), 228 (8), 213 (63), 199
(75), 171 (27), 142 (22), 85 (12), 59 (19); Anal. Calcd for Ct7H23BF3N03: C, 57.17; H,
6.49; N, 3.92. Found: C, 57.36; H, 6.30; N, 3.99.

Table 5.2, Entry 9. N-methyl-N-phenyl-3-trifluoromethyl-5-(4,4,5,5-tetramethyl-

1,3,2-dioxaborolane-2-yl)]-aniline (5.10).

CF3
Me\
N
Ph’
BPin
5.10

The general procedure was applied to 3-chloro-benzotrifluoride (181 mg, 1
mmol). The borylation step was carried out neat with HBPin (290 11L, 256 mg, 2.00
mmol, 2.0 equiv) and dmpe (3 mg, 0.02 mol, 2 mol%) at 150 °C for 4 h. The amination
step was then carried out using Pth (6 mg, 0.03 mol, 3 mol%) and N-methyl-aniline

(129 mg, 1.2 mmol, 1.2 equiv) at 100 °C for 22.5 h. Column chromatography

208

 

(hexanes/CH2CI2 2:1) furnished the desired product (488 mg, 65% yield) as a light yellow
waxy solid. 1H NMR (C6D6, 500 MHz) 6 8.09 (m, 1 H), 7.82 (d, J = 2.5 Hz, 1 H), 7.34
(m, 1 H), 7.02-6.96 (m, 2 H), 6.86-6.77 (m, 3 H), 2.73 (s, 3 H), 1.05 (br s, 12 H, 4 CH3 of
BPin); ”C NMR {'H} (C6D6, 125 MHz) 8 149.4 (C), 148.4 (C), 131.5 (q, 2Jc-p = 31.6
Hz, C), 129.8 (CH), 127.3 (CH), 125.2 (q, 'Jop = 272.3 Hz, CF3), 123.7 (CH), 123.3
(CH), 122.8 (q, 3J0; = 3.6 Hz, CH), 117.1 (q, 3Jon = 3.0 Hz, CH), 84.1 (C), 39.8 (CH3),
24.8 (4 CH3 of BPin); ”F NMR (C6D6, 282 MHz) 8 —62.6; “B NMR (C6D6, 96 MHz) 8
30.3; FT-IR (neat) V: 2980, 2936, 1591, 1497, 1470, 1439, 1391, 1373, 1331, 1298,
1271, 1169, 1144, 1125, 1084, 966, 929, 872, 849, 710, 700, 687 cm"; GC MS (EI) m/z
(% relative intensity): M+ 377 (100). Anal. Calcd for C20H23BF3NO2: C, 63.68; H, 6.15;
N, 3.71. Found: C, 64.03; H, 5.78; N, 3.49; HRMS (El): m/z 377.1779 [(m; Calcd for
C20H23BF3NO2: 377.1774].

Table 5.2, Entry 10. N-Phenyl-3-methoxy-544,4,5,5-tetr3methyl-1,3,2-dioxaborolyl-

2-yI)-aniline (5.11).

OMe

Ph
BPin

5.11

The general procedure was applied to 3-chloroanisole (285 mg, 2 mmol). The
borylation step was carried out neat with HBPin (580 11L, 512 mg, 4.00 mol, 2 equiv)
and dmpe (6 mg, 0.04 mol, 2 mol%) at 150 °C for 12 h. The amination step was then
carried out using 2-dicyclohexylphosphino-2’-(NJV-di-methylamino)biphenyl (32 mg,
0.08 mol, 4 mol%) and aniline (242 mg, 2.60 mmol, 1.30 equiv) at 100 °C for 17 h.

Column chromatography (pentane/ether 4:1) furnished the desired product (405.5 mg,

209

irri- ..1: ‘l

 

62.4% yield) as a light yellow waxy solid. lH NMR (C6D6, 300 MHz) 6 7.46 (d, J = 2.0
Hz, 1 H), 7.37 (d, J = 2.4 Hz, 1 H), 7.05-7.00 (m, 2 H), 6.92-6.89 (m, 2 H), 6.81-6.79 (t, J
=2.4 Hz, 1 H), 6.78-6.73 (m, 1 H), 5.19 (br s, 1 H), 3.33 (s, 3 H), 1.12 (br s, 12 H, 4 CH3
of BPin); ”C NMR {‘H} (C613,, 75 MHz) 8 160.9 (C), 144.6 (C), 143.5 (C), 129.5 (CH),
121.1 (CH), 118.2 (CH), 117.7 (CH), 111.9 (CH), 107.7 (CH), 83.8 (C), 54.8 (CH3), 24.9
(4 CH3 of BPin); 11B NMR (C6D6, 96 MHz) 6 31.8; FT-IR (neat) V: 3360, 2978, 1588,
1497, 1437, 1373, 1310, 1246, 1194, 1163, 1144, 1057, 970, 909, 853, 743, 699 cm"; GC
MS (EI) m/z (% relative intensity): M 325 (100), 225 (7); Anal. Calcd for C19H24BNO3:
C, 70.17, H, 7.44, N, 4.31. Found: C, 69.85, H, 6.68, N, 4.50. HRMS (EI): m/z 325.1857
[(M‘); Calcd for C19H24BNO3: 325.2154].

Table 5.2, Entry 11. N-PhenyI-3-(N,N-dimethyl)-5-(4,4,5,5-tetramethyl-l,3,2-

dioxaborolane-Z-yI)-aniline (5.12).

NMez
H\
N
Ph’
BPin
5.12

The general procedure was applied to 3-chloro-N,N-dimethyl aniline (312 mg, 2
mmol). The borylation step was carried out neat with HBPin (580 11L, 512.0 mg, 4.00
mmol) and dmpe (6 mg, 0.04 mol, 2 mol%) at 150 °C for 18 h. The amination step was
then carried out using 2-dicyclohexylphosphino-2’-(N,N-di-methylamino)biphenyl (32
mg, 0.08 mol, 4 mol%) and aniline (242 mg, 2.6 mmol, 1.30 equiv) at 100 °C for 17 h.
Column chromatography (pentane/T HF 5:1) furnished the desired product (494 mg, 73%
yield, mp 133-134 °C) as a white solid. 1H NMR (C6D6, 300 MHz) 6 7.39 (d, J = 1.5 Hz,

1 H), 7.32 (d, J= 2.5 Hz, 1 H), 7.10-7.04 (m, 2 H), 6.98-6.94 (m, 2 H), 6.79-6.74 (m, 1

210

 

H), 6.55 (t, J= 2.3 Hz, 1 H), 5.15 (br s, 1 H), 2.52 (s, 6 H), 1.14 (br s, 12 H, 4 CH3 of
BPin); 13C NMR {'H} (C6D6, 75 MHz) 6 151.7 (C), 144.6 (C), 143.8 (C), 129.5 (CH),
120.3 (CH), 117.6 (CH), 114.8 (CH), 113.4 (CH), 106.6 (CH), 83.6 (C), 40.3 (CH3), 24.9
(4 CH3 of BPin); “B NMR (C6D6, 96 MHz) 8 32.03; FT-IR (neat) v: 3366, 3048, 2978,
2932, 2801, 1584, 1497, 1470, 1437, 1414, 1383, 1298, 1275, 1250, 1217, 1143, 1120,
1016, 968, 849, 754, 736, 708, 698 cm"; GC-MS (E1) m/z (% relative intensity): M" 338
(100), 309 (7) 237 (5). Anal. Calcd for C20H27BN2O2: C, 71.02; H, 8.04; N, 8.28. Found:
C, 71.05; H, 8.05; N, 8.25.

Table 5.3, Entry 1. N-Phenyl-2-chloro-4-(4,4,5,5-tetramethyl-l,3,2-diox3borolane-2-

yl)-aniline (5.143 + 5.14b).

 

Hc
Cl 5 BPin
6 4
PhHN 1 3 Hb
Ha
5.148 5.148
93% 7%

The general procedure was applied to 1,2-di-chlorobenzene (294 mg, 2 mmol).
The borylation step was carried out neat with HBPin (435 mg, 3.00 mmol, 1.50 equiv)
and dmpe (6 mg. 0.04 mol, 2 mol%) at 100 °C for 4 h. The amination step was then
carried out using 2-dicyclohexylphosphinobiphenyl (28 mg, 0.08 mol, 4 mol%) and
aniline (242 mg, 2.6 mmol, 1.30 equiv) at 100 °C for 24 h. The ratio of the two isomers
in the crude reaction mixture by GC was 93:7. Column chromatography (hexane/CH2C12
1:2) furnished a mixture of two isomers (300 mg, 46% combined yield) as alight yellow
oil. The ratio of the two isomers in the isolated mixture by GC was 95:5. The presence of

two three-bond cross peaks from carbon C1 to protons Hb and He in the gHMBC

211

 

 

spectrum was used to assign the major isomer as N-phenyl-2-chloro-4-(4,4,5,5-
tetrarnethyl-l,3,2-dioxaborolane-2-yl)-aniline. 1H NMR (C6D6, 500 MHz) 6 (5.143) 8.24
(d, J= 1.3 Hz, 1 H), 7.82 (dd, J= 8.2, 1.5 Hz, 1 H), 7.14 (d, J= 8.2 Hz, 1 H) 7.01-6.98
(m, 2 H), 6.84-6.81 (m, 1 H), 6.78-6.77 (m, 2 H), 6.08 (br s, l H), 1.11 (br s, 12 H, 4 CH3
of BPin); ”C NMR {'H} (C60,, 125 MHz) 8 (5.14a)143.5 (C), 140.8 (C), 136.9 (CH),
134.8 (CH), 129.5 (CH), 123.5 (CH), 121.6 (CH), 120.9 (C), 114.2 (CH), 83.7 (C), 24.9
(4 CH3 of BPin); “B NMR (C60,, 96 MHz) 8 30.9; FT-IR (neat) v: 3407, 3050,2978,
2930, 1593, 1524, 1499, 1470, 1431, 1354, 1265, 1221, 1144, 1098, 1049, 965, 882, 822,
752, 729, 694, 669 cm]; GC MS (EI) m/z (% relative intensity): M+ 329 (100), 331 (35),
328 (27), 230 (13), 194 (10). Anal. Calcd for C13H21BCINO2: C, 65.59; H, 6.42; N, 4.25.
Found: C, 66.18; H, 6.88; N, 3.98. HRMS (E1): m/z 329.1355 [(M+); Calcd for
CrgH2rBClNO2: 329.1354].

Table 5.3, Entry 2. Attempted amination of 2,5-di-chloro-l-(4,4,5,5-tetramethyl-
1,3,2-dioxaborolane-2-yl)-benzene.

In a dry box, 2,5-di-chloro-1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-
benzene (273 mg, 1 mol, 1 equiv), anhydrous K3P04 (297 mg, 1.40 mmol, 1.40 equiv),
Pd2db33 (9 mg, 0.01 mol, 1 mol%), 2-(dicyclohexylphosphino)biphenyl (14 mg, 0.04
mol, 4 mol%), aniline (118 ML, 1.30 mmol, 1.30 equiv) and DME (3mL) were added.
The flask was then sealed, removed from the dry box, stirred at 100 °C for 24 hr, and the
reaction was monitored by GC-FID/MS. GC analysis after 24 hr showed 95% conversion
of the starting boron pinacolate ester. The combined GC yield of two isomeric arylamine
boronate esters was about 10%. GC ratio of two isomeric arylamine boronotae esters was

7:1. Deborylated aryl amine (approximately 3% by GC) was also observed along with

212

 

small amounts of Suzuki products. Attempted isolation was not successful and no clean
arylamine boronate ester was isolated.
Table 5.3, Entry 3. N-Phenyl-4-(trifluoromethyl)-2-(4,4,5,5-tetramethyl-l,3,2-
dioxaborolane-2-yl)-aniline (5.16).
BPin
F30 NHPh

5.16

The general procedure was applied to 4-chlorobenzotrifluoride (722 mg, 4.00
mmol, 2.00 equiv). The borylation step was carried out neat with HBPin (256 mg, 2
mmol, 1 equiv) and dmpe (6 mg, 0.04 mol, 2 mol%) at 150 °C for 4 h. The ratio of the
two borylated isomers by GC was 95:5. 13 C NMR spectroscopy was used to assign the
major borylated isomer as 4-chloro-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolane-2-yl)-
benzotrifluoride. The amination step was then carried out using
2-dicyclohexylphosphino-2'-(N,N-di-methylamino)biphenyl (32 mg, 0.08 mol, 4 mol
%) and aniline (242 mg, 2.60 mmol, 1.30 equiv) at 100 °C for 8 h. Coltunn
chromatography (hexane/CH2C12 2:1) furnished the desired product (329 mg, 45% yield)
as a light yellow solid. Analytically pure material was obtained by recrystallization from
benzene, mp 110-111 °C. 1H NMR (CDCI3, 500 MHz) 6 8.03 (br s, 1 H), 7.99 (d, J = 2
Hz, 1 H), 7.47 (dd, J = 8.8, 2.2 Hz, 1 H), 7.39-7.36 (m, 2 H), 7.26-7.24 (m, 2 H), 7.17 (d,
J= 8.8 Hz, 1 H) 7.13-7.10 (m, 1 H), 1.39 (br s, 12 H, 4 CH3 of BPin); 13C NMR {'H}
(C6D6, 125 MHz) 8 154.0 (C), 141.3 (C), 135.0 (q, 3J0. = 3.8 Hz, cm, 130 (q, 3J0. =
3.8 Hz, CH), 129.8 (CH), 125.7 (q, 'JC-F = 270.4 Hz, CF3), 123.8 (CH), 122.1 (CH),

120.0 (q, chq: = 32.6 Hz, C), 112.5 (CH), 84.3 (C), 24.6 (4 CH3 of BPin); ”F NMR

213

 

(C6D6, 282 MHz) 8 -61.4; “B NMR (C613,, 96 MHz) 8 31.0; FT-IR (neat) v: 3380, 2982,
2936,1620,1597,1584,1499,1480,1368,1316,1269,1246,1167,1144,1111,1078,
1065, 860, 754 cm"; GC MS (EI) m/z (% relative intensity): 1W 363 (100), 344(8), 306
(22) 263 (95). Anal. Calcd for C19H21BF3NO2: C, 62.83; H, 5.83; N, 3.86. Found: C,

62.98; H, 5.66; N, 3.90.

214

 

BIBLIOGRAPHY

(1) Suzuki, A. Journal ofOrganometa/lic Chemistry 1999, 5 76, 147-168.

(2) Miyaura, N.; Suzuki, A. Chemical Reviews 1995, 95, 2457-2483.

(3) Muci, A. R.; Buchwald, S. L. In Topics in Current Chemistry 2002; Vol.
219, p 131-209.

(4) Wolfe, J. P.; Wagaw, S.; Marcoux, J. F.; Buchwald, S. L. Accounts of
Chemical Research 1998, 31, 805-818.

(5) Hartwig, J. F. Accounts of Chemical Research 1998, 31, 852-860.

(6) For recent advances in Cu-catalyzed carbon-heteroatom bond-forrning

reactions, see: Ley, S. V.; Thomas, A. W. Angewandte Chemie-International Edition
2003, 42, 5400-5449.

(7) Cho, J. Y.; Tse, M. K.; Holmes, D.; Maleczka, R. E.; Smith. M. R. Science
2002, 295, 305-308.

(8) Ishiyama, T.; Takagi, J.; Ishida, K.; Miyaura, N.; Anastasi, N. R.; Hartwig,
J. F. Journal of the American Chemical Society 2002, 124, 390-391.

(9) Ishiyama, T.; Takagi, J.; Yonekawa, Y.; Hartwig, J. F.; Miyaura, N.
Advanced Synthesis & Catalysis 2003, 3 45, 1 103-1 106.

(10) Ishiyama, T.; Nobuta, Y.; Hartwig, J. F.; Miyaura, N. Chemical
Communications 2003, 2924-2925.

(11) Maleczka, R. E.; Shi, F.; Holmes, D.; Smith, M. R. Journal of the
American Chemical Society 2003, 125, 7792-7793.

(12) For a review on tandem catalysis, see: Fogg, D. E.; dos Santos, E. N.
Coordination Chemistry Reviews 2004, 248, 2365-2379.

215

 

 

(l3) Miura, Y.; Oka, H.; Momoki, M. Synthesis 1995, 1419-1422.

(14) Miura, Y.; Momoki, M.; Nakatsuji, M.; Teki, Y. Journal of Organic
Chemistry 1998, 63, 1555-1565.

(15) Miura, Y.; Nishi, T.; Teki, Y. Journal of Organic Chemistry 2003, 68,
10158-10161.

(16) Barder, T. E.; Walker, S. D.; Martinelli, J. R.; Buchwald, S. L. Journal of
the American Chemical Society 2005, 127, 4685-4696.

(17) Read, M. W.; Escobedo. J. O.; Willis, D. M.; Beck, P. A.; Strongin, R. M.
Organic Letters 2000, 2, 3201-3204.

(18) Chotana, G. A.; Holmes, D.; Maleczka, R. E., Jr.; Smith, M. R., 111
manuscript in preparation.

(19) For a discussion of costs involved in product isolation, see: Anderson, N.
G. Organic Process Research & Development 2004, 8, 260-265.

(20) Jonckers, T. H. M.; Maes, B. U. W.; Lemiere, G. L. F.; Dommisse, R.
Tetrahedron 2001, 5 7, 7027-7034.

(21) Miyaura, N.; Ishiyama, T.; Sasaki, H.; Ishikawa, M.; Satoh, M.; Suzuki,
A. Journal of the American Chemical Society 1989, I I I, 314-321.

(22) Old, D. W.; Wolfe, J. P.; Buchwald, S. L. Journal of the American
Chemical Society 1998, 120, 9722-9723.

(23) Holland, R.; Spencer, J.; Deadman, J. J. Synthesis-Stuttgart 2002,
2379-2382.

(24) Gong, B. 0.; Hong, F.; Kohm, C.; Jenkins, 5.; Tulinsky, J.; Bhatt, R.; de
Vries, P.; Singer, J. W.; Klein, P. Bioorganic & Medicinal Chemistry Letters 2004, 14,
2303-2308.

(25) Shi, F.; Smith, M. R., 111; Maleczka, R. E., Jr. Organic Letters 2006, 8,
1411-1414.

216

 

 

(26) Merola, J. S.; Kacmarcik, R. T. Organometallics 1989, 8, 778-784.

(27) Uson, R.; Oro, L. A.; Cabeza, J. A. Inorganic Syntheses 1985, 23, 126-30.

217

CHAPTER 6
Part A: Synthesis of Borylated Aromatic Alkynes by One-Pot
Borylation/Sonogashira Coupling
Introductions
Iridium catalyzed aromatic C—H activation/borylation, first reported by Iverson
and Smith in 1999,l has emerged as one of the most convenient methodology for the

2 Because

regioselective functionalization of aromatics and heteroaromatics?‘l
selectivities in iridium catalyzed borylation are determined by sterics as oppose to
electronic effects, this new synthetic tool provides unique regioselectivities which are
complementary to those found in electrophilic aromatic substitution” and directed ortho

metalation .1415

An important feature of iridium-catalyzed borylation is the tolerance to a
variety of functional groups such as halogens, ester, amide, acyl (in 5-membered
heterocycles), and nitrile. However functional group tolerance to side chain alkene or
unhindered alkyne has not been reported with present catalyst systems.

Borylated aromatic alkynes are usually intermediates in the synthesis of
extensively conjugated polymeric materials.'6 Aromatic alkynyl boronate esters/acids
have also found applications in diverse areas such as crystal engineering,17 biological
inhibition,‘8 molecular sensing,l9 chirality and structural assignment,20 etc. The boronic
ester/acid functionality is usually introduced on the aromatic alkyne either by

metalation2| 27'

or by Pd catalyzed borylation of aromatic halides.23 Direct C—H bond
borylation will reduce the number of steps towards synthesis of borylated aromatic

alkynes. This will also allow access to the unique regioselectivities associated with

aromatic borylation in the target molecule. Further, reduction of alkyne to alkene will

218

 

provide access to aromatic alkenyl boronate esters. We therefore decided to investigate
the potential tolerance of alkynyl group in iridium catalyzed aromatic borylation. Herein,
we describe our results on attempted borylation of aromatic alkynes, and the synthesis of
borylated aromatic alkynes by one-pot borylation/Sonogashira coupling.
Results and Discussion

Attempted borylation of phenyl acetylene (6.1) with [Ir(OMe)(COD)]2/dtbpy
catalyst system was unsuccessful. Considering that the terminal C—H bond in acetylene
may be acidic enough (pKa 25) towards [Ir(OMe)(COD)]2, we examined l-phenyl-l-
propylene (6.2) and di-phenyl acetylene (6.3) for possible aromatic borylation. Neither of
these underwent aromatic borylation with [Ir(OMe)(COD)]2/dtbpy catalyst system
(Scheme 6.1). Although these borylation were attempted without pre-generating the

active catalyst, it is unlikely that the results will be different with pre-generation.

Scheme 6.1. Attempted borylation of di-phenyl acetylene.
1 equiv B2Pin2,

QCECQ 1.5 m0|°/ollr(COD)(0Me)121A No Borylation
3 mol% d‘bpy, 25 °C

6.3

 

It was also found that the addition of 10 mol% of diphenylacetylene halts the

ongoing borylation of an otherwise suitable substrate as shown in Scheme 6.2.

Scheme 6.2. Borylation inhibition by aromatic alkyne.

50% conversion

— —

 

 

 

M . .
e 1 equiv BpPinp, Me Me 10 mol%
@CI 1.5 mol% [lr(COD)(OMe)]2,; CI + Cl PhCCPh No Further
3 mol% dtbpy, 25°C ' ——’ Borylation
_ PinB _
5.4 6.5

219

 

Attempted borylation of di-phenyl acetylene with (Ind)Ir(COD)/dmpe at 150 °C
gave a mixture of products arising from hydrogenation, hydroboration, and catalytic
borylation. These results suggest that alkynyl group binds tightly with the active
borylation catalyst at room temperature, and at elevated temperatures the alkynyl group
becomes a reactive partner.

During the course of this project, Hata et al. reported borylation of
alkynylporphyrin 6.6 to synthesize borylated alkynylporphyrin 6.7 (Scheme 6.3).24 It is
likely that the presence of two bulky substituents on alkyne hinder its binding with the

active [Ir] catalyst, thus allowing catalytic borylation to take place.

Scheme 6.3. Borylation of alkynylporphyrin.

tBu tBu

 

4 equiv B2Pin2
4 mol% [Ir(OMe)(CODll2
8 mol% dtbpy
1-4-dioxane, 70%

: TMS

 

 

tBu tBu

6.6 6.7

Our results on attempted borylation of unhindered aromatic alkynes prompted us
to sought alternate routs for the synthesis of simple borylated aromatic alkynes. Our
success in one-pot borylation/amination for the synthesis of aromatic aminoboronate
esters had shown that under anhydrous conditions, the C—Halogen bond in a

haloarylboronate ester could be selectively employed in C—N coupling while keeping the

220

 

 

C-B bond completely intact.7‘8 We therefore decided to test the viability of Sonogashira

25.26

coupling of haloarylboronate esters.

When this work was started, there were no examples of tolerance of boronic ester

group during the Sonogashira reaction. Subsequent to our initial reports,27‘28

some reports
have appeared where Sonogashira coupling has been carried out in the presence of
boronic ester group.'8"9‘29'3' Nevertheless, the direct introduction of boronic ester
functionality by iridium catalyzed aromatic C—H activation along with its unique
regioselectivities will have its own advantages.

3-Bromo-5-BPin-benzotrifluoride (6.8) was subjected to Sonogashira coupling as
a test substrate (Scheme 6.4). Using Fu‘s conditions,32 the Sonogashira coupling stopped
after about 90% conversion of the substrate in 18 h, possibly due to the homocoupling of
the phenyl acetylene. We were, however, pleased to observe the formation of the desired
borylated aromatic alkyne without any significant deborylation. The presence of CuI
co-catalyst during Sonogashira coupling can result in oxidative homocoupling of alkynes.
Buchwald has shown that a copper co-catalyst may also inhibit Sonogashira coupling.33

Shifting to copper free conditions reported by Soheili34 resulted in full conversion of

substrate in 10 h and the resulting borylated aromatic alkyne was isolated in 75% yield.

221

Scheme 6.4. Sonogashira coupling of 3-bromo-5-BPin-benzotrifluoride.

1.2 equiv HCCPh,

1.2 equiv HN(iPr)2
3 mol% [Pd(PhCN)QCl2,
RC 6 mol% PtBu3, 2 mol% Cul
Dioxane, r.t.,18 h

> 90% conversion

 

 

 

Br
PinB 1.1 equiv HCCPh. F3C 6.9
6.8 2 equiv DABCO : Ph
2.5 mol% [(al|y|)PdC|]2.
10 mol% PtBu3, PinB

Acetonitrile, r.t.,10 h . .
75% isolated yield

With this success, we moved to the one-pot sequence of borylation/Sonogashira
coupling. We could envision at least two potential issues towards this approach. Firstly,
residual iridium catalyst/ligand may affect the subsequent Sonogashira coupling.
Secondly, iridium is known to catalyze the polymerization of aromatic alkynes.35
3-Bromobenzotrifluoride was borylated using (Ind)Ir(COD)/dmpe catalyst system and the
intermediate boronate ester was then subjected to Sonogashira coupling without isolation.
The coupling went smoothly without any interference from residual iridium
catalyst/borylation by-products and the desired product was isolated in 64% yield. Other
substrates were also utilized in this one-pot methodology. The general one-pot
borylation/Sonogashira coupling sequence is shown in Scheme 6.5 and the yields of some

borylated alkynes are presented in Table 6.1.

222

 

Scheme 6.5. One-pot borylation/Sonogashira coupling.

R1

85

R3

1. 1.5 equiv HBPin
2 mol% (Ind)Ir(COD)L

 

2 mol% dmpe,

150 °C
2. pump down

 

Rs

'1

BPin

3. 1.3 equiv HCCR,
2 equiv DABCO

R4

 

 

2.5 mol%[(allyl)PdCl]:
10 mol% PIBU3,

Acetonitrile, r.t.

6
6.9 - 6.22

Table 6.1. Preparation of borylated aromatic alkynes by One-pot aromatic borylation/

Sonogashira coupling of aryl bromides according to scheme 6.5.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Entry Substrate Borylation Alkyne Sonogashira Product
Time (h) Time (h)
R‘ 32 R3 R4 R5 36 %yield
1 CF3 H Br 3 Ph : H 5 CF3 H Ph—E 64 (6.9)
2 Me H Br 12 Ph :: H 12 Me H Ph—T‘: 61 (6.10)
3 OMe H Br 16 Ph _ H 4 OMe H Ph—E 52 (6.11)
4 NM92 H Br 24 Ph : H 20 NMe2 H Ph—E 70 (6.12)
5 CI H Br 12 Ph : H 12 Cl H Ph—E 37 (6.13)
6D CN H Br 2 Ph :: H 2 CN H Ph—E 52 (6.14)
7 Me H Br 12 TMS : H 4 Me H TMS—E 65 (6.15)
8 CI H Br 4 TMS : H 4 CI H TMS—E 59 (6.16)
99C CN H Br 2 TMS :: H 2 CN H TMS—E 47 (6.17)
10 Me Me Br 10 Ph : H 18 Me Me Ph—E 77 (6.18)
11 Me Br Me 4 Ph : H 40 Me Phi Me 70 (6.19)
12 Br H Br 8 TMS : H 2 TMS-T: H TMS—E 54 (6.20)
13 Br Br H 8 TMS : H 2 TMS—E: TMS—7': H 57 (6.21)
14 Br Br H 4 Ph : H 9 Ph——: Ph—E H 78 (6.22)

 

 

aSee experimental section for specific details. b3 mol% [lr(OMe)(COD0]2/dtbpy
was used for borylation. cBorylation was carried out with 0.6 equiv of nglnz.

223

 

 

Both electron rich as well as electron deficient aryl bromides were used as
electrophiles. Phenyl acetylene and TMS acetylene were employed as the alkyne partner.
Functional groups such as Cl, CN, and OMe were tolerated which can potentially be
further elaborated. Entries 10 and 11 show that a hindered C—Br bond in a bromoaryl
boronate ester can undergo selective Sonogashira coupling without any deborylation of
the easily accessible C—B bond. Double Sonogashira coupling can be carried out starting
from l,3-di-bromobenzene (entry 12). Attempted mono-Sonogashira coupling on the
intermediate boronic ester of 1,2-di-bromobenzene using 0.9 equiv of TMS-acetylene
resulted in a 1:3 mixture of two regioisomers, however the di-Sonogashira product was
the major species observed by GC-F ID. The resulting borylated aromatic enediynes were
isolated in good yields by using 2.2 equiv of alkyne (entries 13 and 14). It might be
however possible to achieve good selectivity in mono-Sonogashira coupling, without
forming the di-Sonogashira product, by using a less active catalyst system.

To expand the scope of this methodology to heteroaromatics, we examined the
one-pot borylation/Sonogashira coupling of 3-bromothiophene as shown in Scheme 6.5.
The diborylation was complete in 1 h, however upon subsequent Sonogashira coupling,

extensive deborylation was observed.
Scheme 6.6. Attempted di-borylation Sonogashira coupling of 3-bromothiophene.

2.5 equiv HBPin, 1.1 equiv HCCPh,

S 1.5 mol% [Ir(COD)(OMe)]2, PinB S BPin 2 equiv DABCO .
= o debo Iatton
\ / 3 mol% dtbpy, 25 °C, 1 h V 2-5 mol /. [(allyllPHCllz. W
10 mol% PtBu3,
3' Br Acetonitrile, r.t.,4 h

 

224

 

Considering that presence of iridium may have caused deborylation, we tested
Sonogashira coupling on isolated 2-bromo-5-BPin-thiphene. Although the Sonogashira
coupling was complete in 2 h, about 80% of the coupled product was deborylated. These
results suggest that the presence of BPin functionality on the 2-position of thiophene does
not survive Sonogashira conditions. Zheng30 has also reported deborylation during
microwave assisted Sonogashira coupling of 2-borylated heteroaromatics. It might be
however possible to tolerate BPin group in heteroarenes on a position further away from
the heteroatom (or with better catalysts).

In conclusion, we have developed an efficient one-pot aromatic C—H activation
borylation/Sonogashira coupling protocol for the synthesis of borylated aromatic alkynes
starting from simple aryl bromides. This methodology tolerates a variety of functional
groups and several borylated alkynes were prepared in good to high yields. Further
elaboration of these synthetically useful intermediates for possible applications in
material sciences needs to be investigated. Extension of this methodology to
heteroaromatic aryl halides, and inclusion of aryl chlorides as coupling partner will also

be useful.

225

 

 

CHAPTER 6
Part B: Synthesis of Borylated Aromatic Thioethers by One-Pot Borylation/C—S
Coupling
Introduction

Our success in one-pot borylation/cross coupling reactions of aryl halides to
synthesize aromatic amino boronate esters7 and aromatic alkynyl boronate esters
prompted us to further expand the scope of one-pot methodology for the synthesis of
multiply functionalized aromatic building blocks starting from simple aryl halides. We
were particularly interested in C—S and C—0 couplings since aromatic ethers/thioethers
have a wide range of applications. Aromatic thio boronate esters and borylated aromatic
ethers are usually prepared by metalation or by Miyaura’s Pd catalyzed borylation36 of
aryl halides. Application of iridium catalyzed aromatic C—H activation/borylation for the
incorporation of boronic ester group can reduce the number of steps towards the synthesis
of these molecules. However the iridium catalyzed borylation of aromatic ethers is very
slow due to the electron rich nature of substrate. Although there is one example of
tolerance of SMe group during iridium catalyzed aromatic borylation,6 less reactivity
similar to aromatic ethers is expected in other aromatic thioethers.

Iridium catalyzed aromatic C—H activation/borylation of aryl halides followed by
C—S/C—O coupling at the C-Halogen bond can be an alternate route for these compounds.
There is no example in literature where a C—B bond survives during C—S/C—O bond
forming reaction. Further the C—B bond has often been employed in the construction of

C—S/C—O bond.”38 We were however optimistic that under anhydrous conditions, the

226

desired chemoselective transformation at the C—Halogen bond might be achieved while
keeping the C—B bond completely intact.
Results and Discussion

As a first step, we subjected isolated boronic ester derived from
3-bromoiodobenzene to C—S coupling conditions reported by Buchwald.39 Coupling with
analytical grade thiophenol resulted in deborylation. However, with distilled thiophenol
and 10 mol % CuI catalyst loading, the coupling went smoothly in DME solvent and the
borylated thioether was isolated in 84% yield. Next, we examined the one-pot
borylation/C—S coupling sequence starting from simple 3-substituted aryl iodides. We
were delighted that newly formed C—B bond survived during the subsequent C—S
coupling step. Also, the residual iridium catalyst/borylation by products did not cause any
complication in the C—S coupling step. The general one-pot borylation/C—S coupling
procedure is shown in Scheme 6.6. The isolated yields for borylated aromatic thioethers
are shown in Table 6.2.

As per literature,39 functional groups such as alkyl, alkoxy, Cl, Br, and CF 3 were
tolerated under these conditions. However, we noticed that aliphatic sulfides, when used
as coupling partners, were much less reactive under these conditions and the C-S

coupling step was not complete even after one week at 80 °C.

227

 

 

 

Scheme 6.7. One-pot borylation/C-S coupling of aryl iodides.

 

 

 

 

r _
R 1. 0.8-1 equiv B2Pin2 R 3. 1.3 PhSH, R
l 1.5-3 mol% [Ir(OMe)(COD)]2; l 2 equiv K2C03, ‘ SPh
3-6 mol% dtbpy, r.t. a 10 mol% Cul, a
2. pump down PinB DME, 80 °C PinB
R = Me, OMe, Cl, Br, CF3 6.23-6.27

Table 6.2. Preparation of aromatic thioethers boronate esters by One-pot aromatic

borylationlC-S coupling of aryliodides according to scheme 6.7.

 

 

Entry Aryl Iodide Borylation C—S Coupling Product %yield
Time (h) Time (h)
Me Me
18 GI 48 36 SPh 73
6.23
PinB
MeO MeO
2a Q—I 36 24 SPh 77
6.24
PinB
CI Cl
3b G1 12 24 SPh 43
6.25
PinB
Br Br
4b Dr 12 24 SPh 26
6.26
PinB
F30 F30
5b GI 12 24 SPh 71
6.27

PinB

 

a. 1 equiv of szlnz and 6 mol% [Ir] was used. b. 0.8 equiv of B2Pin2 and 3 mol% [Ir] was used.

228

We have previously reported that aromatic borylation can be carried out in the
presence of SMe functional group (Figure 6.1).6 However, borylation on di-aryl
substituted sulfides can potentially take place on both of the aromatic rings. In cases
where borylation of only one of the two aryl rings is desired, one-pot borylation/C-S

coupling sequence will provide the desired product as a single regioisomer.

CN CN CN

1.5 mol% [Ir(OMe)(COD)]2, =

 

3.0 mol% dtbpy, + ,
THF, 80 °C. 16 h, 55% BF'”
SMe SMe SMe
90 10
2.7a 2.7b

Figure 6.1. Functional group tolerance of SMe group in lr catalyzed aromatic borylation.

Migita has reported the Pd(PPh3)4 catalyzed nucleophillic substitution of aryl
bromides with thiolate anions using NaO’Bu base (Eq 6.1).40 Attempted C—S coupling of
3-bromo-5-BPin-toluene under these conditions resulted in a 50:50 mixture of the desired
product along with the deborylated product. No C—S coupling was observed using the

weaker base, K2C03.

2 equiv t-BuONa
ArX + RSH > ArSR (6.1)
8 mol%Pd(PPh3)4

 

In conclusion, one-pot borylation/C—S coupling is a convenient route for the

synthesis of borylated aromatic thioethers.

229

Attempted C—O Coupling of Borylated Aryl Chloride.

Attempted C-O coupling“ on an isolated hindered borylated aryl chloride met
with much less success as significant deborylation was observed (Scheme 6.7). This is
probably due to high tendency of the C-B bond to undergo transmetallation with

(alkoxo)-Pa|]adium ([1) complexes.42

Scheme 6.7. Attempted C—O coupling of 2-Chloro-5-BPin-m-xylene.

2 equiv n-BuOH,

 

CI O-nBu O-nBu
Me Me 2 mol /° H110“); Me Me Me Me
2.5 mol% ligand, +
1.5 GQUIV CSQCOS,
BPin Toluene, 25 C, 3 h BPin
6.28 6.29 6.30
GC-FID ratio 80 : 20

PIBU2

Formation of the desired product as the major species is promising. This suggests

Ligand =

that the formaion of C—0 bond is much faster as compared to the breaking of C—B bond.
Use of a more active catalyst for C—O coupling, less n-BuOH, and more active aryl
bromide in place of the aryl chloride, may result in Clean C—O coupling without any
deborylation. The present study was limited to a single substrate. Detailed studies of this
reaction, along with differently substituted aryl halides as starting materials needs to be

carried out.

230

 

Experimental Details and Spectroscopic Data Part A
Materials

All commercially available Chemicals were used as received or purified as
described. Bis(r]4-l,5-cyClooctadiene)-di-u-methoxy-diiridium(l) [Ir(OMe)(COD)]2,
(nS-Indenyl)(Cyclooctadiene)iridium {(Ind)Ir(COD)}, and Pinacolborane (HBPin) were
prepared per the literature procedures.”4S 4,4’-Di-t-butyl-2,2'-bipyridine (dtbpy),
bis(pinacolato)diboron (B2Pin2), and 3-bromobenzonitrile were sublimed before use.
Liquid aryl bromides were refluxed over CaH2, distilled, and degassed. Phenyl acetylene
was distilled before use. Acetonitrile was distilled over activated molecular sieves.
n-Hexane was refluxed over sodium, distilled, and degassed. Silica gel (230-400 Mesh)
was purchased from EMD”.
General Procedure

In a glove box, (Ind)Ir(COD) (8 mg, 0.02 mmol, 2 mol% Ir), dmpe (3 mg, 0.02
mmol, 2 mol%), HBPin (256 mg, 2.0 mmol, 2 equiv), and aryl halide (1 mmol, 1 equiv)
were transferred into a Schlenk flask equipped with a magnetic stirring bar. The flask was
stoppered, removed from the glove box, and stirred at 150 °C until the borylation was
judged complete by GC-FID/MS. The reaction mixture was allowed to cool to room
temperature and subsequently placed under high vacuum for 1-2 h. The Schlenk flask
was brought into the dry box and l,4-diazabicyclo[2.2.2]octane [DABCO] (225 mg, 2
mmol, 1 equiv), allylpalladium chloride dimer (9 mg, 0.025 mmol, 2.5 mol%), PtBu; (20
mg, 0.1 mmol, 10 mol%), alkyne (1.1-1.3 mmol, 1.1-1.3 equiv) and acetonitrile (3mL)
were added.3‘1 The flask was then stoppered, and stirred at room temperature until the

Sonogashira coupling was judged complete by GC-FID. After completion, 10 mL of

231

water were added to the reaction mixture. The reaction mixture was extracted with ether
(10 mL x 3). The combined ether extractions were washed with brine (10 mL), followed
by water (10 mL), dried over MgSOa before being concentrated under reduced pressure
on a rotary evaporator. The crude material was then subjected to column
Chromatography.

Table 6.1, Entry 1. 3-(Phenylethynyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-
yl)-benzotrifluoride (6.9).

F30

BPin

//
Pb
6.9

The general procedure was applied to 3-bromobenzotrifluoride (279 ILL, 450 mg,
2 mmol, 1 equiv). The borylation step was carried out with HBPin (436 1.1L, 384 mg, 3.00
mmol, 1.50 equiv) for 3 h. The Sonogashira coupling step was carried out with phenyl
acetylene (242 uL, 225 mg, 2.20 mmol, 1.1 equiv) for 5 h. Gradient column
chromatography (pentanezdichloromethane 4:1 -> pentanezdichloromethane 1:1)
furnished the desired product as orange yellow oil, which solidified on standing (473 mg,
64% yield, mp 74-75 °C). IH NMR (CDCI3, 300 MHz): 6 8.12 (br s, 1 H), 7.97-7.98 (m,
1 H), 7.83-7.84 (m, 1 H), 7.48-7.53 (m, 2 H), 7.32-7.36 (m, 3 H), 1.35 (br s, 12 H, 4 CH;
of BPin); ”C NMR {'H} (CDCI3, 125 MHz): 8 141.0 (CH), 131.7 (2 CH), 130.6 (q, 3J0.
= 3.8 Hz, CH), 130.5 (q, 3J8-.. = 3.8 Hz, CH), 130.4 (q, 2JC.F = 31.6 Hz, C), 128.6 (CH),
128.4 (2 CH), 123.9 (q, 'Jc-p = 272 Hz, CF3), 123.8 (C), 123.7 (C), 91.0 (C), 87.8 (C),

84.4 (2 C), 24.7 (4 CH3 of BPin); "B NMR (CDCI3, 96 MHz): 8 30.6; ”F NMR (CDC13,

232

 

 

 

282 MHz) 6 -63.0; FT-IR (neat) V: 2980, 1601, 1493, 1369, 1306, 1277, 1169, 1130,
966, 898, 871, 847, 756, 704, 688 cm"; GC-MS (El) m/z (% relative intensity): M+ 372
(100), 357 (10), 286 (18), 272 (12); HRMS (FAB): m/z 372.1510 [(M+); Calcd. for
C21H20BF3O2: 372.1508].

Table 6.1, Entry 2. 3-(Phenylethynyl)—5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolane-2-
yl)-toluene (6.10).

Me

BPin

//
Ph
6.10

The general procedure was applied to 3-bromotoluene (122 11L, 171 mg, 1 mol,
1 equiv). The borylation step was carried out with HBPin (290 11L, 256 mg, 2.00 mmol,
2.00 equiv) for 12 h. The Sonogashira coupling step was carried out with phenyl
acetylene (121 11L, 112 mg, 1.10 mmol, 1.1 equiv) for 12 h. Column chromatography
(pentane/dichloromethane 1:1, Rf 0.8) furnished the desired product as yellow oil, which
solidified on standing (193 mg, 61% yield, mp 73-75 °C). lH NMR(CDC13, 500 MHz): 6
7.80 (s, 1 H), 7.57-7.58 (m, 1 H), 7.47-7.50 (m, 2 H), 7.43-7.44 (m, 1 H), 7.30-7.34 (m, 3
H), 2.34 (s, 3 H), 1.34 (br s, 12 H, 4 CH; of BPin); ”C NMR {‘H} (CDCI3, 125 MHz): 8
137.3 (C), 135.3 (CH), 135.2 (CH), 134.7 (CH), 131.6 (2 CH), 128.3 (2 CH), 128.1 (CH),
123.6 (C), 122.8 (C), 89.6 (C), 89.1 (C), 83.9 (2 C), 24.9 (4 CH3 of BPin), 21.0 (CH3);
”8 NMR (CDCI3, 96 MHz): 8 31.7; FT-IR (neat) V: 2976, 1595, 1491, 1417, 1385,

1371, 1317, 1289, 1207, 1143, 966, 852, 756, 706, 690 cm'l; GC-MS (EI) m/z (% relative

233

intensity): M+ 318 (100), 304 (15), 233 (11), 219 (12); HRMS (FAB): m/z 318.1794
[(M”); Calcd for C2tH23BO2: 318.1791].
Table 6.1, Entry 3. 3-(PhenylethynyI)-5-(4,4,5,5-tetr3methyl-1,3,2-dioxaborolane-2-
yI)-anisole (6.11).

M30

BPin

//
Ph
6.11

The general procedure was applied to 3-bromoanisole (254 11L, 374 mg, 2 mol,
1 equiv). The borylation step was carried out with HBPin (580 uL, 512 mg, 4.00 mmol,
2.00 equiv) for 16 h. The Sonogashira coupling step was carried out with phenyl
acetylene (286 ILL, 266 mg, 2.60 mmol, 1.3 equiv) for 4 h. Gradient column
chromatography (hexanes/dichloromethane 1:1 —> hexanes/dichloromethane 0:1)
furnished the desired product as yellow oil (343 mg, 52% yield). 1H NMR (CDCI3, 500
MHz): 6 7.59 (dd, J= 1.5, 0.7 Hz, 1 H), 7.49-7.51 (m, 2 H), 7.31-7.33 (m, 3 H), 7.29 (dd,
J: 2.7, 0.7 Hz, 1 H), 7.14 (dd, J= 2.7, 1.5, Hz, 1 H), 3.83 (s, 3 H), 1.34 (br s, 12 H, 4
CH3 of BPin); ”C NMR {‘H} (CDCh, 125 MHz): 8 158.9 (C), 131.6 (2 CH), 130.7
(CH), 128.3 (2 CH), 128.2 (CH), 123.9 (C), 123.3 (C), 119.8 (CH), 119.6 (CH), 89.22
(C), 89.20 (C), 84.0 (2 C), 55.4 (OCH3), 24.9 (4 CH3 of BPin); “B NMR (CDCI3, 96
MHz): 6 30.6; FT-IR (neat) V: 2980, 1581, 1373, 1224, 1143, 1057, 966,850, 756, 704
cm"; GC-MS (E1) m/z (% relative intensity): M 334 (100), 319 (10), 276 (6), 248 (15),

234 (21); HRMS (FAB): m/z 334.1742 [(M*); Calcd for C21H23BO3: 334.1740].

234

 

Table 6.], Entry 4. N,N-Di-methyl-3-(phenylethynyl)-5-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolane-Z-yl)-aniline (6.12).
M62N

BPin

//
Ph
6.12

The general procedure was applied to N,N-dimethyl-3-bromoaniline (400 mg, 2
mol, 1 equiv). The borylation step was carried out with HBPin (580 ILL, 512 mg, 4.00
mmol, 2.00 equiv) for 24 h. The Sonogashira coupling step was carried out with phenyl
acetylene (242 11L, 225 mg, 2.20 mmol, 1.1 equiv) for 20 h. Column chromatography
(pentane/ether 4:1, R] 0.5) furnished the desired product as yellow oil (488 mg, 70%
yield). 1H NMR (C6D6, 300 MHz): 6 8.02 (br s, l H), 7.50-7.53 (m, 2 H), 7.47 (d, J = 2.4
Hz, 1 H), 7.11 (dd, J= 2.6, 1.5 Hz, 1 H), 6.95-7.05 (m, 3 H), 2.42 (s, 6 H), 1.13 (br s, 12
H, 4 CH3 of BPin); ”C NMR {'H} (C6D5, 75 MHz): 8 150.3 (C), 131.9 (2 CH), 128.5 (2
CH), 128.1 (CH), 127.5 (CH), 124.3 (C), 124.0 (C), 119.5 (CH), 118.4 (CH), 91.5 (C),
89.0 (C), 83.8 (2 C), 40.0 (2 CH3), 25.0 (4 CH3 of BPin); “B NMR (CDCI3, 96 MHz): 8
31.0; FT-IR (neat) V: 2978, 2930, 2799, 1587, 1489, 1429, 1386, 1269, 1143, 1010, 966,
846, 756, 704, 690 cm"; GC-MS (El) m/z (% relative intensity): M+ 347 (100), 289 (2),

247(10): HRMS (FAB): m/z 347.2060 [(M”); Calcd for C22H26BNO2: 347.2057].

235

Table 6.1, Entry 5. 3-(Phenylethynyl)-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolane-2-
yl)-chlorobenzene (6.13).

CI

BPin

//
Ph
6.13

The general procedure was applied to 3-bromochlorobenzene (118 11L, 191 mg, 1
mol, 1 equiv). The borylation step was carried out with HBPin (290 ILL, 256 mg, 2.00
mmol, 2.00 equiv) for 12 h. The Sonogashira coupling step was carried out with phenyl
acetylene (121 11L, 112 mg, 1.10 mmol, 1.1 equiv) for 12 h. Column chromatography
(pentane/dichloromethane 4:3, R" 0.8) furnished the desired product as a light yellow
solid (117 mg, 37% yield, mp 45-46 °C). 1H NMR (CDC13, 300 MHz): 6 7.84 (dd, J =
1.6, 1.0 Hz, 1 H), 7.71 (dd, J = 2.2, 1.0 Hz, 1 H), 7.57 (dd, J = 2.2, 1.6 Hz, 1 H),
7.48-7.51 (m, 2 H), 7.32-7.34 (m, 3 H), 1.34 (br s, 12 H, 4 CH3 of BPin); 13C NMR {'H}
(CDCI3, 75 MHz): 6 136.0 (CH), 134.2 (CH), 133.9 (C), 133.7 (CH), 131.7 (2 CH), 128.5
(CH), 128.4 (2 CH), 124.7 (C), 122.9 (C), 90.5 (C), 88.0 (C), 84.4 (2 C), 24.9 (4 CH3 of
BPin); 1‘B NMR (CDCI3, 96 MHz): 6 29.8; FT-IR (neat) V: 2978, 1562, 1412, 1356,
1142, 966, 862, 756, 700, 690 cm'l; GC-MS (EI) m/z (% relative intensity): M+ 338
(100), 340(33), 324 (18), 280 (5), 252 (59); HRMS (FAB): m/z 338.1247 [(M); Calcd

for C20H20BCIO2: 338.1245].

236

Table 6.1, Entry 6. 3-(PhenyIethynyl)-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolane-2-
yl)-benzonitrile (6.14).
NC

BPin

//
Ph
6.14

The general procedure was applied to 3-bromobenzonitrile (182 mg, 1 mol, 1
equiv). The borylation step was carried out with HBPin (290 11L, 256 mg, 2.00 mmol,
2.00 equiv), [Ir(OMe)(COD)]2 (10 mg, 0.015 mol, 3 mol% Ir), and dtbpy (8 mg, 0.03
mol, 3 mol%) at room temperature for 2 h. The Sonogashira coupling step was carried
out with phenyl acetylene (121 11L, 112 mg, 1.10 mmol, 1.1 equiv) for 2 h. Column
chromatography (dichloromethane, Rf0.7) furnished the desired product as a light yellow
solid (171 mg, 52% yield, mp 83-85 °C). 1H NMR (CDCI3, 300 MHz): 6 8.14 (dd, J =
1.7, 1.2 Hz, 1 H), 7.99 (dd, J= 1.7, 1.2 Hz, 1 H), 7.84 (t, J= 1.7 Hz, 1 H), 7.48-7.51 (m,
2 H), 7.33-7.38 (m, 3 H), 1.34 (br s, 12 H, 4 CH3 of BPin); ”C NMR {1H} (CDCI3, 75
MHz): 6 141.7 (CH), 137.4 (CH), 136.8 (CH), 131.7 (2 CH), 128.9 (CH), 128.4 (2 CH),
124.4 (C), 122.5 (C), 118.1 (C), 112.6 (C), 91.7 (C), 87.0 (C), 84.7 (2 C), 24.9 (4 CH3 of
BPin); llB NMR(CDC13, 96 MHz): 6 29.7; FT-IR (neat) V: 3061, 2980, 2932, 2231 (s),
2212 (w), 1589, 1491, 1415, 1377, 1329, 1298, 1143, 1122, 966, 897, 848, 756, 698, 690
cm}; GC-MS (El) m/z (% relative intensity): M+ 329 (100), 314 (8), 244 (46), 230 (27);

HRMS (FAB): m/z 330.1668 [(M“); Calcd for C21H21BNO2: 330.1665].

237

 

 

 

Table 6.1, Entry 7. 3-(TrimethylsilyIethynyI)-5-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolane-2-yl)-toluene (6.15).

Me

BPin

//
TMS
6.15

The general procedure was applied to 3-bromotoluene (122 11L, 171 mg, 1 mmol,
1 equiv). The borylation step was carried out with HBPin (218 uL, 192 mg, 1.50 mmol,
1.50 equiv) for 12 h. The Sonogashira coupling step was carried out with trimethylsilyl
acetylene (156 ML, 108 mg, 1.10 mmol, 1.1 equiv) for 4 h. Column chromatography
(pentane/ether 9:1, Rf 0.8) furnished the desired product as yellow oil (204 mg, 65%
yield). lH NMR(CDC13, 500 MHz): 6 7.73 (d, J= 0.5 Hz, 1 H), 7.54 (d, J= 0.7 Hz, 1 H),
7.36 (m, 1 H), 2.29 (s, 3 H), 1.32 (br s, 12 H, 4 CH3 of BPin), 0.21 (s, 9 H, 3 CH3 of
TMS); ”C NMR {‘H} (CDCI3, 125 MHz): 8 137.1 (C), 135.6 (CH), 135.4 (CH), 135.0
(CH), 122.5 (C), 105.3 (C), 93.6 (C), 83.9 (2 C), 24.9 (4 CH3 of BPin), 20.9 (CH3), -0.02
(3 CH3 of TMS); “B NMR (CDC13, 96 MHz): 8 30.3; FT-IR (neat) it: 2978, 2154, 1591,
1383, 1365, 1248, 1145, 966, 848, 760, 706 cm"; GC-MS (EI) m/z (% relative intensity):
M 314 (15), 299 (100), 199 (11); HRMS (FAB): m/z 314.1875 [(M+); Calcd for

C13H27BOZSII 314.1873].

238

Table 6.1, Entry 8. 3-(Trimethylsilylethynyl)-5-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolane—Z-yl)-chlorobenzene (6.16).

CI

BPin

//
TMS
6.1 s

The general procedure was applied to 3-bromochlorobenzene (118 uL, 191 mg, 1
mmol, 1 equiv). The borylation step was carried out with HBPin (218 11L, 192 mg, 1.50
mmol, 1.50 equiv) for 4 h. The Sonogashira coupling step was carried out with
trimethylsilyl acetylene (184 11L, 128 mg, 1.30 mmol, 1.3 equiv) for 4 h. Gradient
column chromatography (hexanes/dichloromethane 1:1 —» hexanes/dichloromethane 0:1)
furnished the desired product as yellow oil (196 mg, 59% yield). ‘H NMR (CDCI3, 500
MHz): 6 7.76 (dd, J= 1.6, 1.0 Hz, 1 H), 7.68 (dd, J: 2.2, 1.0 Hz, 1 H), 7.49 (dd, J= 2.2,
1.6 Hz, 1 H), 1.31 (br s, 12 H, 4 CH3 of BPin), 0.21 (s, 9 H, 3 CH3 of TMS); 13C NMR
{'H} (CDCI3, 125 MHz): 6 136.3 (CH), 134.4 (CH), 134.0 (CH), 133.8 (C), 124.4 (C),
103.4 (C), 95.6 (C), 84.3 (2 C), 24.8 (4 CH3 of BPin), -0.2 (3 CH3 of TMS); 11B NMR
(CDCI3, 96 MHz): 6 30.7; FT-IR (neat) V: 2978, 2166, 1562, 1352, 1143, 966, 927, 844,
760, 702 cm"; GC-MS (EI) m/z (% relative intensity): M+ 334 (8), 320 (100), 219 (10);

HRMS (FAB): m/z 335.1407 [(M”); Calcd for C17H25BOZSiCl: 335.14055].

239

 

Table 6.1, Entry 9. 3-(Trimethylsilylethynyl)-5-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolane-2-yl)-benzonitrile (6.17).

NC

BPin

//
TMS
6.17

The general procedure was applied to 3-bromobenzonitri1e (182 mg, 1 mol, 1
equiv). The borylation step was carried out with BzPinz (153 mg, 0.60 mmol, 1.2 equiv of
boron), [Ir(OMe)(COD)]2 (10 mg, 0.015 mol, 3 mol% Ir), and dtbpy (8 mg, 0.03 mol,
3 mol%) at room temperature for 2 h. The Sonogashira coupling step was carried out with
trimethylsilyl acetylene (156 11L, 108 mg, 1.10 mmol, 1.1 equiv) for 2 h. Column
chromatography (pentane/ethylacetate 9:1, R] 0.7) furnished the desired product as
yellow oil (154 mg, 47% yield). lH NMR(CDC13, 500 MHz): 6 8.05 (dd, J = 1.7, 1.0 Hz,
1 H), 7.96 (dd, J= 1.7, 1.2 Hz, 1 H), 7.75 (t, J= 1.7 Hz, 1 H), 1.32 (br s, 12 H, 4 CH3 of
BPin), 0.21 (s, 9 H, 3 CH3 of TMS); 13C NMR {‘11} (CDCI3, 125 MHz): 6 142.0 (CH),
137.6 (CH), 137.1 (CH), 124.1 (C), 117.9 (C), 112.3 (C), 102.3 (C), 97.1 (C), 84.7 (2 C),
24.8 (4 CH3 of BPin), -03 (3 CH3 of TMS); “B NMR (CDCI3, 96 MHz): 6 30.5; FT-IR
(neat) V: 2961, 2235, 2158, 1589, 1369, 1250, 1143, 968, 954, 846, 760, 700 cm";
GC-MS (EI) m/z (% relative intensity): M+ 325 (3), 311 (100), 210 (3); HRMS (FAB):

m/z 326.1748 [(M“); Calcd for C13H25B02SiN: 32617477].

240

 

 

Table 6.], Entry 10. 3-(Pbenylethynyl)-5—(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-
yl)-o-xy1ene (6.18).
Me

Me BPin

//
Ph
6.18

The general procedure was applied to 3-bromo-o-xylene (136 11L, 185 mg, 1
mol, 1 equiv). The borylation step was carried out with HBPin (290 uL, 256 mg, 2.00
mmol, 2.00 equiv) for 10 h. The Sonogashira coupling step was carried out with phenyl
acetylene (143 11L, 132 mg, 1.30 mmol, 1.3 equiv) for 18 h. Column chromatography
(pentane/dichloromethane 1:2, R; 0.8) furnished the desired product as a yellow solid
(255 mg, 77% yield, mp 104-105 °C). lH NMR(CDC13, 500 MHz): 6 7.88 (s, 1 H), 7.57
(s, 1 H), 7.51-7.54 (m, 2 H), 7.30-7.36011, 3 H), 2.50 (s, 3 H), 2.31 (s, 3 H), 1.35 (br s, 12
H, 4 CH3 of BPin); 13C NMR {'11} (CDCI3, 125 MHz): 8 141.7 (C), 136.5 (CH), 136.1
(C), 135.8 (CH), 131.4 (2 CH), 128.3 (2 CH), 127.9 (CH), 123.7 (C), 122.9 (C), 92.7 (C),
88.9 (C), 83.8 (2 C), 24.9 (4 CH3 of BPin), 20.1 (CH3), 17.7 (CH3); “B NMR (CDC13, 96
MHz): 6 30.9; FT-IR (neat) 17: 2978, 1398, 1389, 1143, 966, 854, 756, 686 cm"; GC-MS
(EI) m/z (% relative intensity): M+ 332 (100), 318 (14), 275 (6), 247 (8), 232 (20), 218

(12); HRMS (FAB): m/z 332.1948 [(M‘); Calcd for C22H25B02: 33219477].

241

 

Table 6.1, Entry 11. 2—(PhenyIethynyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane—2-
yl)-m-xylene (6.19).

Me

Ph€—©~BPin

Me
6.19

The general procedure was applied to 2-bromo-m-xylene (134 11L, 185 mg, 1
mmol, 1 equiv). The borylation step was carried out with HBPin (290 11L, 256 mg, 2.00
mmol, 2.00 equiv) for 4 h. The Sonogashira coupling step was carried out with phenyl
acetylene (143 11L, 132 mg, 1.30 mmol, 1.3 equiv) for 40 h. Gradient column
chromatography (hexanes/dichloromethane 2:1 —> hexaneszdichloromethane 0:1)
furnished the desired product as yellow oil (233 mg, 70% yield). 1H NMR (CDC13, 500
MHz): 6 7.55-7.57 (m, 2 H), 7.54 (s, 2 H), 7.33-7.39 (m, 3 H), 2.53 (s, 3 H), 1.37 (br s,
12 H, 4 CH3 of BPin); 13C NMR {'11} (CDCI3, 125 MHz): 6 139.4 (2 C), 132.8 (2 CH),
131.4 (2 CH), 128.4 (CH), 128.2 (CH), 125.8 (C), 123.7 (C), 99.0 (C), 87.3 (C), 83.8 (2
C), 24.8 (4 CH3 of BPin), 20.9 (2 CH3); “B NMR (CDCI3, 96 MHz): 6 31.3; FT-IR (neat)
17: 2978, 1606, 1385, 1365, 1315, 1238, 1143, 856, 756, 686 cm"; GC-MS (El) m/z (%
relative intensity): M+ 332 (100), 318 (5), 247 (22), 233 (16), 218 (9); HRMS (FAB): m/z

332.1950 [(M*); Calcd for C22H25B02: 332.1948].

242

 

 

Table 6.1, Entry 12. 1,3-Bis-(trimethylsilylethynyl}5-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolane—Z-yD-benzene (6.20).

TMS

\\
BPin I

//
TMS
6.20

The general procedure was applied to 1,3-di-bromobenzene (121 uL, 236 mg, 1
mol, 1 equiv). The borylation step was carried out with HBPin (218 11L, 218 mg, 1.50
mmol, 1.50 equiv) for 8 h. The Sonogashira coupling step was carried out with
trimethylsilyl acetylene (312 (ALL, 216 mg, 2.20 mmol, 2.2 equiv) for 2 h. Column
chromatography (pentane/dichloromethane 2: 1 , Rf 0.7) furnished the desired product as
yellow oil (212 mg, 54% yield). 1H MWR(CDC13, 500 MHz): 6 7.82 (d, J = 1.7 Hz, 2 H),
7.62 (t, J = 1.7 Hz, 1 H), 1.30 (br s, 12 H, 4 CH3 of BPin), 0.20 (s, 18 H, 6 CH3 of 2
TMS); 13C NMR {1H} (CDCI3, 125 MHz): 6 137.9 (2 CH), 137.4 (CH), 122.9 (2 C),
104.0 (C), 94.8 (C), 84.1 (2 C), 24.8 (4 CH3 of BPin), .01 (6 CH3 of2 TMS); “B NMR
(CDC13, 96 MHz): 6 30.2; FT-IR (neat) 37: 2961, 2899, 2154, 1583, 1412, 1371, 1250,
976, 844, 760, 702 cm"; GC-MS (El) m/z (% relative intensity): M+ 396 (14), 382 (100),

282 (7); HRMS (FAB): m/z 396.2116 [(M‘); Calcd for C22H33BOZSi: 396.2112].

243

Table 6.1, Entry 13. 1,2-Bis-(trimethylsilylethynyl)-4-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolane-Z-yD-benzene (6.21).

TMS

TMS : BPin

6.21
The general procedure was applied to 1,3-di-bromobenzene (121 11L, 236 mg, 1 mol, 1
equiv). The borylation step was carried out with HBPin (218 11L, 218 mg, 1.50 mmol,
1.50 equiv) for 8 h. The Sonogashira coupling step was carried out with trimethylsilyl
acetylene (340 11L, 236 mg, 2.40 mmol, 2.4 equiv) for 2 h. Column chromatography
(pentane/dichloromethane 2:1, Rf 0.7) furnished the desired product as a light yellow
solid (226 mg, 57% yield, 'mp 123-124 °C). lH NMR(CDC13, 500 MHz): 6 7.89 (dd, J =
1.2, 0.6 Hz, 1 H), 7.62 (dd, J= 7.8, 1.2 Hz, 1 H), 7.41 (dd, J= 7.8, 0.6 Hz, 1 H), 1.31 (br
s, 12 H, 4 CH3 of BPin), 0.25 (s, 9 H, 3 CH3 of 2 TMS), 0.23 (s, 9 H, 3 CH3 of 2 TMS);
13C NMR {‘H} (CDCI3, 125 MHz): 6 138.7 (CH), 133.9 (CH), 131.4 (CH), 128.0 (C),
125.2 (C), 103.4 (C), 103.2 (C), 99.8 (C), 98.2 (C), 84.1 (2 C), 24.9 (4 CH3 of BPin), 0.03
(3 CH3 of 2 TMS), -0.01 (3 CH; of 2 TMS); “B NMR (CDCI3, 96 MHz): 6 30.8; FT-IR
(neat) 17: 2978, 2961, 2899, 2157, 1599, 1390, 1356, 1250, 964, 924, 844, 760, 684 cm];
GC-MS (El) m/z (% relative intensity): M 396 (88), 381 (57), 339 (18), 282 (100);

HRMS (FAB): m/z 396.2119 [(M+); Calcd for C22H33BOZSi: 396.2112].

244

 

Table 6.1, Entry 14. 1,Z-Bis-(phenylethynyl)-4—(4,4,5,5-tetramethyl-1,3,2-
dioxaborolane-Z-yl)-benzene (6.22).

Ph

\\

Ph BPin

6.22

The general procedure was applied to 1,2-di-bromobenzene (121 11L, 236 mg, 1
mmol, 1 equiv). The borylation step was carried out with HBPin (290 11L, 256 mg, 2.00
mmol, 2.00 equiv) for 4 h. The Sonogashira coupling step was carried out with phenyl
acetylene (242 11L, 225 mg, 2.20 mmol, 2.2 equiv) for 9 h. Column chromatography
(dichloromethane, R; 0.8) furnished the desired product as yellow oil (313 mg, 78%
yield). 1H NMR (CDC13, 500 MHz): 6 8.01 (d, J= 1.2 Hz, 1 H), 7.71 (dd, J= 7.6, 1.2 Hz,
1 H), 7.53-7.57 (m, 5 H), 7.31-7.33 (m, 6 H), 1.35 (br s, 12 H, 4 CH3 of BPin); 13C NMR
{'H} (CDCI3, 125 MHz): 6 138.2 (CH), 133.9 (CH), 131.7 (2 CH), 131.6 (2 CH), 131.0
(CH), 128.5 (Cl-l), 128.37 (2 CH), 128.34 (2 CH), 128.30 (CH), 128.1 (C), 125.3 (C),
123.5 (C), 123.2 (C), 94.8 (C), 93.5 (C), 88.6 (C), 88.4 (C), 84.1 (2 C), 24.9 (4 CH3 of
BPin); “B NMR (CDCI3, 96 MHz): 6 30.1; FT-IR (neat) 17: 3059, 2978, 2930, 2214,
1599, 1491, 1400, 1358, 1143, 1107, 964, 916, 854, 756, 688 cm"; MS (EI) m/z (%
relative intensity): M+ 404 (88), 389 (3), 318 (34), 304 (85), 276 (50); HRMS (FAB): m/z

404.1950 [(M+); Calcd for C23H25B02: 404.1948].

245

 

Experimental Details and Spectroscopic Data Part B
Materials

All commercially available chemicals were used as received or purified as
described. 4,4’-Di-tert-butyl-2,2’-bipyridine (dtbpy) and Bis(pinacolato)diboron (BzPinz)
were sublimed before use. Aryl iodides were refluxed over CaH2, distilled, and degassed.
Benzenethiol was distilled before use. Anhydrous potassium carbonate and copper iodide
were obtained by heating at 150 °C under vacuum for 7 days. Ethylene glycol dimethyl
ether (DME) and n-hexane was refluxed over sodium, distilled, and degassed.
General Procedure

In a glove box, a Schlenk flask, equipped with a magnetic stirring bar, was
charged with the corresponding aryl iodide (2 mmol, 1 equiv). Two separate test tubes
were charged with [Ir(OMe)(COD)]2 (20 mg, 0.03 mol, 3 mol% Ir) and dtbpy (16 mg,
0.06 mol, 3 mol%). BzPinz (1.6-2.0 mmol, 0.8 to 1 equiv) was added to the
[Ir(OMe)(COD)]2 test tube. n—Hexane (2 mL) was added to the dtbpy containing test tube
in order to dissolve the d'bpy. The dtbpy solution was then mixed with the
[Ir(OMe)(COD)]2 and BzPinz mixture. After mixing for one minute, the resulting solution
was transferred to the Schlenk flask containing the aryl iodide. Additional n-hexane (1
mL) was used to wash the test tubes and the washings were transferred to the Schlenk
flask. The flask was stoppered, and the reaction mixture was stirred at room temperature
until the borylation was judged complete by GC-FID/MS. The reaction mixture was
placed under high vacuum for 2 h to remove the volatile materials. Anhydrous K3CO3
(553 mg, 4 mol, 2 equiv), CuI (40 mg, 0.2 mmol, 10mol%), benzenethiol (2.6 mmol,

1.3 equiv) and DME (3mL) were added.39 The flask was then stoppered, removed from

246

 

the dry box and stirred at 80 °C in an oil bath until the reaction was judged complete by
GC-FID. The flask was cooled down to room temperature and 10 mL of water were
added to the reaction mixture. The reaction mixture was extracted with ether (10 mL x 3).
The combined ether extractions were washed with brine (10 mL), followed by water (10
mL), dried over MgSO4 before being concentrated under reduced pressure on a rotary
evaporator. The crude material was then subjected to column chromatography. Isolated
yields are not optimized.

Table 6.2, Entry 1. 2-(3-Methyl-5-(phenylthio)phenyl)-4,4,5,5-tetramethyl-l,3,2-
dioxaborolane—Z-yl (6.23).

Me

SPh
PinB
6.23

The general procedure was applied to 3-iodotoluene (436 mg, 256 11L, 2.00 mol,
1 equiv). The borylation step was carried out with B2Pin2 (508 mg, 2.00 mmol, 1.00
equiv, 2.00 equiv of boron) and 6 mol% [1r] at room temperature for 48 h. The C-S
coupling step was carried out at 80 °C for 36 h. Column chromatography
(pentane/dichloromethane 2:1) furnished the desired product as a white solid (477 mg,
73% yield, Rf: 0.5, mp 84-85 °C). 1H NMR (C6D6, 300 MHz): 6 8.26 (br s, 1 H), 7.83
(br s, 1 H), 7.33-7.34 (m, 1 H), 7.27-7.31 (m, 2 H), 6.80—6.92 (m, 3 H), 1.94 (s, 3 H,
CH3), 1.07 (br s, 12 H, 4 CH3 of BPin); 13C NMR {1H} (C6D6, 75 MHz): 6 138.8 (C),
137.4 (C), 136.3 (CH), 136.0 (CH), 135.4 (CH), 135.1 (C), 130.5 (2 CH), 129.3 (2 CH),

126.6 (CH), 83.8 (2 C), 24.8 (4 CH3 of BPin), 20.9 (CH3); “B NMR (C6D6, 96 MHz): 6

247

 

31.2; FT-IR (neat) V: 2978, 1352, 1317, 1213, 1143, 966, 858, 738, 708 cm]; GC-MS
(EI) m/z (% relative intensity): M)“ 326 (100), 312(4), 240 (17), 226 (11); Anal. Calcd for
C(9H23BOzs: C, 69.95; H, 7.10. Found: C, 69.54; H, 7.19.
Table 6.2, Entry 2. 2-(3-Methoxy-5.(phenyltbio)phenyl)-4,4,5,5-tetramethyl-1,3,2-
dioxaborolane-2-yl (6.24).

MeO

sen
PinB
6.24

The general procedure was applied to 3-iodoanisole (468 mg, 239 11L, 2.00 mol,
1 equiv). The borylation step was carried out with BzPinz (508 mg, 2.00 mmol, 1.00
equiv, 2.00 equiv of boron) and 6 mol% [Ir] at room temperature for 36 h. The C-S
coupling step was carried out at 80 °C for 24 h. Column chromatography (pentane/ether
4:1) furnished the desired product as a white solid (525 mg, 77% yield, Rf: 0.7, mp 81-
83 °C). 1H NMR (C6D6, 300 MHz): 6 8.01 (br s, 1 H), 7.60 (br s, 1 H), 7.29-7.32 (m, 2
H), 7.17-7.18 (m, 1 H), 6.82-6.92 (m, 3 H), 3.16 (s, 3 H, CH3), 1.07 (br s, 12 H, 4 CH3 of
BPin); 13C NMR {'H} (C6D6, 75 MHz): 6 160.5 (C), 137.1 (C), 136.6 (C), 131.1 (2 CH),
130.8 (CH), 129.4 (2 CH), 126.9 (CH), 120.7 (CH), 119.1 (CH), 84.0 (2 C), 54.7 (OCH3),
24.8 (4 CH3 of BPin); “B NMR (C60,, 96 MHz): 6 31.0; FT-IR (neat) 17: 3060, 2978,
2934, 2835, 1570, 1469, 1446, 1350, 1255, 1230, 1143, 1101, 1051, 966, 858, 704 cm];
GC-MS (EI) m/z (% relative intensity): M 342 (100), 327 (5), 256 (13), 242 (12); Anal.

Calcd for C19H23B038: C, 66.68; H, 6.77. Found: C, 66.58; H, 7.02.

248

 

 

Table 6.2, Entry 3. 2-(3—Chloro-S-(phenylthio)phenyl)-4,4,5,5-tetramethyl-1,3,2-
dioxaborolane-Z-yl (6.25).
CI

SPh
PinB
6.25

The general procedure was applied to 3-iodochlorobenzene (477 mg, 250 (AL,
2.00 mol, 1 equiv). The borylation step was carried out with BzPinz (406 mg, 1.60
mmol, 0.80 equiv, 1.60 equiv of boron) at room temperature for 12 h. The C-S coupling
step was carried out at 80 °C for 24 h. Gradient column chromatography
(pentane:dichloromethane 4:1 -* pentanezdichloromethane 1:1) furnished the desired
product as a white solid (297 mg, 43% yield, mp 83-84 °C). 1H NMR (C6D6, 300 MHz):
6 8.06 (dd, J= 1.8, 0.9 Hz, 1 H), 7.96 (dd, J= 2.0, 0.9 Hz, 1 H), 7.41 (t, J= 2.0 Hz, 1 H),
7.19-7.23 (m, 2 H), 6.83-6.87 (m, 3 H), 1.01 (br s, 12 H, 4 CH3 of BPin); l3C NMR {‘H}
(CDCI3, 75 MHz): 6 137.7 (C), 134.9 (CH), 134.7 (C), 134.6 (C), 133.0 (CH), 132.7
(CH), 131.5 (2 CH), 129.3 (2 CH), 127.5 (CH), 84.3 (2 C), 24.8 (4 CH3 of BPin); 11B
NMR (C6D6, 96 MHz): 6 30.7; FT-IR (neat) 17: 3061, 2980, 2932, 2835, 1552, 1342,
1143, 964, 871, 844, 792, 742, 700, 691 cm"; GC-MS (EI) m/z (% relative intensity): M+
346 (100), 331 (9), 260 (31), 246 (14); Anal. Calcd for ClgHzoBClOZS: C, 62.36; H, 5.81.

Found: C, 62.13; H, 5.56.

249

 

 

Table 6.2, Entry 4. 2-(3-Bromo-5—(phenylthio)phenyl)-4,4,5,5—tetramethyl-l,3,2-
dioxaborolane-Z-yl (6.26).
Br

SPh
PinB
6.26

The general procedure was applied to 3-iodobromobenzene (566 mg, 256 11L,

2.00 mol, 1 equiv). The borylation step was carried out with BzPinz (406 mg, 1.60
mmol, 0.80 equiv, 1.60 equiv of boron) at room temperature for 12 h. The C-S coupling
step was carried out at 80 °C for 24 h. Gradient colmnn chromatography
(pentane:dichloromethane 3:1 —’ pentanezdichloromethane 1:1) fill‘l’liSth the desired
product as a white solid (204 mg, 26% yield, mp 105-106 °C). 1H NMR (CDCI3, 500
MHz): 6 7.77 (dd, J= 1.9, 0.9 Hz, 1 H), 7.73 (dd, J= 1.8, 0.9 Hz, 1 H), 7.44 (t, J= 1.8
Hz, 1 H), 7.25-7.34 (m, 5 H), 1.31 (br s, 12 H, 4 CH3 of BPin); 13C NMR {‘H} (CDCI3,
125 MHz): 6 137.8 (C), 135.9 (CH), 135.7 (CH), 135.4 (CH), 134.8 (C), 131.4 (2 CH),
129.4 (2 CH), 127.5 (CH), 123.0 (C), 84.3 (2 C), 24.8 (4 CH3 of BPin); 11B NMR
(CDC13, 96 MHz): 6 30.8; FT-IR (neat) 17': 2978, 1340, 1143, 964, 871, 843, 765, 741,
700 cm"; GC-MS (EI) m/z (% relative intensity): M 392 (100), 390 (99), 306 (27), 292

(16); Anal. Calcd for ClgHzoBBrOZS: C, 55.27; H, 5.15. Found: C, 55.67; H, 5.06.

250

 

 

 

Table 6.2, Entry 5. 2-(3-trifluoromethyl—S—(pbenylthio)phenyl)-4,4,5,5-tetramethyl-
1,3,2-dioxaborolane-2-yl (6.27).
F30
SPh
PinB
6.27

The general procedure was applied to 3-iodobromobenzene (544 mg, 290 11L,
2.00 mmol, 1 equiv). The borylation step was carried out with BzPinz (406 mg, 1.60
mmol, 0.80 equiv, 1.60 equiv of boron) at room temperature for 12 h. The C-S coupling
step was carried out at 80 °C for 24 h. Gradient column chromatography
(pentane:dichloromethane 3:1 —’ pentanezdichloromethane 1:2) furnished the desired
product as a white solid (.537 mg, 71% yield, mp 87-88 °C). 1H NMR (C6D6, 500 MHz):
6 8.25 (br s, 2 H), 7.70 (m, 1 H), 7.18-7.22 (m, 2 H), 6.83-6.87 (m, 3 H), 1.01 (br s, 12 H,
4 CH3 of BPin); 13C NMR {‘H} (CDCI3, 125 MHz): 6 140.0 (CH), 137.1 (C), 134.4 (C),
131.5 (2 CH), 131.1 (q, 2J¢-p = 32.2 Hz, C), 129.7 (q, 3Jc-p = 3.7 Hz, CH), 129.6 (q, 3J0}:
= 3.7 Hz, CH), 129.4 (2 CH), 127.7 (CH), 123.8 (q, lJ01: = 273 Hz, CF3), 84.4 (2 C), 24.8
(4 CH3 of BPin); “B NMR (C613,, 96 MHz): 6 30.7; ”F NMR(CDC13, 282 MHz) 6
-62.7; FT—IR (neat) V: 3063, 2980, 2934, 1603, 1365, 1331, 1294, 1271, 1169, 1130,
1099, 964, 875, 847, 748, 706, 686 cm"; GC-MS (El) m/z (% relative intensity): M+ 380
(100), 365 (6), 294 (11), 280 (12); Anal. Calcd for ClgHzoBF302SZ C, 60.01; H, 5.30.

Found: C, 60.02; H, 5.05.

251

 

BIBLIOGRAPHY

(1) Iverson, C. N.; Smith, M. R. Journal Of The American Chemical Society
1999, 121, 7696-7697.

(2) Cho, J. Y.; Iverson, C. N.; Smith, M. R. Journal Of The American
Chemical Society 2000, 122, 12868-12869.

(3) Tse, M. K.; Cho, J. Y.; Smith, M. R. Organic Letters 2001, 3, 2831-2833.

(4) Cho, J. Y.; Tse, M. K.; Holmes, D.; Maleczka, R. 13.; Smith, M. R. Science
2002, 295, 305-308.

(5) Maleczka, R. E.; Shi, F.; Holmes. D.; Smith, M. R. Journal Of The
American Chemical Society 2003, 125, 7792-7793.

(6) Chotana, G. A.; Rak, M. A.; Smith, M. R. Journal Of The American
Chemical Society 2005, 127, 10539—10544.

(7) Holmes, D.; Chotana, G. A.; Maleczka, R. E.; Smith, M. R. Organic
Letters 2006, 8, 1407—1410.

(8) Shi, F.; Smith, M. R.; Maleczka, R. E. Organic Letters 2006, 8, 1411-
1414.

(9) Paul, S.; Chotana, G. A.; Holmes, D.; Reichle, R. C.; Maleczka, R. 13.;
Smith, M. R. Journal Of The American Chemical Society 2006, 128, 15552-15553.

(10) Ishiyama, T.; Takagi, J.; Ishida, K.; Miyaura, N.; Anastasi, N. R.; Hartwig,
J. F. Journal Of The American Chemical Society 2002, 124, 390-391.

(11) Boller, T. M.; Murphy, J. M.; Hapke, M.; Ishiyama, T.; Miyaura, N.;
Hartwig, J. F. Journal Of The American Chemical Society 2005, 127, 14263—14278.

(12) Takagi, J.; Sato, K.; Hartwig, J. F .; Ishiyama, T.; Miyaura, N. Tetrahedron
Letters 2002, 43, 5649-5651.

252

(l3) Holleman, A. F. Chemical Reviews 1924, I, 187-230.

(14) Wittig, G.; Pockels, U.; Droge, H. Berichte Der Deutschen Chemischen
Gesellschaft 1938, 71, 1903-1912.

(15) Gilman, H.; Bebb, R. L. Journal Of The American Chemical Society 1939,
61, 109-112.

(16) Goldfinger, M. B.; Crawford, K. B.; Swager, T. M. Journal Of Organic
Chemistry 1998, 63, 1676-1686.

(17) Maly, K. E.; Maris, T.; Wuest, J. D. Crystengcomm 2006. 8, 33-35.

(18) Nakamura, H.; Kuroda, H.; Saito, H.; Suzuki, R.; Yamori, T.; Maruyama,
K.; Haga, T. Chemmedchem 2006, 1, 729-740.

(19) Zheng, S.-L.; Lin, N.; Reid, 8.; Wang, B. Tetrahedron 2007, 63, 5427-
5436.

(20) Yashima, 13.; Nimura, T.; Matsushima, T.; Okamoto, Y. Journal Of The
American Chemical Society 1996, 118, 9800-9801.

(21) Laus, G.; Muller, A. G.; Schottenberger, H.; Wurst, K.; Buchmeiser, M.
R.; Ongania, K. H. Monatshefte Fur Chemie 2006, 13 7, 69-75.

(22) Letsinger, R.; Savereid.Tj; Feare, T. E.; Nazy, J. R. Journal of Organic
Chemistry 1961, 26, 1271-&.

(23) Takase, M.; Nakajima, A.; Takeuchi, T. Tetrahedron Letters 2005, 46,
1739-1742.

(24) Hata, H.; Yamaguchi, S.; Mori, G.; Nakazono, S.; Katoh, T.; Takatsu, K.;
Hiroto, S.; Shinokubo, H.; Osuka, A. Chemistry-An Asian Journal 2007, 2, 849-859.

(25) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Letters 1975, 4467-
4470.

253

 

(26) Chinchilla, R.; Najera, C. Chemical Reviews 2007, 107, 874-922.

(27) Chotana, G.; Holmes, D.; Maleczka, R. E.; Smith, M. R. In Abstracts of
Papers, 2301h ACS National Meeting, Washington, DC, United States, Aug. 28-Sept. l,
2005 2005, p ORGN-312.

(28) Shi, F.; Holmes, D.; Chotana, G. A.; Gong, Y.; He, W.; Smith, M. R.;
Maleczka, R. E. In A bstracts, 36th Central Regional Meeting of the American Chemical
Society, Indianapolis, IN, United States, June 2-4 2004, p GEN-3 84.

(29) Perttu, E. K.; Arnold, M.; Iovine, P. M. Tetrahedron Letters 2005, 46,
8753-8756.

(30) Zheng, S.—L.; Reid, 3.; Lin, N.; Wang, B. Tetrahedron Letters 2006, 4 7,
2331-2335.

(31) Schwier, T.; Rubin, M.; Gevorgyan, V. Organic Letters 2004, 6, 1999-
2001.

(32) Hundertmark, T.; Littke, A. F.; Buchwald, S. L.; Fu, G. C. Organic Letters
2000, 2, 1729-1731.

(33) Gelman, D.; Buchwald, S. L. Angewandte Chemie-International Edition
2003, 42, 5993-5996.

(34) Soheili, A.; Albaneze-Walker, J.; Murry, J. A.; Dormer, P. G.; Hughes, D.
L. Organic Letters 2003, 5, 4191-4194.

(35) Marigo, M.; Marsich, N.; Farnetti, E. Journal Of Molecular Catalysis A-
Chemical 2002, 187, 169-177. '

(36) Ishiyama, T.; Murata, M.; Miyaura, N. Journal Of Organic Chemistry
1995, 60, 7508-7510.

(37) Tzschucke, C. C.; Murphy, J. M.; Hartwig, J. F. Organic Letters 2007, 9,
761-764.

254

(38) Kar, A.; Sayyed, I. A.; Lo, W. F.; Kaiser, H. M.; Beller, M.; Tse, M. K.
Organic Letters 2007, 9, 3405-3408.

(39) Kwong, F. Y.; Buchwald, S. L. Organic Letters 2002, 4, 3517-3520.

(40) Migita, T.; Shimizu, T.; Asami, Y.; Shiobara, J.; Kato, Y.; Kosugi, M.
Bulletin Of The Chemical Society Of Japan 1980, 53, 1385-1389.

(41) Torraca, K. E.; Huang, X. H.; Parrish, C. A.; Buchwald, S. L. Journal Of
The American Chemical Society 2001, 123, 10770-10771.

(42) Miyaura, N.; Suzuki, A. Chemical Reviews 1995, 95, 2457-2483.

(43) Uson, R.; Oro, L. A.; Cabeza, J. A. Inorganic Syntheses 1985, 23, 126-30.

(44) Tucker, C. E.; Davidson, J.; Knochel, P. Journal of Organic Chemistry
1992, 57, 3482—3485.

(45) Merola, J. S.; Kacmarcik, R. T. Organometallics 1989, 8, 778-784.

255

CHAPTER 7
Getting the Sterics Just Right: A Five-Coordinate Iridium Trisboryl Complex that
Reacts with C—H bonds at Room Temperature

Introduction

In many transition metal catalyzed processes, ligand dissociation or some other
rearrangement of the metal “catalyst” is required to generate the metal species that reacts
with substrate(s) in the catalytic cycle. Such is the case for lr-catalyzed borylations of C—
H bonds, where the five-coordinate boryl complexes believed to be responsible for C—H
functionalization have not been observed. The closest approach to the five-coordinate
complexes in phosphine and dipyridyl ligated systems are the six-coordinate complexes
7.11 and 7.2.2 While both of these compounds will borylate spz-hybridized C—H bonds,
ligand dissociation precedes the key C—H interaction between the hydrocarbon and the Ir

CCDlCl’.

Scheme 7.1. Generation of five-coordinate intermediates for C—H borylation.

BPin PM BPin o
M93P\'lr,BPin ‘ 93 Mestl'r/BPin BPin = B’
T_____—- \
MeaP’ I\BPin Me3P’ \BPin o
PM83
7.1 7.2

 

 

 

 

 

7.4

Because Ir-catalyzed borylations exhibit unusual chemo and regioselectivities, the

reactivity of five-coordinate trisboryl complexes could offer important information

256

regarding the catalytic reaction. Ignoring the well-known maxim that true reactive
intermediates are rarely isolable, we set out to prepare five-coordinate complexes that
react directly with arenes and heterocycles. Herein we describe our results in this
direction.
Results and Discussion

We expected that the choice of Ir starting material ligand would be critical to
successful preparation of five-coordinate complexes. Since compound 7.3 retains an
nz-olefln from the starting material, we felt that displacement of an arene with a bidentate
Chelating ligand might yield the desired five-coordinate complexes since 112-coordination
of the expelled arene would carry the penalty of disrupting its aromaticity (Scheme 7.2).
The mesitylene trisboryl complex, 7.5, was selected as the starting material, since the

mesitylene methyl groups block access to the arene sp2 C—H bonds.

Scheme 7.2. Arene route to five-coordinate boryl complexes.

L . .
go)— BPIn BPm
I _EL__.. (kl/8P") ”E33193 LJr/BPin
P. Bx'K'IBPin -CeHaMes L’ ‘BPin L’ 1‘BPin
'” BHn <—/
7.5
aromaticity
disrupted

7.5 reacts with dmpe (l,2-bis(dimethylphosphino)ethane) to yield a new species,
7.6. 3 IP NMR spectra revealed two chemically inequivalent P environments at —1 1.1 and
—50.9 ppm for 7.6 present in a 2:1 ratio respectively along with small amounts of an

unidentified species (7.7) (Figure 7.1).

257

7.6

7.6

 

 

 

1 I 7 f

 

-60 -70 pp-

Figure 7.1. 31P NMR of 7.6, a small amount of an unknown compound 7.7 is also
present.

The 3 1P NMR signal of the unidentified product 7.7 appears as a doublet at —48.7
ppm ((1, J = 23 Hz). Its chemical shift is very close to the unbound starting phosphine
ligand. lH NMR spectra of crude reaction mixtures also showed that unreacted 7.5 was
present in addition to resonances for 7.6 with the ratio 1:2 ratio of 7.5:7.6. At this point, it
was clear that 7.6 was a dinuclear species, which could be obtained in good yield by

adjusting the stoichiometry (Eq 1).

PinB BPin

 

\ /
PinB—IrI—P’ . .
:|: 3/2 dm e / \ PmB\ Bpm (71)
lr- + p ‘CGHSMear M9213 PMez /P—lr/—BPin '
. / \"BPin I \
P'”B BPin

M92P PMGZ

7.5 7.6 \J

258

While catalytic borylation of l,3-bis-trifluoromethylbenzene (7.8) is complete in
l h at 150 °C with equimolar (4 mol%) loadings of 7.5 and dmpe, no conversion was
observed with 2 mol% of pure dimer 7.6 under similar conditions (Figure 7.2). However
borylation with 2 mol% 7.6 did go to full conversion after 48 h at 150 oC. Monitoring the
reaction with 2 mol% 7.6 by 3]P NMR showed disappearance of peaks at —1 1.1 and —50.9
along with appearance of several new peaks during the first 24 h at 150 °C. Similarly
with 4 mol% of 7.5 and 6 mol% dmpe, no borylation was observed after 6 h at 150°C,
although borylation ultimately did complete after 48 h. These results are consistent with
our previous observation that catalysis ceases abruptly when ler ratios reach 3:1. The
formation of 7.6 suggests that a significant portion of the Ir may be sequestered in an
inactive form. Consequently, the efficiency of the active forms of Ir phosphine catalysts

may have been significantly underestimated.

4 mol% (MesH)Ir(BPin)3 Full conversion in 1 h

 

 

 

 

4 mol% dmpe _ I:30 CE":
150 °C '
F30 CF3 BF
4 equiv U + HBPin In
7.9
7'8 2 mol% (dmpe)"2(BPl“)6 ‘ No conversion in 1 h
150 °C ' complete after 48 h

Figure 7.2. Borylation results of 1,3-bis-trifluoromethylbenzene.

The most obvious tact for preparing a five-coordinate complex is to increase the
steric demands of the phosphine ligand. Indeed, 7.5 reacts cleanly with
l,2-bis(di-tert-butylphosphino)-ethane (dtbpe) in pentane in 36 h to afford a new
complex, 7.10. The reaction time was found to be much shorter (2 h) using THF as the

solvent. The reaction can easily be monitored by the disappearance of signal for the

259

 

 

starting dtbpe ligand in 3 1P NMR and appearance of a single new peak at 93 ppm. Pure
product is obtained in quantitative yield after removing the THF solvent and mesitylene
under vacuum. The 3'P NMR and IH NMR spectra of 7.10 are consistent with a
five-coordinate structure (Eq 7.2). This was confirmed by X-ray crystallography and the
structure of 7.10 is shown in Figure 7.3. The geometry about Ir is a distorted square
pyramid. The Ir atom lies only 0.14 A above the least-squares plane defined by the
phosphorus and basal boron atoms. The apical boron atom shows the most pronounced
distortion. The Ir—Bl vector is ~15° away from being normal to the basal plane, canting
towards the boryl groups and away from the phosphine ligand. Unique boryl resonances
cannot be discerned in low temperature lH NMR spectra (up to —80 in C7D3), indicating
either isochronus chemical shifts or rapidly exchanging boryl environments. Similarly a
single chemical shift for the t-Bu methyl groups were observed at —1.26 ppm ((1, 3JH_p =

l 1.9 HZ) ll‘l C7D3.

 

R BP
go} 9‘ m
I + m TC”: :1“ a QPN /BPin (7.2)
Pin B/'r\"BPin RQP PR2 _ 6 3 e3 IP’ r\BPin
BP'“ RIF? 7.10, R = tBu
7.5 7.11.13 = iPr

The structure of 7.10 differs from the most closely related boron compound,
trans-erl(BCat)2(PEt3)2 (Cat = catecholate),3 which is a distorted trigonal bipyrarnid
with trans axial phosphines. Given that many nominally five-coordinate d6 transition
metal structures are stabilized by agostic interactions from C—H bonds in their ligand
periphery, we have examined this possibility for 7.10. NMR and IR spectra lack the
signatures associated with agostic C—H interactions, which is consistent with the solid

state structure where the closest Ir—C distance of 3.169(9) A falls outside the range of

260

 

2.65—2.94 A for 1r compounds with bona fide agostic interactions, and is ~ 0.5 A longer

examples.

than the distances for five-coordinate Ir

 

7.10 7.11
Figure 7.3. X-ray structures of compounds 7.10 and 7.11 with BPin methyl groups
omitted. The black carbons are those with the closest Ir contacts. In both cases. the Ir-C
distances are significantly longer than those in compounds with Ir C-H agostic

interactions.

 

0 i
85:5?“0 P P 8?-
l ‘H' 83
0 Q
7.10 7.12 7.11

Figure 7.4. A comparison of the orientation for the B3 boryl ligands in structures 7.10
and 7.11 with the qualitative transition state 7.12. For compound 7.10, rotation about the
lr-B bond is required to reach the transition state, whereas the boryl orientation in 7.11

is ideal for cleaving the arene C—H bond.

7.10 reacts only slowly with arenes at room temperature (Scheme 7.3). This is not
surprising considering the crowded environment at the metal center (Figure 7.3) and is

consistent with the low catalytic activity of in situ generated catalysts using dtbpe as the

261

 

 

Chelating ligand. To ease the steric crowding at the Ir center, compound 7.11, the
isopropyl analog of 7.10, was prepared in analogous fashion. The spectroscopic data and
solid-state structure for 7.11 are similar to those for 7.10 (Figure 7.3). The closest lr—C
contact (3.419 A) is even longer than that in 7.10, reflecting a bona fide five-coordinate

structure for 7.11.

Scheme 7.3. Relative reactivity of 7.10 and 7.11 with 1,3-bis-trifluoromethylbenzene.

F3C CF3
WUCFS + 7.10 10% NMR yield
06012» after 48 h

 

25 °C
BPin
F3C CF3
MU + 7.11 C D Quantitative NMR
6 12
25 o C yield after 48 h
BPin

Relative to 7.10, 7.11 is significantly more reactive at room temperature as the
stoichiometric borylation with l,3-bis-trifluoromethy[benzene 7.8 attests (Scheme 7.3).
Stoichiometric reaction of 7.11 with 2-methylthiophene was also complete in 4 h at room
temperature. This enhancement clearly arises from steric relief, and a comparison
between the putative transition state for C-H functionalization, depicted by structure
7.12, and structures 7.10 and 7.11 shows how a relatively subtle change in the ligand
alters accessibility to the transition state (Figure 7.4). Computational studies show that
the transition state for C—H scission is very late and is assisted by interaction arene
hydrogen and one of the boryl ligands. For this to occur, the participating boryl ligand
(B3 in structures 7.10 and 7.11) must be oriented such that the boron p orbital is
orthogonal to the basal plane of the square pyramid. Certainly, other factors will be

important in determining relative rates, but access to the proper boryl orientation will be

262

 

 

critical. As seen in Figure 7.4, the dihedral angle 0 between the plane defined by BB and
its oxygen atoms and the basal plane in 7.10 is considerable (0 = 48°), while the boryl
plane in 7.11 is virtually coplanar with the basal plane (0 = 4°). Thus, transition state 7.12
should be readily accessible from structure 7.11, while the boryl ligand in 7.10 must
reorient for the boryl p orbital to be accessible.

Although both 7.1.0 and 7.11 stoichiometrically react with electron deficient
arenes as well as with heteroaromatic substrates, neither of them catalyzed aromatic
borylation at room temperature. It is worthwhile to mention here that both 7.10 and 7.11
are stable in C6D6 and C7D3 for several hours at room temperature, allowing their
characterization in these solvents. However, both of these do catalyze benzene borylation
at elevated temperatures (Figure 7.5). Again 7.11 is more reactive than 7.10 for

borylation at elevated temperatures.

 

 

 

 

2 mol% 7-10 g ~ 80% conversion in 30 h
150 °c by 1H NMR
excess 0606 + HBPin
2 mol% 7-11 = ~ 80% conversion in 12 h
150 °c by 1H NMR

Figure 7.5. Catalytic aromatic borylation with 7.10 and 7.11 at 150 °C.

While attempted room temperature catalytic borylation with 7.11, we noticed that
the light yellow color of solution of 7.11 in THF immediately decolorized upon addition
of HBPin (Eq 7.3). Although no aromatic borylation was observed in the initial room
temperature llB NMR, the initial 3'P NMR showed absence of signal corresponding to

7.11 (86.5 ppm). The major product (~95%) in the initial 3 IP NMR was at 68 ppm (7.13)

263

along with small amount of another peak (~5%) at 54 ppm (7.14). It was clear that 7.11
and excess (~4 equiv) HBPin react together, in the absence of arene substrate, to form

these new species.

1 mol%

F3C C' , (dippe)lr(BPin)3 7.11
+ HBPin = 7.13 + 7.14 (7.3)
86.5 ppm

68 ppm 54.3 ppm

 

in an attempt to identify 7.13, 7.11 was reacted with 10 equiv of HBPin in THF
for 15 minutes (Eq 7.4). After removal of solvent under vacuum, the crude product was
crystallized from a mixture of HBPin and 1,3-bis-trifluoromethylbenzene (7.8). The
crystal structure of product showed an iridium complex having almost linear lr-B-O angle
(170°), and a short lr-B bond length (1.95 A), indicative of lr-B double bond.
Braunschweig has reported borylene complexes of Pt and some early transition metals.4
However the present complex is the first one which has both boryl as well as borylene
ligands. Another interesting feature is the breaking of a strong B—O bond at room
temperature, although another B—O bond is formed at the same time to compensate for

the loss in energy.

 

1.THF,15 minute .'P' H

2 Pumped down IPi\P\:r/BPin
d' IBP' +1 HBP' ‘ > '/ \ . 7.4
(Ippe)r( "1):: O In 3. crystalization fromamixture iPr' P H BP'” ( )

. B
of HBPin and 7.8 Pr 1

Considering the high reactivity of the five coordinate complex 7.11, it was

important to check the possibility of aliphatic borylation with this compound. Reaction of

264

7.11 with 25 equiv of HBPin in cyclohexane (Clez) did not show any borylation by HB
NMR after 6 h at 150 °C. Considering that cyclohexane has only secondary C—H bonds,
and HBPin is a less reactive partner as compared to BzPinz, we decided to test catalytic
borylation of n-octane with BzPinz. After heating a solution of BzPinz in n-octane at 80
°C for 1 h with 5 mol% 7.11, small amounts of HBPin were observed by HB NMR,
although no borylated octane was observed in the GC-FID. The source of hydride for the
formation of HBPin is not clear. The hydride may come from the isopropyl methyl
groups in phosphine ligand, the glass surface, or from another source. Upon heating at
150 °C for 24 h, the llB NMR showed complete consumption of BzPinz. A peak around
30 ppm in the HB NMR indicated the formation of C-borylated product. A doublet was
also observed due to the formation of HBPin. The GC-FID data showed formation of
octyl-BPin (single regioisomer). No more conversion was observed upon further heating
with the newly formed HBPin. Similarly, n-hexane and pentane were also borylated at
150 °C and single borylated regioisomers were observed by GC-FID.

Hartwig et al. have reported Rh, Ir, and Ru catalyzed aliphatic C—H borylations‘6
Their reported conditions for [Ir] catalyzed aliphatic borylation are much harsher than
described in this chapter. With 10 mol% of Cp*IrH4 at 200 °C, yields for the borylation
of n-octane never exceeded above 20%. However with 10 mol% Cp*Ir(C2H4)2, afier 10
days at 200 °C, 58% yield was obtained, indicating that in situ generated HBPin is also
used in borylation. They have observed high selectivity for terminal functionalization in
straight chain hydrocarbons. It is therefore plausible to think that in the present case, the

terminal C—H bond are borylated. Our results are very preliminary, and further research

265

including optimization of catalytic conditions, identification of regioisomers, isolation of
products, screening of substrates etc, needs to be carried out.

Based on reactivity of 7.5 with dippe and dtbpe, we expected that
l,2-bis(diphenylphosphino)ethane (dppe) might also give a 5-coordinate complex as the
sole product. However reaction of 7.5 with 1.5 equiv of dppe in THF solvent after 0.5 h

showed three products by 3 1P NMR (Figure 7.6).

7.16

7.15

7.17

7.15

 

 

 

 

 

 

60 so to 30 20 10 o -10 -20 pp-

Figure 7.6. 31P NMR of crude reaction of dppe with 7.5.

Two broad resonances in 2:1 ratio at 6.1 and —16.7 ppm respectively are
tentatively assigned to the dimeric complex 7.15 (due to similarity with dmpe result). A
doublet at —12.6 ppm (J = 31 Hz) for an unknown product 7.16 was also observed. The
chemical shift of this doublet is very close to that for unbound dppe. These two results
are similar to the reactivity of 7.5 with dmpe. Consistent with the downfield shifts for

7.10 (93 ppm) and 7.11 (86.5 ppm), another single resonance at 59 ppm was also

266

observed and was tentatively assigned to the monomeric complex 7.17 (See Figure 7.8).
It seems that dppe ligand exhibit reactivities similar to both dmpe as well as dtbpe/dippe.
No further attempt was made to isolate/fully characterize these products.

Apart from the less steric bulk of dmpe and dppe, ability to assess transoid
conformation may also be responsible for the formation of dimeric complexes 7.6 and
7.15. To restrict the possible formation of dimeric complex via assess to the transoid
conformation, 1,2-bis(diphenylphosphino)benzene 7.18 was reacted with 7.5 in THF. To
our surprise, about 94% product in the 3 IP NMR (after 2 h at room temperature) belonged
to a single down field resonance at 67.8 ppm (Figure 7.7), tentatively assigned to the
monomeric complex 7.19 (Figure 7.8). Less than 6% area in the 3 IP NMR belonged to
small down field (relative to starting phosphine ligand which appears at —12.3 ppm)
resonances at 33 and 39.5 ppm.

7.19

 

 

 

 

 

 

__ k A‘ J L; A A“ A L. A A u “4 AA- A “A __ L “A A A
.. fir.. m— 7 —.a .. v w —— V WWW fl w
T 7"" l 1' ' T" "V A " i

V v T‘" 1 'V _T ‘1“ Y" 1 ' V 3'” 7' Y J 7 'Y'T '7" 1‘ 1"”? l' '1 '7‘ I Y 'T' I l T""Y"' 1_T1 ’l I f—T—fi"'l '

l - .
80 70 60 50 4O 30 20 10 0 pplll

Figure 7.7. 31P NMR of crude reaction of 7.18 with 7.5.

267

Since both dppe and 7.18 have similar steric demands, formation of monomeric
7.19 in case of reaction of 7.5 with 7.18, indicates that inability to assess transoid
conformation disfavors dimer formation (or favor the monomeric complex formation)

(Figure 7.8).

PinB BPin
PinB—ir—P‘fPh P1 n8 ppm ph PhBPin ph‘ PhilaPin
¥fi --P .BPin -—P~. -BPin
~|r ‘lr‘
”Fir/1Q.) Pth7P—'f BP'" L‘P’ ‘BPin ©L‘P,’ ‘BPin
Ph PI‘Ph Ph Ph Ph Ph
Ph’ “Ph
7.15 7.17 7.19
(tentative)

Figure 7.8. Proposed formulation of 7.15, 7.17, and 7.19 based on 31P NMR data.

More interestingly, as opposed to 7.10 and 7.11, which were stable in C6D6 for
short periods of time, 7.19 reacts immediately with C6D6. Stoichiometric reaction of 7.19
with 1,3-bis-trifluoromethylbenzene was also instantaneous. One possible explanation for
the enhanced reactivity of 7.19 relative to 7.11 could be the planer backbone of the
phosphine ligand. Unfortunately, 7.19 is also not stable in other solvents (such as THF)
for long periods of time to allow its crystallization. Due to this limitation, we were unable
to get pure product for full characterization.

The enhanced reactivity of 7.19 prompted us to examine its catalytic activity at
room temperature. As opposed to 7.11, 1 mol% of 7.18 did catalyze the borylation of
3-chloro-benzotrifluoride at room temperature, although only 36% conversion was
observed by GC-FID after 96 h (Figure 7.9). A combination of 0.5 mol%
[Ir(OMe)(COD)]2 and 1 mol% 7.18 also showed about 20% borylation of the same

substrate after 96 h at room temperature. Despite low conversions, these are the first

268

examples where a phosphine-based ligand is shown to catalyze aromatic borylation at
room temperature. It is worthwhile to mention here that in contrast to the reaction of
HBPin with 7.11, addition of HBPin to an orange solution of 7.19 in THF did not cause

any immediate decolorization.

 

1 mol% 7.19 4' 36% conversion by
THF, r.t. 96 h GC-F'D

 

F30 Cl
0 +1.5HBPin

0.5 mol% [Ir(OMe)(COD)]2

1 mol% 7-181 47 20% conversion by
THF, r.t.. 96 n GC-FID

 

Figure 7.9. Room temperature catalytic borylation with 7.19.

Conclusions

In summary, the steric influence of the Chelating diphosphinoethane ligands has a
dramatic effect on the structures and reactivities of the trisboryl complexes obtained by
reactions with the arene complex 7.5. It is interesting that even though equimolar
solutions of 7.5 and dmpe are catalytically active for borylation, the major product 7.6
obtained by reaction of 7.5 and dmpe is inactive. Consequently, it is conceivable that the
active catalytic species for the phosphine-supported catalysts are present in very low
concentration. Significantly, the first five-coordinate boryl complexes that react with
arenes at room temperature have been obtained by increasing the steric requirements of
the phosphine substituents. Still further detailed investigation of several preliminary
results described in this chapter needs to be carried out in order to uncover the secrets of

borylation chemistry.

269

Experimental Details and Spectroscopic Data
General Methods

All commercially available chemicals were used as received unless otherwise
indicated. Pinacolborane (HBPin containing 1% NEt3) was generously supplied by
BASF. (1]5 -lndenyl)(cyclooctadiene)iridium (I) {(Ind)Ir(COD)} and
bis-(di-iso-propylphosphino)-ethane (dtppe) were prepared per the literature procedure.7‘8
We are thankful to Prof. Gregory L. Hillhouse (University of Chicago) for a generous gift
of bis-(di-tert-butylphosphino)-ethane (dtbpe). Mesitylene was refluxed over sodium,
distilled, and degassed. Tetrahydrofuran was obtained from a dry still packed with
activated alumina and degassed before use. All the experiments were carried out in a
glove box under a nitrogen atmosphere or by using standard Schlenk techniques.
Synthesis of(17°-MesH)lr(BPin)3 (7.5)

eds}
Ir

PinB/ \Blgiiil’m

7.5

The literature prep9 for the BCat analogue was modified to synthesize the
(nb-MesH)Ir(BPin)3 (7.5). (Ind)Ir(COD) (1 g, 2.4 mmol, 1 equiv) and HBPin (3.5 mL,
3.1 g, 24 mmol, 10 equiv) were dissolved in 10 mL mesitylene in a Schlenk flask in a
glove box. The flask was stoppered, brought out of the glove box, and heated in a 75 °C
oil bath for 12 h. Mesitylene was removed under high vacuum to give a viscous dark
brown oil. The crude mixture was then triturated with 2 mL of cold hexamethyldisiloxane
and filtered to give a white solid (680 mg). Additional material (45 mg) was obtained

upon filtering the concentrated filtrate. Combined yield (725 mg, 44%, mp 164-166 °C

270

 

 

dec). 'H NMR (C613,, 500 MHz): 6 5.62 (s, 3 H), 2.24 (s, 9 H, 3 CH3), 1.33 (s, 36 H, 3
BPin); l3C NMR {'H} (C60,, 500 MHz): 6 118.1 (C), 96.9 (CH), 81.0 (C), 25.7 (CH3 of
BPin), 19.7 (CH3 of mesitylene); HB NMR (CbDb, 96 MHz): 6 33.2: Anal. Calcd for
9711431113206: C, 46.77; H, 6.98. Found: C, 47.13; H, 7.18.

Synthesis of (dmpe)3lr2(BPin)6 (7.6)

PinB BPin/
PinB—lr—PL‘

\ PinB /BPin
MGZLPMez/

l—PIr/\—BPin
Mezp PM92

\J

7.6

In a 20 mL vial, equipped with a magnetic stirring bar, (n6-MesH)Ir(BPin)3 (7.5)
(174 mg, 0.25 mmol, 1 equiv) was dissolved in THF (1 mL). Bis-(di-methylphosphino)-
ethane (dmpe) (57 mg, 0.37 mmol, 1.5 equiv) was weighed out in a test tube and was
transferred to the reaction vial by dissolving in THF (1 mL x 2). The reaction was stirred
at room temperature for 0.25 h. The crude reaction mixture was pumped down under high
vacuum to remove volatiles. Small amounts (5-10% by 3'P NMR) of unknown product
7.7 was still present with this stoichiometry of dmpe and 7.5, however 3'P NMR signal
for 7.7 disappear after heating at 150 °C for 5-10 minutes in a 4:1 mixture of
1,3-bis-(trifluoromethyl)-benzene/HBPin (without appearance of any new peak in the 3 IP
NMR under these conditions). Upon cooling to room temperature, complex 7.6
crystallized as a white solid. lH NMR (Cst, 500 MHz): 6 2.10 (s, 4 H), 1.82 (d, J: 9.2
Hz, 12 H), 1.68 (d, J = 6.7 Hz, 12 H), 1.38 (s, 24 H), 1.34 (d, overlapped with the BPin

singlet, 8 H), 1.33 (s, 24 H), 1.29 (s, 24 H), 1.2-1.02 (br, 8 H); "B NMR (C613,, 160

271

MHz): 6 37.3; 3|P NMR (CbDb, 202 MHz): 6 -11.1 (s, 4 P), -50.9 (s, 2 P); Anal. Calcd for
C54Hizolf2860|2P62 C, 40.62, H, 7..58 Found: C, 40.81; H, 7..56

Synthesis of (dtbpe)lr(BPin)3 (7.10)

tBU\ BPin

In a 20 mL vial, equipped with a magnetic stirring bar, (n6-MesH)lr(BPin)3 (7.5)
(174 mg. 0.25 mmol. 1 equiv) was dissolved in THF (1 mL).
Bis-(di-tert-butylphosphino)-ethane (d'bpe) (80 mg, 0.25 mmol, 1 equiv) was weighed
out in a test tube and was transferred to the reaction vial by dissolving in THF (1 mL x
2). The reaction was stirred at room temperature for 2 h. 3'P NMR showed full
consumption of the starting phosphine ligand and the appearance of a single new peak.
The crude reaction mixture was pumped down under high vacuum to give the desired
complex 7.10 as a light yellow solid (yield 220 mg, quantitative, mp 108-110 °C dec). lH
NMR (C7D3, 500 MHz): 6 1.60-1.54 (m, 4 H), 1.35 (s, 36 H, 3 BPin), 1.25 (d, 3J11_p =
11.9 Hz, 36 H, 12 CH3), lH NMR(C6D12, 500 MHz): 6 1.88-1.80 (m, 4 H), 1.28 (d, 3J11_p
= 11.9 Hz, 36 H, 12 CH3 of d’bpe), 1.19 (s, 36 H, 12 CH3 of 3 BPin); ”C NMR {'H}
(C7D3, 125 MHz): 6 81.1 (s, 6 C), 37.14-37.05 (m, 4 C), 30.5 (s, 12 CH3 of d’bpe), 26.4
(s, 12 CH3 of BPin), 25.50-25.28 (m, 2 CH2); ”B NMR (C7D3, 160 MHz): 6 34.7; 31P
NMR (C7D3, 202 MHz): 6 93.0; Anal. Calcd for C36H76IrB306P2: C, 48.50; H, 8.59.

Found: C, 48.53; H, 8.65.

272

Synthesis of (dippe)lr(BPin)3 (7.11)

TLPR BPin
| rL\P\:r/BPII'1

iPrX/P’ ‘BPin

iPr
7.11

In a 20 mL vial, equipped with a magnetic stirring bar, (n°-MesH)Ir(BPin)3 (7.5)
(202 mg, 0.29 mmol, 1 equiv) was dissolved in THF (1 mL).
Bis-(di-iso-propylylphosphino)-ethane (d'ppe) (76 mg, 0.29 mmol, 1 equiv) was weighed
out in a test tube and was transferred to the reaction vial by dissolving in THF (1 mL x
2). The reaction was stirred at room temperature for 2 h. 3 IP NMR showed full
consumption of the starting phosphine ligand and the appearance of a single new peak.
The crude reaction mixture was pumped down under high vacuum to give the desired
complex 7.11 as a yellow-orange solid (yield 242 mg, quantitative, mp 114-116 °C dec).
lH NMR (C7D8, 500 MHz): 6 2.52-2.42 (m, 4 H), 1.41-1.38 (m, 4 H), 1.33 (s, 36 H, 3
BPin), 1.12-1.06 (m, 24 H), lH NMR (C6D12, 500 MHz): 6 2.56-2.44 (m, 4 H), 1.68-1.60
(m, 4 H), 1.15 (s, 36 H, 3 BPin), 1.17-1.01 (m, 24 H); ”C NMR {‘H} (C7138, 500 MHz):
6 80.8 (s, 6 C), 27.01-26.85 (m, 4 C), 26.1 (s, 12 CH3 of BPin), 24.80-24.53 (m, 2 CH2),
19.7 (s, 6 CH3 of d’ppe), 19.4 (s, 6 CH3 of crops); "B NMR (C7D3, 160 MHz): 6 39.1; 3'1)
NMR (C7Dg, 202 MHz): 6 86.5; Anal. Calcd for C32H631rB3O6P2: C, 46.00; H, 8.20.

Found: C, 46.23; H, 8.76.

273

Stoichiometric borylation of 1,3-bis-trifluromethylbenzene with (dippe)lr(BPin)3

(dippe)lr(BPin)3 (7.11) (33 mg, 0.04 mmol, 1 equiv) was weighed out in a test
tube and was transferred to a J. Young NMR tube using C0D” (175 11L x 4).
l,3-bis-trifluoromethylbenzene (6.2 11L, 0.04 mmol, 1 equiv) was syringed in to the J.
Young NMR tube. 1,4-bis-trifluoromethylbenzene (6.2 11L, 0.04 mmol, 1 equiv) was also
syringed in to the J. Young NMR tube as an internal standard. The J. Young NMR tube
was capped and the reaction was monitored by 'H, 3'P, and llB NMR. The NMR yield
after 48 h at room temperature was 104%.

The analogous stoichiometric reaction of 7.11 with 2-methyl thiophene was
complete in 4 h at room temperature.
Stoichiometric borylation of 1,3-bis-trifluromethylbenzene with (dtbpe)lr(BPin)3

(dtbpe)1r(BPin)3 (7.10) (36 mg, 0.04 mmol, 1 equiv) was weighed out in a test
tube and was transferred to a J. Young NMR tube using C6D” (175 11L x 4).
l,3-bis-trifluoromethylbenzene (6.2 uL, 0.04 mmol, 1 equiv) was syringed in to the J.
Young NMR tube. l,4-bis-trifluoromethylbenzene (6.2 11L, 0.04 mmol, 1 equiv) was also
syringed in to the J. Young NMR tube as an internal standard. The J. Young NMR tube
was capped and the reaction was monitored by 'H, 3'P, and IB NMR. The NMR yield

after 48 h at room temperature was 10%.

274

 

BIBLIOGRAPHY

(l) Cho, J. Y., Michigan State University, 2002.

(2) Boiler, T. M.; Murphy, J. M.; Hapke, M.; Ishiyama, T.; Miyaura, N.;
Hartwig, J. F. Journal of the American Chemical Society 2005, 12 7, 14263-14278.

(3) Clegg, W.; Lawlor, F. J.; Marder, T. B.; Nguyen, P.; Norman, N. C.;
Orpen, A. G.; Quayle, M. J.; Rice, C. R.; Robins, E. G.; Scott, A. J.; Souza, F. E. S.;
Stringer, G.; Whittell, G. R. Journal of the Chemical Society-Dalton Transactions 1998,
301-309.

(4) Braunschweig, H.; Kollann, C.; Rais, D. Angewandte Chemie-
lnternational Edition 2006, 45, 5254-5274.

(5) Chen, H. Y.; Schlecht, S.; Semple, T. C.; Hartwig, J. F. Science 2000, 287,
1995-1997.

(6) Murphy, J. M.; Lawrence, J. D.; Kawamura, K.; Incarvito, C.; Hartwig, J.
F. Journal of the American Chemical Society 2006, 128, 13684-13685.

(7) Merola, J. S.; Kacmarcik, R. T. Organometallics 1989, 8, 778-784.

(8) Baldwin, L. C.; Fink, M. J. Journal of Organometallic Chemistry 2002,
646, 230-238.

(9) Nguyen, P.; Blom, H. P.; Westcott, S. A.; Taylor, N. J.; Marder, T. B.
Journal of the American Chemical Society 1993, 115, 9329-9330.

275

APPENDICES

276

Appendix A. Summary of preliminary crystal data and structure refinement for 7.6.

Empirical formula
Formula weight
Temperature
Wavelength
Crystal system
Space group

Unit cell dimensions

Volume

Z
Density (calculated)

Absorption coefficient

F(000)

Crystal size

Theta range for data collection
Index ranges

Reflections collected
Independent reflections

Completeness to theta = 25.00°

Refinement method

Data / restraints / parameters

Goodness-of—fit on F2
Final R indices [l>2sigma(l)]
R indices (all data)

Absolute structure parameter

Largest diff. peak and hole

C54H12036112012P6

1596.58

293(2) K

0.71073 A

Orthorhombic

Pca21

a = 31.795(6) A or: 90°.
b = 10.407(2) A (3= 90°.
c = 22.943(5) A y = 90°.

7592(3) A3
4

1.397 Mg/m3

3.677 min-1
3256

0.18 x 0.16 x 0.12 mm3

1.28 to 25.00°.

-37<=h<=37, -12<=k<=12, -27<=l<=27
55026

13386 [R(int) = 0.2008]

100.0 %

Full-matrix least-squares on F2

13386/1/758

1.063

R] = 0.0742, wR2 = 0.1508
R1 = 0.1609, wR2 = 0.1855
0.514(15)

4.989 and -1.677 e.A'3

277

 

Appendix A. Summary of crystal data and structure refinement for (dtbpe)lr(BPin)3 7.10.

Empirical formula
Formula weight
Temperature
Wavelength
Crystal system
Space group

Unit cell dimensions

Volume

Z
Density (calculated)

Absorption coefficient

F(000)

Crystal size

Theta range for data collection
Index ranges

Reflections collected
Independent reflections
Completeness to theta = 23.36°

Absorption correction

Refinement method

Data / restraints / parameters
Goodness-of—fit on F 2

Final R indices [I>251gma(l)]
R indices (all data)

Largest diff. peak and hole

C36H76331r06P2

891.54

293(2) K

0.71073 A

Triclinic

P-l

a = ll.651(4) A 01-“- 73.82(3)°.
b = 12.035(4) A B: 76.42(3)°.
c = 17.151(4) A y = 69.37(2)°.

2136.6(11)A3
2

1.386 Mg/m3

3.238 mm-1
924

0.40 x 0.22 x 0.18 mm3

1.85 to 23.36°.

-1 l<=h<=12, -8<=k<=l3, -18<=l<=19
9677

6106 [R(int) = 0.0668]

98.4 %

None

Full-matrix least-squares on F2

6106/0/457

1.031
R1 = 0.0581, wR2 = 0.1428
R1 = 0.0653, wR2 = 0.1477

4.276 and -4159 e.A-3

278

 

Summary of crystal data and structure refinement for (dippe)1r(BPin)3 7.11.

Empirical formula
Formula weight
Temperature
Wavelength
Crystal system
Space group

Unit cell dimensions

Volume

Z
Density (calculated)

Absorption coefficient

F (000)

Crystal size

Theta range for data collection
Index ranges

Reflections collected
Independent reflections
Completeness to theta = 23.31°

Absorption correction

Refinement method

Data / restraints / parameters

Goodness-of-fit on F 2
Final R indices [l>2sigma(l)]
R indices (all data)

Largest diff. peak and hole

C32 H68 133 If 06 P2

835.43

173(2) K

0.71073 A

Monoclinic

P 21/c

a = 17.821(4) A 01: 90°.
b = 12.668(3) A B: 104.80(3)°.
c= 18.491(4)A y=90°.

4035.9(14) A3
4

1.375 Mg/m3

3.424 rum-1
1720

0.25 x 0.19 x 0.16 mm3

1.97 to 23.31°.

-19<=h<=19, -14<=k<=l4, -20<=l<=20
34198

5816 [R(int) = 0.0803]

99.9 %

Semi-empirical from equivalents

Full-matrix least-squares on F2

5816/247/417

1.040
R1 = 0.0464, wR2 -— 0.0999
R1 = 00685,sz = 0.1097

1.706 and -1 .458 eA-3

279

Summary of crystal data and structure refinement for 7.18.

Empirical formula
Formula weight
Temperature
Wavelength
Crystal system
Space group

Unit cell dimensions

Volume

Z
Density (calculated)

Absorption coefficient

F (000)

Crystal size

Theta range for data collection
Index ranges

Reflections collected
Independent reflections
Completeness to theta = 29.20°
Absorption correction

Max. and min. transmission

Refinement method

Data / restraints / parameters
Goodness-of—fit on F2

Final R indices [l>2sigma(l)]
R indices (all data)

Largest diff. peak and hole

C38H80B4F61r08P2

1076.40

173(2) K

0.71073 A

Monoclinic

P 21/n

a = 12.6467(15) A 01: 90°.
b = 1 1.3423(13) A B: 93.481(2)°.
c = 39.579(5) A y = 90°.

5666.9(11) A3
4

1.262 Mg/m3

2.471 mm-1
2212

0.035 x 0.013 x 0.003 mm3

1.66 to 29.20°.

-16<=h<=17, -15<=k<=15, -52<=l<=51
67440

14253 [R(int) = 0.1050]

92.8 %

Semi-empirical from equivalents

1.0000 and 0.828647

Full-matrix least-squares on F2

14253 / 18 / 693

1.032
R1 = 0.0568, wR2 = 0.1125
R1 = 0.1170, wR2 = 0.1357

1.429 and -1.989 6A3

280