STOICHIOMETRIC AND CATALYTIC
C–H BORYLATIONS OF ARENES
By
Sean Michael Preshlock

A DISSERTATION
Submitted to
Michigan State University
in partial fulfillment of the requirements
for the degree of
Chemistry – Doctor of Philosophy
2013

ABSTRACT
STOICHIOMETRIC AND CATALYTIC
C–H BORYLATIONS OF ARENES
By
Sean Michael Preshlock
Regioselective catalytic transformation of carbon-hydrogen bonds to other
functional groups represents a long-standing challenge in homogeneous and
heterogeneous catalysis. The Ir-catalyzed C–H activation/borylation has emerged as a
useful method for synthesizing various aryl and heteroaryl boronic esters with regiochemistry
complimentary to traditional methods and tolerant of various functional groups. The steric
dominance of C–H activation/borylation has allowed for the synthesis of new aromatic building
blocks which were previously unaccessible or hard to synthesize.

With the aid of high throughput experimentation (HTE), we designed reaction
screens that would not only optimize Ir-catalyzed C-H borylation reactions for more
challenging substrates, but also broaden the scope of this chemistry by assessing the
efficiency and compatibility of the reactions as functions of precatayst, boron reagent,
ligand, order of addition, temperature, solvent and substrate.
We then sought to apply these results to unprotected anilines which were inert
under conventional Ir-catalyzed C-H borylation conditions. Building off a recent report
from our research group that utilized a unique outer sphere directing effect to obtain ortho functionalized C-H borylation products from NBoc protected anilines, we
investigated whether we could use HBPin as a traceless protecting/directing group for the
borylation of primary anilines under more forcing conditions. Our attempts were
successful and provided for a one-pot protection/deprotection procedure that used a lower

catalyst loading and gave products in better to comparable yields than the NBoc protected
borylation reaction.
Using

an

6

(η -C6Me3H3)Ir(BPin)3

as

starting

material,

five-coordinate

6

bisphosphine complexes can be synthesized by displacement of the η -C6Me3H3 with the
incoming phosphine ligands. Using this method we have isolated the transF

Ir(PAr3 )2BPin3 complex which is thought to be the active catalyst for the ortho-C-H
directed borylation of benzoate esters first discovered by Miyaura. The transF

Ir(PAr3 )2BPin3 complex is not catalytically competent with HBPin as borylating
reagent. We have since been able to develop silylphosphine chelates (Figure 8) that are
compatible with HBPin while retaining the unique selectivity shown with the
F

Ir(PAr3 )2BPin3 complex. Studies to further improve on the silylphosphine ligand design
and extend the substrate scope are ongoing.

Copyright by
SEAN MICHAEL PRESHLOCK
2013

Tacos and candy bars

vi

ACKNOWLEDGMENTS

I would like to thank, first and foremost, my lab mates in the Mitch Smith Research
group. It is true that you are influenced by your surroundings and they undoubtedly had the
largest impact on my development as a chemist. I would like to thank my seniors, Abbas, Britt
and Appi, for welcoming me into the group and relating all of the borylation lab lore that had
come before my time. I would like to thank the chemist who came and went while I was in the
lab, Bala, Jon and Phil, I learned at a lot from them and we shared many adventures. I would also
like to thank the next generation of Junior Borylation Rangers, Behnaz, Don, Buddha, Dmitry,
Kristen, and Tim, it is up to you to carry on the borylation torch and I wish you the best in
publishing my unfinished projects. Yu Ling and Olive Oyl, you guys are great too and I wish you
the best of luck with your research.
I would like to offer a very special thanks to Mitch. The C-H borylation chemistry he
discovered was an absolute joy to work on and it was a fulfilling and enlightening experience to
take part in its further development. I would also like to thank Mitch for the great opportunity I
had while doing research at Rahway.
I owe a great many thanks to Rob Maleczka for the excellent discussions and suggestions
along the way. The members of his group who worked on the borylation project along with me,
Luis, Monica, Li, Suzi, Damith, Fung Yi and Ruwi, all did exceptional work and I learned a
great deal from their research as well.
During my time as a graduate student, I also had the tremendous opportunity to do
research in an industrial environment at Merck. Shane and Peter offered exceptional guidance
while I was there and it was a remarkable learning experience.
vii

I would like to thank dynamic duo Dan and Kermit for all the help with NMR at MSU
and Richard for his help with X-Ray structures; I know it was not easy with some of my less than
stellar crystals. Also, Pete Dormer and Thomas Williamson gave me great help with the NMR
instruments at Merck. The members of Merck’s Automation and Catalysis group were a joy to
work with and gave great guidance.
I would like to offer a special thanks to the brave men and women I served with during
my time as a CEM 415 TA (Thanks, Phil, Colin and Behnaz, those were certainly the days of
high adventure).
My parents Mike and Debra and my brother Phil offered great moral support among so
many other things that I will forever be grateful for. I could always tell you were proud of me.
I would like to thank the Spencer family for being my home away from home. I could
never ask for better friends. I would also like to thank the Comptons for making my long stay in
East Lansing such an enjoyable one.
I would also like to thank my old roommate Alex for always assuring me that no matter
what, I was still good enough for government work; Strength and Honor, bud.

viii

TABLE OF CONTENTS

LIST OF TABLES ......................................................................................................................... xi
LIST OF FIGURES ..................................................................................................................... xiii
KEY TO SYMBOLS AND ABBREVIATIONS ...................................................................... xviii
CHAPTER 1
INTRODUCTION ...........................................................................................................................1
C-H Bond Activation and Functionalization in Aromatic Compounds ...........................................1
Arylboronic Acids ............................................................................................................................4
Ir C-H Borylation Chemistry ...........................................................................................................6
Chemioselectivty of C-H Activation/Borylation Catalysts ..............................................................8
Regioselectivity of Ir C-H Activation/Borylation Catalysis ............................................................8
Mechanism .......................................................................................................................................9
Deviations From Sterically Directed Regioselectivity via Electronic Bias ...................................11
REFERENCES ..............................................................................................................................19
CHAPTER 2
OPTIMIZATION OF IRIDIUM CATALYZED C-H BORYLATIONS ......................................22
Introduction ....................................................................................................................................22
Identification of Reaction Variables ..............................................................................................23
Orders of Addition Effects for Room Temperature Reactions ......................................................28
Effects of Borylating Reageant on Relative Reactivity .................................................................29
General Ligand and Precatalyst Trends for Room Temperature Reaction Screen ........................29
Temperature effects on optimization screens ................................................................................31
Solvent Effects on Catalyst Formation at Room Temperature ......................................................33
Solvent Effects on Catalyst Formation at Elevated Temperature ..................................................37
Elevated Temperature Reaction Screen Preformed on 5a in Multiple Solvents ...........................38
Phosphine Ligated Iridium Borylation Catalysts ...........................................................................41
Ligand Effects; Electron Donating Ability and Constrained Geometry ........................................43
Kinetic Experiments with (tmphen)Ir(BPin)3(COE) and (dtbpy)Ir(BPin)3(COE .........................46
C-H Borylation in Open vs. Closed Systems .................................................................................50
Ligand to Metal Ratio and Catalyst Loading Study.......................................................................52
Precatalyst Stability and Aging Studies .........................................................................................55
REFERENCES ..............................................................................................................................58
CHAPTER 3
CHELATE DIRECTED C-H BORYLATIONS ...........................................................................61
Ester directed C-H borylation ........................................................................................................61
ix

F

Synthesis of Discrete 5 Coordinate (Ar 3P)2Ir(BPin)3 Trisboryl Complex..................................62
F

Mechanistic Insights into (Ar 3P)2Ir(BPin)3 Catalytic Cycle .......................................................66
REFERENCES ..............................................................................................................................81
CHAPTER 4
BPIN AS A TRACELESS DIRECTING GROUP FOR C-H BORYLATIONS ..........................83
Traceless BPin protected borylation of heterocycles .....................................................................83
Application of BPin as traceless protecting group with primary anilines .....................................87
Optimization ..................................................................................................................................89
Solvent Effects on Regioselectivity ...............................................................................................92
Ligand Effects on Regioselectivity ................................................................................................93
Applications ...................................................................................................................................96
Borylation of Aminopyridines .......................................................................................................98
REFERENCES ............................................................................................................................100
CHAPTER 5
EXPERIMENTAL .......................................................................................................................102
REFERENCES ............................................................................................................................249

x

LIST OF TABLES

Table 1.1

Regioselectivity for C-H borylations with veratrole (1) and benzodioxole (2) ........14

Table 2.1

Temperature Effects on Relative Conversions for 1,2,3-trimethoxybenzene (4a).. .30

Table 2.2

Temperature Effect on Catalyst Stability..................................................................40

Table 2.3

Borylation of 2,6-dimethylanisole (7a) ....................................................................44

Table 2.4

Ligand to Metal Ratios and Catalyst Loading Study ................................................52

Table 2.5

Ligand to Metal Ratio with preformed (tmphen)Ir(COE)BPin3 ...................................53

Table 2.6

Metal Additive Screen for In-Situ Precatalyst Generation .......................................57

Table 3.1

Borane effects on ortho-directed borylation of 10a .................................................72

Table 3.2

Ligand effects on ortho-directed borylation of methyl benzoate (10a) ...................78

Table 3.3

Borane effects on ortho-directed borylation of methyl benzoate (10a) ....................79

Table 4.1

Borane and Solvent Effects on Borylation of 3-chloroaniline (22a) with tmphen ...90

Table 4.2

Borane and Solvent Effects on Borylation of 3-chloroaniline (22a) with dtbpy ......91

Table 4.3

Solvent Screen for 3-(trifluoromethyl)anilines (20a) ..............................................92

Table 4.4

Ligand effects on borylation of 3-(trifluoromethyl)anilines (20a) ..........................94

Table 4.5

Traceless BPin protected borylation of anilines .......................................................95

Table 5.1

Ligand to Metal Ratio with preformed (tmphen)Ir(COE)BPin3 ................................ 131
xi

Table 5.2

Solvent Screen for 3-(trifluoromethyl)anilines (20) ..............................................153

Table 5.3

Crystal data and structure refinement for 37 ..........................................................182

Table 5.4

Crystal data and structure refinement for Trans-(Ar 3P)2Ir(BPin)3 (12) ..............183

Table 5.5

Crystal data and structure refinement for Trans-(Ar 3P)2Ir(H)(BPin)2 (13) ........184

F

F

xii

LIST OF FIGURES

Figure 1.1

Synthesis of organo ruthenium aryl complexes by Chatt and Davidson ....................1

Figure 1.2

Synthesis of Fe(dmpe)2(H)(C6H4Me .........................................................................2

Figure 1.3

Catalytic intramolecular cyclization of 2,6-xylyl isocyanide .....................................2

Figure 1.4

Intermolecular C-H activation/ functionalization reactions with trialkylsilanes ........3

Figure 1.5

Thermodynamics of methane borylation ....................................................................5

Figure 1.6

Stoichiometric C-H boryaltion of aromatic and aliphatic substrates ..........................6

Figure 1.7

First catalytic aromatic C-H activation /borylation reaction ......................................7

Figure 1.8

Chemo- and regioselective comparisons for iridium and rhodium catalysts ..............8

Figure 1.9

Borylation of benzene with (η -C6H3Me3)Ir(BPin)3 .....................................................10

6

Figure 1.10 Proposed catalytic cycle............................................................................................11
Figure 1.11 Electronic effects in product distribution..................................................................12
Figure 1.12 Steric hinderance of veratrole (1) and benzodioxole (2) .........................................13
Figure 1.13 5-coordinate Iridium Catalyst ...................................................................................13
Figure 1.14 Limiting descriptions of the C-H activation transition states ...................................15
Figure 1.15 . Correlation of ΔE with the charge developed on the aryl group (TS 1 in Figure
1.14). For interpretation of references color in this and all other figures, the reader is referred to
the electronic version of this dissertation.......................................................................................16
xiii

Figure 1.16 Ligand design for enhanced regioselectivity ............................................................17
Figure 1.17 Regioselective borylations with 1,3-difluorobenzene ..............................................18
Figure 2.1

Precatalys Selected for Reaction Screens .................................................................23

Figure 2.2

Room Temperature Reaction Screen With 3-bromotoluene.....................................25

Figure 2.3

Precatalyst and ligand complexation ........................................................................28

Figure 2.4

Rate equation ............................................................................................................29

Figure 2.5

Elevated temperature reaction screen preformed on N,N-dimethyltoluidine (5a) ...32

Figure 2.6

(dtbpy)Ir(BPin)3(COE) and (tmphen)Ir(BPin)3(COE) ............................................34

Figure 2.7

Solvent Effects on Catalyst Generation at Room Temperatue .................................... 35

Figure 2.8

[(tmphen)Ir(CH(BPin)2)Cl2]2...................................................................................36

Figure 2.9

Solvent effects on catalyst generation with 1,3-dimethoxybenene (6a) ..................37

Figure 2.10 Multivariable Solvent Screen....................................................................................39
Figure 2.11 Phosphine Ligand Screen..........................................................................................41
Figure 2.12 Elevated Temperature Phosphine Ligand Screen .....................................................42
2

1

Figure 2.13 (dmpbz-κ P)Ir((BPin)3(dmpbz-κ P) ........................................................................43

Figure 2.14 Decay of 6a during the reaction with HBPin or B2pin2 ...........................................45

xiv

Figure 2.15 ln[arene] vs. time over two half-lives .......................................................................47

Figure 2.16 Catalytic resting states for kinetic experiments with (tmphen)Ir(BPin)3(COE) with
B2Pin2 (A) and HBPin (B) ............................................................................................................48
Figure 2.17 Proposed catalytic cycle for (dtbpy)Ir(BPin)3(COE) from ref. 5 .............................48

Figure 2.18 Kinetic Experiments with (tmphen)Ir(BPin)3(COE) at variable catalyst loadings ..49
Figure 2.18 C-H Borylation in Open vs. Closed Systems with 8a...............................................51
Figure 2.20 Precatalyst Stability and Aging Study ......................................................................54
Figure 3.1

Ester directed C-H borylation ...................................................................................61

Figure 3.2

Cis and Trans-(Ar 3P)2Ir(BPin)3 .............................................................................62

Figure 3.3

Trans-(Ar 3P)2Ir(BPin)3 (9b) .................................................................................63

Figure 3.4

Variable temperature

Figure 3.5

Ester coordination to (Ar 3P)2Ir(BPin)3 complex....................................................66

Figure 3.6

Stiochiometric borylation of methyl 3-(trifluoromethyl)benzoate (11a) .................67

Figure 3.7

Trans-(Ar 3P)2Ir(H)(BPin)2 (12) ............................................................................68

Figure 3.8

Borylation of methyl benzoate (10a) with excess (Ar 3P)2Ir(BPin)3 ......................69

Figure 3.9

Trans-(Ar 3P)2Ir(H2BPin)(BPin)2 (13) ..................................................................70

F

F

31

F

P NMR of Cis and Trans-(Ar 3P)2Ir(BPin)3 .....................65
F

F

F

F

xv

Figure 3.10 Proposed catalytic cycle for the chelate directed borylation of aryl esters with
F
(Ar 3P)2Ir(BPin)3 ..........................................................................................................................71
Figure 3.11 Designing more reactive Iridium catalysts ...............................................................73
Figure 3.12 Synthesis of silylboranes ..........................................................................................74
Figure 3.13 Silyl-directed ortho borylation of alkylamines .........................................................75
Figure 3.14 N-(dimethylsilyl)-N,N-bis(2-pyridyl)amine (14b) ..................................................76
2

Figure 3.15 Synthesis of Ir(κ -SiNpy2)3......................................................................................76

Figure 3.16 Synthesis of SiPbz ligands ........................................................................................77
Figure 4.1

Borylation of indole ..................................................................................................83

Figure 4.2

Base assisted protection of heterocycles with HBPin ...............................................84

Figure 4.3

In-situ protection of heterocycles with HBPin .........................................................85

Figure 4.4

Comparison of Boc and traceless directed borylation of heterocycles .....................86

Figure 4.5

Outer-sphere ortho directed iridium catalyzed C-H borylation of aniline................87

Figure 4.6

Synthesis of N-BPin-3-(trifluoromethyl)aniline (20b) ............................................88

Figure 4.7

Ortho borylation of N-BPin-3-(trifluoromethyl)aniline (20b) ................................88

Figure 4.8

Proposed Reaction Mechanism .................................................................................89

Figure 4.9

Borylation of 3-chloro-N-methylaniline (21a) ........................................................89

Figure 4.10 Borylation of o-anisidine ..........................................................................................97
xvi

Figure 4.11 Putative transition state for ortho-borylation of 2-substituted anilines ....................98
Figure 4.12 Traceless BPin protected borylation of amino pyridines ..........................................99
Figure 5.1

2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)-benzenamine (37) ....173

xvii

KEY TO SYMBOLS AND ABBREVIATIONS

acac

acetylacetonate

Å

Ångstrom

bbnbox

2,2’-bis[(4S)-4-benzyl-2-oxazoline]

β

bite angle

BCat

catecholatoboryl

BCat*

4-tert-butyl-catecholatoboryl

Beg

1,3,2-dioxborolane

Boc

tert-butoxycarbonyl

box

2,2’-bisoxazoline

BPin

pinacolatoboryl

COE

cis-cyclooctene

COD

1,5-cyclooctadiene

Cpme

cyclopentyl methylether

Cp

cyclopentadienyl

Cp*

pentamethylcyclopentadienyl

xviii

dcpe

1,2-bis(dicyclohexylphosphino)ethane

diim

(2,3,5,6,8,9-hexahydrodiimidazo[1,2-a:2',1'-c]pyrazine)

dippe

1,2-bis(di-iso-propylphosphino)ethane

dmabpy

(4,4’-bis(dimethylamino)-2,2’-bipyridine)

dmpbz

1,2-bis(dimethylphosphino)benzene

dmpe

1,2-bis(dimethylphosphino)ethane

dppbz

1,2-bis(diphenylphosphino)benzene

dppe

1,2-bis(diphenylphosphino)ethane

dtbpe

1,2-bis(di-tert-butylphosphino)ethane

dtbpy

4,4’-di-tert-butyl bipyridine

EAS

electrophilic aromatic substitution

equiv

equivalent

GC-FID

gas chromatography flame ionization detection

gCOSY

gradient-selected correlated spectroscopy

η

eta, hapicity

Ind

indenyl

i

Pr

iso-propyl

xix

κ

kappa, denotes how many and which atoms of a ligand are binding

K

equilibrium constant

M

metal

m

meta

MesH

mesitylene

µ

mu, denotes bridging ligand

n

normal (straight chain hydrocarbon)

NMR

Nuclear Magnetic Resonance

o

ortho

ORTEP

Oak Ridge Thermal Ellipsiod Plot Program

p

para

phen

(1,10-phenanthroline)

π

pi, degree of pyramidality

ppm

parts per million

R

general susbstituent

t1/2

half-life

tmphen

3,4,7,8-tetramethyl-1,10-phenanthroline

xx

CHAPTER 1
INTRODUCTION

C-H Bond Activation and Functionalization in Aromatic Compounds
The catalytic transformation of carbon-hydrogen bonds to other functional groups
represents a long-standing challenge in homogeneous and heterogeneous catalysis as C-H bonds
are the most ubiquitous chemical linkages in Nature. Unfortunately, hydrocarbons are also
among the least reactive organic compounds. The C-H bonds in aromatics are of very low
acidity/ basicity, low polarity, and bond energies typically in the range of 115 Kcal/mol,
accounting for their relative lack of reactivity. Over the past several decades, significant
advances have been made in the use of transition metal complexes to facilitate the cleavage of
these bonds and for the inclusion of these organometallic complexes in organic transformations.

1

Perhaps, the earliest example of C-H activation by a transition metal complex was reported in
1963 for the reaction of nickelocene and azobenzene, although the reaction was not well
2

defined. By 1965, Chatt found that Ru(dmpe)2, (dmpe is (1,2-bis(dimethylphosphino)ethane),
generated from the reduction of Ru(dmpe)2Cl2, was capable of giving intermolecular C-H
oxidative addition of the aromatic solvent (Figure 1.1).

3

Figure 1.1. Synthesis of organo ruthenium aryl complexes by Chatt and Davidson.

1

Figure 1.2. Synthesis of Fe(dmpe)2(H)(C6H4Me).

Years later, Ittel and coworkers found that the related iron anologue of the Chatt
compound could undergo reversible C-H reductive elimination/ oxidative addition with a varaity
4

of monosubstituted arenes. The most intriguing aspect of this reaction was that the product
distribution of isomers of Fe(dmpe)2(H)(C6H4Me) showed a near statistical distribution of meta
and para-tolyl regioisomers with no evidence of the ortho regioisomer, showing that the C-H
activation event was governed by sterics rather than electronics (Figure 1.2). This was in stark
contrast to the more well known main group metalation reactions which give products dependant
on directing groups or the electrophilic aromatic substitution reactions that are governed by
electronics.
Figure 1.3. Catalytic intramolecular cyclization of 2,6-xylyl isocyanide.

The further functionalization of the metal-carbon bonds that result from C-H activation has
proven to be far more difficult than C-H bond activation itself. In order for a transition metal to
enact the functionalization of C-H bonds, the initial C-H activation step needs to be followed by
a successive functionalization step. This involves the replacement of a carbon-hydrogen bond
2

with a carbon functional group bond. Jones and co-workers were able to demonstrate this by
using the original Ru(dmpe)2(H)(naphtyl) to achieve catalytic intramolecular cyclizations of 2,6xylyl isocyanide (Figure 1.3).

5

Figure 1.4. Intermolecular C-H activation/ functionalization reactions with trialkylsilanes.

Despite the huge achievement that the intramolecular C-H activation/ functionalization
demonstrated, a more desirable system would invole C-H activation of one molecule followed by
coupling of an external functional group of a separate molecule. Berry and co-workers were able
to provide an excellent example of an intermolecular C-H activation/ functionalization reaction
coupling various aromatic substituents with trialkylsilanes using a rhodium catalyst (Figure
6

1.4).

Still, selective C-H bond activation and subsequent functionalization of unreactive

hydrocarbons remains among the most significant challenges in homogenous catalyst design.

7

The requirement that these transformations provide good chemo-, regio-, stereo-, and
enantioselective products further increases the difficulty of these reactions.

3

Arylboronic Acids
The use of organoboron reagents in reactions with carbon electrophiles, such as organic
halides, has seen tremendous attention with the development of transition metal catalyzed
coupling reactions over the last few decades. Transition metal catalysts, especially those
containing Pd

8

9

and Ni , have been found to convert the otherwise relatively unreactive

organoboron derivatives into highly versatile reagents for the formation of carbon-carbon bonds.
It is reasonable to state that Zn, B, and Sn are currently the three most commonly used metals in
Pd catalyzed cross-coupling.

10

Some of the advantages organoboron derivatives have over

organozinc compounds in these cross coupling reactions are represented by their greater stability
towards air and moisture and lower reactivity towards common organic electrophiles. A
significant advantage of organoboron reagents relative to organostannanes is their reduced
toxicity. However, there have been some reports of boronic acid genotoxicity.
The traditional method for the synthesis of organoboronic acids and esters is the reaction
of alkoxyboranes with alkyllithiums or Grignard reagents. Although this method is common for
the large-scale production of organoboranes, catalyzed reactions are of interest for obtaining
organoboranes with different chemo and regioselectivities than that provided by the uncatalyzed
synthesis. Palladium-catalyzed cross-coupling reactions with tetraalkoxydiboron
dialkoxyboranes

12

11

and

provided a one-step procedure for deriving aromatic boronates from various

organic electrophiles, such as aromatic halides and triflates. The discovery of these novel crosscoupling reactions provided access to a variety of boronic esters directly from arylhalides with
increased functional group tolerance. Yet, the regioselectivity of the arylboronic esters produced

4

from the Pd-catalyzed cross-coupling reaction as well as the alkyllithium and Grignard reagents
is dependent on the availability of the corresponding arylhalides. Since the mechanism for
halogenation of aromatics is a form of electrophilic substitution, which is governed by
electronics, many simple meta substituted reagents require overly elaborate and inefficient
syntheses. A number of transition metal-mediated C-H activation reactions are known to produce
22

products determined by the sterics of a substrate more so than its electronics , raising the
possibility that metal mediated C-H functionalization reactions could be able to give products
with selectivities complementary to those of electrophilc aromatic substitution and directed ortho
metallation reactions.
Figure 1.5. Thermodynamics of methane borylation.

Studies concerning the fundamental properties and reaction chemistry of transition metal
boryl complexes weere initiated in the early 1990s. Transition metal-ligand covalent bond
energies are important in understanding the catalysis. However, there have been few data
available for boranes and no thermochemical data for transition metal boryl complexes until
1994. In that year, the theoretical estimation of B-H and B-C bond enthalpies reported by Rablen
13

and Hartwig

gave credence in organoborane synthesis via direct borylation of unsubstituted

hydrocarbons. From the established thermochemical and computational data of borane reagents,
the reaction in figure 1.5 is essentially thermoneutral. Moreover, from the calculated BDE’s for
B-H, C-H, and B-C bonds synthesis of aryl boronic esters directly from boranes and arenes
should be thermodynamically feasible.
5

Figure 1.6. Stoichiometric C-H boryaltion of aromatic and aliphatic substrates.

Ir C-H Borylation Chemistry
Aromatic C-H activation/ borylation was first observed in 1993 by Marder and co6

5

workers during the synthesis of Ir(η -C6H5Me)(BCat)3, (BCat = catecholboryl), from (η C9H7)Ir(COD), (COD = 1,5 cyclooctadiene).

14

Trace amounts of borylated products were

detected in the filtrate by GCMS provided in the supplementary information section, resulting
6

from the reaction of Ir(η -C6H5Me)(BCat)3 and toluene solvent. No mention of this appeared in
the accompanying manuscript, no attempts were made to increase the efficiency of this reaction,
and there was no evidence of catalysis. The first report of C-H activation/ borylation reactions
with moderate to high yields appeared in the literature in 1995.

15

These reactions, shown in

Figure 1.6, involved stoichiometric amounts of monocatecholboryltransition metal complexes
which were capable of borylating both aromatic and aliphatic substrates when subjected to
photolytic dissociation of carbonyl ligands. Regeneration of the boryl complex from the resulting

6

metal hydride products required several steps and external reagents, precluding these complexes
from being catalytically viable.

16

Figure 1.7. First catalytic aromatic C-H activation /borylation reaction.

In 1999 the Smith research group demonstrated the first catalytic aromatic C-H activation
/borylation reaction with a Cp*Ir(PMe3)BPin(H) complex in the presence of HBPin, (BPin =
17

pinacolborane), under thermal conditions (Figure 1.7).
efficient catalysts.

18,19

Ensuing studies lead to vastly more
5

Catalyst generated from readily made (η -C9H7)Ir(COD) and 1,2-

bis(dimethylphosphino)ethane, dmpe, at 150 ˚C yielded 4500 TON.
Later in 1999, a photochemical Re-catalyzed C-H activation/ borylation reaction using
Cp*Re(CO)3 and B2Pin2 under CO (2 atm) was shown to be able to effectively borylate alkanes
with great regioselectivity for primary carbons.

20

Later, Hartwig demonstrated that Cp*Rh(I)
4

complexes, generated by loss of hexamethylbenzene from Cp*Rh(η -C6Me6), are highly
19

effective catalysts for both aliphatic and aromatic C-H borylation under thermal conditions.
Similar to the previous systems, alkanes reacted regiospecifically at the terminal carbon.

7

Chemioselectivty of C-H Activation/Borylation Catalysts
4

Following reports of Cp*Rh(η -C6Me6) showing viability as a catalyst for C-H
activation/borylation, our group did a comparative study focusing on the functional group
tolerance of the Ir- and Rh- precatalysts used.

21

Resulting from this study, was the realization

that although the Rh derived catalysts display good reactivity, their chemo- and regioselectivity
4

is inferior to that of the Ir based systems. Reactions between Cp*Rh(η -C6Me6) and fluorinated
aromatics lead to substantial defluorinated/borylated by products demonstrating the Rh catalysts
inability to tolerate aromatic-halogen bonds, an exceptionally important class of compounds. The
Rh catalyst also showed to be far less selective for discerning between aromatic and benzylic CH activation and sizeable amounts of benzylic borylated products were present in the reaction
mixtures with m-xylene as substrate (Figure 1.8).
Figure 1.8. Chemo- and regioselective comparisons for iridium and rhodium catalysts.

Regioselectivity of Ir C-H Activation/Borylation Catalysis
The regioselectivity of these reactions for arenes are dominated by sterics such that the
least hindered positions undergo C-H activation. Thus, for monosubstituted arenes statistical
8

borylation of the meta- and para-positions is generally observed. More importantly, only the 5position is borylated selectively in 1,3-disubstituted arenes, even for those with ortho-, para22

directing groups.

These aspects of transition metal C-H activation/ borylation show the great

utility of this method for producing arylboronic esters which would otherwise be very difficult to
synthesize. The electronics still have a considerable effect on the rates of the reaction, with
electron poor arenes reacting much faster than electron rich substrates. The Iridium catalyzed CH borylation of arenes also shows remarkable chemoselectivity and tolerates a number of
functional groups including but not limited to halogens, esters, amides, ethers and benzylic
hydrogens.

23

Mechanism
6

5

The phosphine free (η -C6H3Me3)Ir(BPin)3, formed in moderate yields from (η C9H7)Ir(COD) and excess HBPin, was found to react with benzene under elevated temperature
to yield 3 equivalents of PhBPin (Figure 1.9) but catalysis with excess HBPin failed.

18

However,

6

it was shown that addition of a donor ligand such as PMe3 to (η -C6H3Me3)Ir(BPin)3 was found
to generate an active catalyst for the borylation of arenes. Both Ir(BPin)(PMe3)4 and facIr(BPin)3(PMe3)3 complexes were found to react with benzene to produce PhBPin at room
temperature signifying that both Ir(I) and Ir(III) complexes were capable of C-H
activation/borylation. However, the reactivity of these two compounds with iodobenzene were

9

found to be substantially different. Ir(BPin)(PMe3)4 reacted rapidly with iodobenzene, but no
isomers of C6H4I(BPin) were detected in the product mixture. Conversely, fac-Ir(BPin)3(PMe3)3
in iodobenzene gave a mixture of meta and para isomers of C6H4I(BPin) as well as a substantial
amount of PhBPin.
6

Figure 1.9. Borylation of benzene with (η -C6H3Me3)Ir(BPin)3.

These results favored an Ir(III)/ Ir(IV) catalytic cycle over an Ir(I)/ Ir(II). Isolation of the
22b

immediate catalyst precursor (dtbpy)Ir(BPin)3(COE)

, (dtbpy = 4,4’di-t-butyl-2,2’bipydine),
24

complex and the active 16-electron (dippe)Ir(BPin)3 and (dcpe)Ir(BPin)3
subsequent mechanistic studies

25

as well as computational analysis

26

complexes and

all provide further support

for the involvement of an Ir(III)-trisboryl complex as an active component in the catalytic cycle.
(dippe

is

(1,2-bis(diisopropylphosphino)ethane)

and

dcpe

is

(1,2-

bis(dicyclohexylphosphino)ethane)).

The proposed catalytic cycle operates by oxidative addition of B2Pin2 or HBPin to an
Ir(I) species in the presence of a donor ligand, typically bidentate, to generate the active trisboryl
Ir(III) catalyst (Figure 1.10). Ir(I) compounds have been found to be proficient precatalysts
5

include (η -C9H7)Ir(COD), [Ir(COD)Cl]2 and [Ir(OMe)COD]2 and bidentate ligands such as
10

dmpe, dtbpy, or dppe (1,2-bis(diphenylphosphino)ethane) have been employed. The most
commonly used system is [Ir(OMe)COD]2 with dtbpy, where the active catalyst is generated insitu. Oxidative addition of the aromatic substrate to the trisboryl Ir(III) intermediate gives an
Ir(V) species. Reductive elimination of the ArBPin product and subsequent oxdative addition by
B2Pin2 or HBPin to the resulting bisborylIr(III) complex gives an 18e- Ir(V) intermediate.
Reductive elimination of HBPin or H2 regenerates the active trisboryl iridium(III) catalyst.

Figure 1.10. Proposed catalytic cycle.

Deviations From Sterically Directed Regioselectivity via Electronic Bias
As stated early, the regioselectivity of the trisboryl Ir(III) catalysts is largely governed by
the sterics of the substrate. In the absence of significant streric bias, subtle electronic effects can

11

be observed which influence the selectivity as is the case in the reaction below for the borylation
of anisole (Figure 1.11).

17

In the absence of electronic effects, one would expect a statistical

distribution of products giving a product mixture of 2:1 meta to para selectivity. The nearly 4:1
selectivity favoring the meta position most likely arises from electronic effects originating from
the –OMe substituent. These deviations are most likely the result of electronic effects of the
aromatic system; either resonance or inductive or both.

Figure 1.11. Electronic effects in product distribution.

In looking for systems in which to investigate the underlying electronic directing effects
of the substrates, ideally one would want a set of substrates with similar electronics, but with
reduced steric hinderance. The substrates veratrole (1) and benzodioxole (2) were choosen for
these reasons. By replacing the 1,2-dimethoxy moiety in 1 with a methylene linker in 2, the steric
restraint is greatly reduced ortho to the alkoxy functionalizations with minimally perturbing the
electronics of the molecule (Figure 1.12).

12

Figure 1.12. Steric hinderance of veratrole (1) and benzodioxole (2).

6

Using an (η -C6Me3H3)Ir(BPin)3 as starting material, five-coordinate bisphosphine
6

complexes can be synthesized by displacement of the η -C6Me3H3 by the incoming
2

bisphosphine (Figure 1.13). The resulting six-coordinate complex readily loses the η -C6Me3H3
bond arene yielding the five-coordinate complex.

24

Figure 1.13. 5-coordinate Iridium Catalyst.

Investigating stoichiometric and catalytic reactions of the 5-coordinate complex
(dippe)Ir(BPin)3

24

with 1 and 2 it was found that by making the C-H bond ortho to oxygen far

more accessible in 2, the regioselectivity of the product distribution was drastically altered going
from near exclusive borylation at the 4-position in 1 to near exculsive borylation at the 3-position
in 2 (Table 1.1). Stiochiometric and catalytic reactions employing the dipyridyl precatalyst
(dtbpy)Ir(BPin)3(COE) were also examined with similar results.

13

27

Table 1.1. Regioselectivity for C-H borylations with veratrole (1) and benzodioxole (2).

a

Ir complex

substrate

time

(dippe)Ir(BPin)3

1

4h

100

>99

<1

1

4h

130

90

2

(dtbpy)Ir(BPin)3(COE)

1

1h

r.t.

99

1

2 mol % (dtbpy)Ir(BPin)3(COE)

1

9h

r.t.

98

2

(dippe)Ir(BPin)3

2

1h

100

2

98

2 mol % (dippe)Ir(BPin)3

2

1h

130

4

96

(dtbpy)Ir(BPin)3(COE)

2

15 min

r.t.

5

95

2

1h

r.t.

3

91

2 mol % (dippe)Ir(BPin)3

b,c

d

2 mol % (dtbpy)Ir(BPin)3(COE)
a

8 equiv of 1 or 2 were used to minimize diborylation.
c

Temp (°C) meta (%) ortho (%)

b

5

Generated from 2 mol% (η d

C9H7)Ir(COD) and 2 mol% dippe. 8% of the product is 3,5-diborylated. 6% of the product is
3,6-diborylated.

Figure 1.14 shows a transition state representing a proton transfer from an aryl substrate
to the Ir-Boryl σ-bond (left) and a transition state representing a hydride transfer to an “empty”
boron p-orbital of the boryl ligand (right). The actual transition state can be thought to fall
between these two extremes. Calculations found a strong correlation between the activation
‡
barriers (ΔE ) for a number of 5-coordinate Ir complexes and an electronically diverse set of

14

substrates and the energy difference between the reactants and products (ΔE).

27

This correlation

‡
suggested ΔE is an excellent predictor of (ΔE ) and the transition states responsible for oxidative

addition from the 5-coordinate Ir complexes and aryl substrates would mirror TS1 from figure
1.14. Figure 1.15 shows the correlation of energy difference between reactants and products (ΔE)
with the charge developed on the aryl group with linear fits for 6- and 5-membered substrates.
Sterically hindered arenes (red) were omitted from the analysis.

27

Figure 1.14. Limiting descriptions of the C-H activation transition states.

15

Figure 1.15. Correlation of ΔE with the charge developed on the aryl group (TS 1 in Figure 1.14). For interpretation of references
color in this and all other figures, the reader is referred to the electronic version of this dissertation.

16

2,2’-bisoxazoline ligands as well as their 4,4’-disubstituted derivatives have been shown
to both enhance steric bias in some substrates and conversely favor borylation at the most
hindered positions in others.

28

Reactions using the commonly used [Ir(OMe)COD]2/ dtbpy

catalyst system preformed on asymmetric 2,5-disubstituted heterocylces and 1,4-disubstituted
aromatics containing different substituents of similar steric size led to moderate to poor
regioselectivity. Running the reactions under the same conditions with 2,2’-bis[(4S)-4-benzyl-2oxazoline] (bbnbox) as ligand lead to greatly enhanced regioselectivity implying the bbnbox
ligand was far more sensitive to steric repulsion (Figure 1.16).
Figure 1.16. Ligand design for enhanced regioselectivity.

17

The sterically small fluorine functionality had also been shown to give a substantial
electronic directing effect and it was possible to modify the ligands to obtain a 2-borylated
product as the major isomer with a 1,3-difluorobenzene substrate (Figure 1.15). It is very
interesting to note that in the previous case the same bbnbox ligand which showed greater
regioslectivity now demonstrated regioselective borylation at the most sterically crowded
position.

Figure 1.17. Regioselective borylations with 1,3-difluorobenzene.

The reversal of regioselectivity based on steric bias vs. electronic bias warrants further
investigation and highlights the importance of isolating the bisoxazoline Ir catalysts responsible
for C-H activation/borylation to determine what role the bisoxazoline ligands play in altering
these regioselectivities.

18

REFERENCES

19

REFERENCES
1) Jones, W. D. Inorg. Chem. 2005, 44, 4475.
2) Kleiman, P. J.; Dubeck, M. J. Am. Chem. Soc., 1963, 85, 1544.
3) Chatt, J.; Davidson, J. M. J. Chem. Soc., 1965, 843.
4) Tolman, C. A.; Ittel, S. D.; English, A. D.; Jesson, J. P. J. Am. Chem. Soc. 1979, 101,
1742.
5) Jones, W. D.; Kosar, W. P. J. Am. Chem. Soc. 1986, 108, 5640.
6) Ezbiansky, K.; Djurovich, P. I.; LaForest, M.; Sinning, D. J.; Zayes, R.; Berry, D. H.
Organometallics 1998, 17, 1455.
7) Crabtree, R. H. J. Chem. Soc., Dalton, Trans., 2001, 2437.
8) Ishiyama, T.; Miyaura, N. Pure Appl. Chem. 2006, 78, 1369.
9) Zhou, J.; Ru, G. C. J. Am. Chem. Soc. 2004, 126, 1340.
10) Singer, R. D.; Knochel, P. Chem. Rev. 1993, 93, 2117.
11) Ishiyama, T.; Murata, M.; Miyaura, N. J. Org. Chem. 1995, 60, 7508.
12) Murata, M.; Oyama, T.; Watanabe, S.; Masuda, Y. J. Org. Chem. 2000, 65, 164.
13) Rablen, P. R.; Hartwig, J. F. J. Am. Chem. Soc. 1994, 116, 4121.
14) Henk, P. N.; Blom, H. P.; Westcott, S. A.; Taylor, N. T.; Marder, T. B. J. Am. Chem. Soc.
1993, 115, 9329.
15) Waltz, K. M.; He, X.; Muhoro, C.; Hartwig, J. F. J. Am. Chem. Soc. 1995, 117, 11357.
16) Waltz, K. M.; Hartwig, J. F. Science 1997, 277, 211.
17) Iverson, C. N.; Smith, M. R., III. J. Am. Chem. Soc. 1999, 121, 7696.

20

18) Cho, J. Y.; Tse, M. K.; Holmes, D.; Maleczka, R. E.; Smith, M. R., III. Science 2002,
295, 305.
19) Chen, H. Schlecht, S. Semple, T. C., Hartwig, J. F. Science 2000, 287, 1995.
20) Chen, H. Hartwig, J. F. Angew. Chem. Int. Ed. 1999, 38, 3391.
21) Cho, J.-Y.; Iverson, C. N.; Smith, M. R., III J. Am. Chem. Soc. 2000, 122, 12868.
22) (a) Shi, F.; Holmes, D.; Maleczka, R. E., Jr.; Smith, M. R., III. J. Am. Chem. Soc. 2003,
125, 7792. (b) Ishiyama, T.; Takagi, J.; Ishida, K.; Miyaura, N.; Anastasi, N. R.; Hartwig,
J. F. J. Am. Chem. Soc. 2002, 124, 390.
23) Mkhalid, I. A.; Barnard, J. H.; Marder, T. B.; Murph, J. M.; Hartwig, J. F. Chem. Rev.
2010, 110, 890.
24) Chotana, G. C.; Vanchura, B. A., II; Tse, M. K.; Staples, R. J.; Maleczka, R. E., Jr;
Smith, M. R., III Chem. Commun., 2009, 5731.
25) Boller, T. M.; Murphy, J. M.; Hapke, M.; Ishiyama, T.; Miyaura, N.; Hartwig, J. F. J.
Am. Chem. Soc. 2005, 127, 14263.
26) Tamura, H.; Yamazaki, H.; Sato, H.; Sakaki, S. J. Am. Chem. Soc. 2003, 125, 16114.
27) Vanchura, B. A., II; Preshlock, S. M.; Roosen, P. C.; Kallepalli, V. A.; Staples, R. J.;
Maleczka, R. E., Jr; Smith, M. R., III Chem. Commun. 2010, 46, 7724.
28) Chotana, G. A. Ph. D. Thesis, Mich. State University, 2008.
29) Shen, K.; Fu, Y.; Li, J.-N.; Liu, L.; Guo, Q.-X. Tetrahedron, 2007, 63, 1568.

21

CHAPTER 2
OPTIMIZATION OF IRIDIUM CATALYZED C-H BORYLATIONS

Introduction
Since the initial inception of Iridium catalyzed C-H borylation, the reaction has been
utilized to provide a simple, atom economical route to arylboronate esters from an ever
1

expanding list of aromatic, heteroaromatic and polyaromatic substrates. Throughout the course
of its development, many combinations of precatalyst, boron reagent, ligand, and solvent have
2

been used in the literature. Many of these conditions are variants of conditions identified in an
early communication by Ishiyama, Takagi, Hartwig, and Miyaura, utilizing [Ir(OMe)COD]2 as
3

the Ir precatalyst, dtbpy as the ligand, B2Pin2 as the borylating agent, and hexane as the solvent.

Since these initial reports, the substrate scope for C–H borylation has expanded considerably and
the original set of reaction conditions tended to be optimal for comparatively reactive substrates
(e.g. electron deficient arenes). Until recently, there had not been a comprehensive study to look
at the roles that solvent, metal precatalyst, boron reagent, reaction time and temperature, orders
of addition for catalyst generation, etc. might have on borylations as a function of substrate
properties. It is likely that conditions identified as optimal for one substrate class (e.g. electron
deficient arenes) maybe far from ideal for other aromatic substrates with high nitrogen content or
more electron rich aromatic systems. Moreover, the future success for some substrates may hinge
upon factors that have been overlooked. For these reasons, we under took a comprehensive study
of the many factors affecting the Ir catalyzed C–H borylation.

22

Identification of Reaction Variables.
In an effort to develop optimized conditions that could be applicable for C-H borylation
on a wide array of substrates, we focused on the portion of the reaction which is substrate
independent, catalyst generation. Varying the precatalyst, ligand, borylating reagent and the
order which they are mixed can all have an effect on active catalyst generation. This chemistry
has seen a variety of Ir(I) precatalysts and ligands used to access these (L2)Ir(III)BPin3 active
catalysts. Trends in the effectiveness of various Ir(I)-cyclooctadiene catalyst precursors in a
series of [Ir(X)(COD)]2 complexes has been shown to mirror the basicity of X (i.e. OMe > OH >
OPh > OAc > Cl > BF4) for room temperature reactions with electron deficient substrates.

3,4

The ability of [Ir(OMe)(COD)]2 and [Ir(Cl)(COD)]2 catalyst precursors to generate the
(dtbpy)Ir(COE)BPin3 intermediate has also been shown to be greatly affected by the order of
addition of the reagents HBPin or B2Pin2 and dtbpy in non-polar solvents at temperatures up to
5

50 ˚C. In order to truly determine the most desirable precatalyst for maximum active catalyst
generation, we selected a small sample of readily available Ir(I) precatalysts. The four
precatalysts used in the screens were the commercially available compounds [Ir(OMe)(COD)]2,
[Ir(Cl)(COD)]2, Ir(acac)(COD), and (Ind)Ir(COD) (Figure 2.1).
Figure 2.1. Precatalyst Selected for Reaction Screens.

23

To expedite the process of running the number of reactions required in an encompassing
systematic study, reactions were conducted in micro scale 96-well-plate reactors. The ease at
which high-throughput experimentation (HTE) allows researchers to set-up large numbers of
reactions meant reactions could be run in duplicate and entire reaction screens could be repeated
with little effort to certify reproducibility. Reactions conducted in 96-well-plate reactors were set
up under two sets of standardized conditions referred to as Conditions A or Conditions B in the
text. Stock solutions were used to dispense material accurately for each well. To facilitate
comparisons, the relative effectiveness of reaction conditions was determined by analyzing for
the amount of borylated products formed in reactions stopped well before completion.
Microscale Reactions Utilizing Conditions A. In a nitrogen filled glovebox, 50 μL of
solution containing 0.5 μmol Iridium precatalyst dimer (0.01 M stock solution) or 1.0 μmol
Iridium monomer (0.02 M stock solution) in the designated solvent was added to a 1 mL reaction
vial containing a magnetic stir bar. To this solution, 50 μL of stock solution containing 30 μmol
HBPin (0.6 M) or 15 μmol B2Pin2 (0.3 M) was added to the 1 mL reaction vial. 50 μL of
solution containing 1.0 μmol ligand (0.02 M) was added via micro pipette followed by 50 μL of
stock solution containing 20 μmol arylsubstrate (0.4 M) and 2 μmol dodecahydrotripheneylene
internal standard. The reaction vessel was then sealed and stirred at the desired temperature for
an allotted amount of time, at which point the reaction was cooled to room temperature and
quenched by exposure to atmospheric O2.
Microscale Reactions Utilizing Conditions B. In a nitrogen filled glovebox, 50 μL of
solution containing 0.5 μmol Iridium precatalyst dimer (0.01 M stock solution) or 1.0 μmol
Iridium monomer (0.02 M stock solution) in the designated solvent was added to a 1 mL reaction
24

Figure 2.2. Room Temperature Reaction Screen With 3-bromotoluene.

Numbers and bubble area size are assay yields of 3b.
25

vial containing a magnetic stir bar. To this solution, 50 μL of stock solution containing 1.0 μmol
ligand (0.02 M was added to the 1 mL reaction vial. 50 μL of solution containing ) 30 μmol
HBPin (0.6 M) or 15 μmol B2Pin2 (0.3 M) was added via micro pipette followed by 50 μL of
stock solution containing 20 μmol arylsubstrate (0.4 M) and 2 μmol dodecahydrotripheneylene
internal standard. The reaction vessel was then sealed and stirred at the desired temperature for
an allotted amount of time, at which point the reaction was cooled to room temperature and
quenched by exposure to atmospheric O2.

Orders of Addition Effects for Room Temperature Reactions
Our initial screen utilized the substrate 3-bromotoluene (3a) because of its intermediate
reactivity at room temperature. The reactions were stopped prior to completion to facilitate
comparisons and the reaction time of 4 h was chosen because reactions utilizing the standard
literature conditions are at approximately 50% completion at this time. The effects of the order at
which HBPin and dtbpy were added to the reaction solution containing one of four precatalysts
([Ir(OMe)(COD)]2, [Ir(Cl)(COD)]2, Ir(acac)(COD), or (Ind)Ir(COD)) was screened with the
previously mentioned conditions. The differences between reaction conditions A and B, when
HBPin and dtbpy were added to reaction solutions containing [Ir(OMe)(COD)]2 proved to be
irrelevant (see Figure 2.2). Again with [Ir(OMe)(COD)]2 as precatalyst, the same observations
were made when B2Pin2 was used as the borylating reagent under both conditions A and B.
When precatalyst [Ir(Cl)(COD)]2, the immediate synthetic precursor to [Ir(OMe)(COD)]2, was
used a marked drop in reactivity was observed relative to reactions with [Ir(OMe)(COD)]2. The

26

addition of HBPin prior to ligand under these conditions was vital. When dtbpy was added to the
reaction mixture before HBPin, or if B2Pin2 was used as borylating reagent, no borylation was
observed. Reactions run with Ir(acac)(COD) followed the same trends as [Ir(OMe)(COD)]2, all
be it with slightly lower conversions. This drop in reactivity was most likely due to a slower rate
at which Ir(acac)(COD) generates active catalyst relative to [Ir(OMe)(COD)]2, or a lower yield
in the formation of active catalyst from catalyst precursor. The coordinately saturated precatalyst
(Ind)Ir(COD) was found to be inert under the standard reaction conditions at room temperature.
Order of addition became far more important when the more electron rich 3,4,7,8tetramethyl-1,10-phenanthroline (tmphen) was used in reactions with HBPin. The combination
of [Ir(OMe)(COD)]2

with tmphen and HBPin produced 2.5 times as much product when

conditions A were used compared to the identical reaction were order of addition conditions B
were used. A similar 2.0 fold increase in the amount of product formed was observed with
Ir(acac)(COD) using tmphen and HBPin utilizing conditions A compared with conditions B. No
reaction occurred when conditions B were used with [Ir(Cl)(COD)]2 and tmphen with HBPin,
mirroring results seen with dtbpy and this precatalyst. Utilizing [Ir(Cl)(COD)]2 , tmphen and
HBPin with order of addition conditions A gave fairly good reactivity.
The reactivity of these precatalysts with added ligand provides insight into the effects of
1

order of addition on conversion. H NMR experiments show no complex formation in 1:1
mixtures of either [Ir(OMe)(COD)]2 and dtbpy or Ir(acac)(COD) and dtbpy in THFd8 (Figure
2.3). The lack of complexation correlated directly with the absence of any effect on order of
27

6

addition. 1:1 mxtures of [Ir(Cl)(COD)]2 and dtbpy did, however, form a complex in solution.

This complex can be attributed to the lack of reactivity in reactions when [Ir(Cl)(COD)]2 is used
as precatalyst. Similar NMR experiments with tmphen led to the formation of insoluble
7

precipitates with precatalysts [Ir(OMe)(COD)]2, [Ir(Cl)(COD)]2 and Ir(acac)(COD) in THFd8.

In every instance, formation of ligated complexes prior to addition of HBPin corresponds to
lower reactivity compared with reactions were the order of addition was reversed. Likewise,
under conditions were no complex formation between ligand and precatalyst was observed, the
order of addition was found to be irrelevant.
Figure 2.3. Precatalyst and ligand complexation.

28

Figure 2.4. Rate equation derived from Ref 5.
rate = K1

1/2

k2[Ir]

1/2

[benzene]

where K1 = [(dtbpy)IrBPin3][COE]/[ (dtbpy)Ir(COE)BPin3]

Effects of Borylating Reageant on Relative Reactivity
Although the rate equation for catalytic C-H borylation has been experimentally shown to
be zeroth order in borylating reagent (Figure 2.4), the nature of the borylating reagent will still
effect the conversion of precatalyst to active catalyst and consequentially affect the relative rates
5

of reactivity. Of the various borylating reagents known to do Ir catalyzed C-H borylation, only
HBPin and B2Pin2 were included in our reaction screen. Borylating reagents such as HBcat (cat
8,9

= catecholate)

and HBDan (Dan = 1,8-diaminonaphthyl)

10

were precluded from this study for

their relatively lower reactivity and the latter's lack of mechanistic data. Of the reactions
screened using the tmphen ligand, HBPin gave higher conversions than B2Pin2 with every
precatalyst screened. For reactions with the dtbpy ligand, B2Pin2 gave nearly 50% higher
conversions with [Ir(OMe)COD]2, while HBPin, was nearly 50% better with precatalyst 3.

General Ligand and Precatalyst Trends for Room Temperature Reaction Screen.

A relative ordering a precatalyst activity could be given as [Ir(OMe)(COD)]2 >
Ir(acac)(COD) > [Ir(Cl)(COD)]2 consistent with the relative ordering of basicity in the
5

precatalyst’s counter ions being OMe > acac > Cl. The (η -C9H7) fragment would obviously be
29

the most basic counter ion by a large margin, but the lack of reactivity is most likely due to the
inability to displace it under these reaction conditions. A 4,4',5,5'-tetrahydro-2,2'-bioxazole (box)
ligand was subjected to all screened conditions, however no conditions were found which
produced more than trace amounts of product.

Table 2.1. Temperature effects on relative conversions for 1,2,3-trimethoxybenzene (4a).

entry

cond.

ligand

XBPin

T (˚C)

Yield (%)

T (˚C)

Yield (%)

1

A

dtbpy

HBPin

25

6

80

37

2

A

tmphen

HBPin

25

10

80

87

3

B

dtbpy

HBPin

25

7

80

41

4

B

tmphen

HBPin

25

7

80

90

5

A

dtbpy

B2Pin2

25

10

80

74

6

A

tmphen

B2Pin2

25

8

80

88

7

B

dtbpy

B2Pin2

25

13

80

86

8

B

tmphen

B2Pin2

25

8

80

93

Conditions A: Order of addition 1) 5 mol% [Ir], 2) 1.5 equiv HBPin or 0.75 equiv B2Pin2, and 3)
5 mol% Ligand. Conditions B: Order of addition 1) 5 mol% [Ir], 2) 5 mol% Ligand, and 3) 1.5
equiv HBPin or 0.75 equiv B2Pin2. Precatalysts used in table 1.

30

Temperature effects on optimization screens.
As stated in the introduction, more electron rich aromatics require more forcing conditions to
affect borylation, usually in the form of higher reaction temperatures. A preliminary screen with
1,2,3-trimethoxybenzene (4a) was performed to determine the effects this common practice has
on relative conversions in reactions run at 25 ˚C and 80 ˚C. Table 2.1 highlights the results of a
set of experiments with precatalyst [Ir(OMe)(COD)]2 under various conditions. Optimum
conditions for catalyst generation were found to be different at the two reaction temperatures.
The order of addition effects observed with tmphen at room temperature (entries 2 and 4), were
negligible in comparable entries at 80 ˚C. In contrast to experiments run at 25 ˚C, where the
borylating reagent and order of addition determined which ligand was more viable, catalysts
formed with the tmphen ligand outperformed catalysts with dtbpy under identical conditions in
every set of experiments at 80 ˚C. Also, catalysts formed with the dtbpy ligand displayed a large
difference in relative conversions when B2Pin2 was used compared with HBPin at both
temperatures.
Reactions run with the tmphen ligand and 4a as substrate, only gave low conversion at 25 ˚C,
while conversion was nearly complete at 80 ˚C, hindering our ability to draw conclusions about
relative rates by observing only set time points. Rather than decreasing reaction times, a more
electron rich arene was chosen. Since catalyst formation occurs at the beginning of the reaction,
it should be largely substrate independent. For N,N-dimethyltoluidine (5a), conversions after 4 h
were lower. Thus relative rate information could be gleaned from single time point data. With
5a, we screened [Ir(OMe)(COD)]2, [Ir(Cl)(COD)]2, Ir(acac)(COD), or (Ind)Ir(COD), at 80 ˚C
with identical conditions as was done at room temperature with 3a (Figure 2.5). Much higher

31

Figure 2.5. Elevated temperature reaction screen preformed on N,N-dimethyltoluidine (5a).

Numbers and bubble area size are assay yields of 5b.

32

conversions were observed in reactions using tmphen as ligand than with dtbpy. This could be
the result of either a more reactive (tmphen)IrBPin3 catalyst being formed or a much shorter
catalyst life time for complexes formed with dtbpy at this temperature. The order of addition
effects were nonexistent with all ligands and precatalysts with the sole exception of the
combination of HBPin, tmphen and [Ir(Cl)(COD)]2 (column 2, row 2 and column 5, row 2).
The choice of precatalyst [Ir(OMe)(COD)]2, [Ir(Cl)(COD)]2 or Ir(acac)(COD) was irrelevant
with dtbpy ligand. The lower yields with (Ind)Ir(COD) could be the result of an induction period,
however, a definitive conclusion cannot be drawn because data was sampled at one data point.
Precatalyst [Ir(OMe)(COD)]2, preformed slightly better than the others with tmphen.
The most distinct systematic difference in reactivities was in the difference in relative
conversions for experiments run with HBPin as borylating reagent compared with experiments
run with B2Pin2 as borylating reagent. Systems using the dtbpy ligand showed far greater
reactivity with B2Pin2 than analogous reactions with HBPin. Reactions with tmphen were much
less sensitive to changes to the borylating reagent with the lone exception of higher reactivity
occurring with (Ind)Ir(COD), tmphen and B2Pin2 giving nearly 2 times as much borylated
product as equivalent reactions with the precatalyst (Ind)Ir(COD), tmphen and HBPin.

Solvent Effects on Catalyst Formation at Room Temperature.
By

synthesizing

and

isolating

the

5

six

coordinate

catalysts

precursors

(dtbpy)Ir(Bpin)3(COE) and (tmphen)Ir(Bpin)3(COE) (Figure 2.6), we were able to determine if

33

the differences in conversions for different ligands resulted from variability in catalyst generation
or from intrinsic catalyst potency.

The results in Figure 2.7 illustrate the difference in

conversion that can be assumed from 100% catalyst generation with (dtbpy)Ir(Bpin)3(COE) and
(tmphen)Ir(Bpin)3(COE), and from reactions were an unknown amount of active catalyst is
formed from [Ir(OMe)(COD)]2 and respective ligand in-situ.

Figure 2.6. (dtbpy)Ir(BPin)3(COE) and (tmphen)Ir(BPin)3(COE).

While the isolated catalyst precursor (tmphen)Ir(Bpin)3(COE) showed comparable or
higher conversions to (dtbpy)Ir(Bpin)3(COE) in most of the solvents screened, conversions with
in-situ generated catalysts formed from tmphen and [Ir(OMe)(COD)]2 were in most cases lower
than those for in-situ generated catalysts from dtbpy and [Ir(OMe)(COD)]2. This led us to
34

conclude that under these reaction conditions, dtbpy and [Ir(OMe)(COD)]2 formed active
catalysts in much higher yields in both polar and non-polar solvents at 25˚C than tmphen and
[Ir(OMe)(COD)]2 did.

Figure 2.7. Solvent Effects on Catalyst Generation at Room Temperatue.

70
60
50
40
30
20
10
DCM

dioxane

IPAc

NMP

NEt3

Hunig's
Base

hexanes

MTBE

Cpme

MeTHF

THF

0

■ 2.5 mol% [Ir(OMe)COD]2 with 5 mol% dtbpy ■ 5mol% (dtbpy)Ir(BPin)3(COE) ■ 2.5 mol%
[Ir(OMe)COD]2 with 5 mol% tmphen ■ 5mol% (tmphen)Ir(BPin)3(COE)

The worst solvents for generating active catalyst with dtbpy and tmphen appear to be
solvents containing carbonyls such as NMP and IPAc, or the very coordinating 1,4-dioxane
35

demonstrated by the large difference in reactivities of in-situ generated catalysts with that of the
6-coordinated isolated complex (dtbpy)Ir(Bpin)3(COE). Contrary to the popular notion of nonpolar solvents being better for borylation reactions, MeTHF, THF and NMP gave the highest
conversions when starting from the isolated complex (dtbpy)Ir(Bpin)3(COE) . NEt3 appeared to
inhibit reactivity of (dtbpy)Ir(Bpin)3(COE) and catalysts formed in-situ from [Ir(OMe)(COD)]2
and dtbpy. The solvents that gave the highest yield for in-situ catalyst generation with
[Ir(OMe)(COD)]2 and tmphen were hexanes and Hünig's base.

Figure 2.8. [(tmphen)Ir(CH(BPin)2)Cl2]2.

Not all solvents were inert to the Ir catalysts formed during C-H borylation. DCM was
observed to react with (tmphen)Ir(BPin)3(COE) to form a [(tmphen)Ir(CH(BPin)2)Cl2]2 dimer in
quantitative yield when left over night (Figure 2.8). While no structure was isolated, similar
reactions of DCM with (dtbpy)Ir(BPin)3(COE) could account for the low reactivity. Reactions
run with 2.5 mol% [Ir(OMe)COD]2 and 5 mol% dtbpy in MeCN and DMF gave only traces of
borylated products and reactions in DMSO showed no product formation.

36

Figure 2.9. Solvent effects on catalyst generation with 1,3-dimethoxybenene (6a).

100
90
80
70
60
50
40
30
20
10
0
THF

hexanes

Hunig's Base

NMP

IPAc

■ 2.5 mol% [Ir(OMe)COD]2 with 5 mol% dtbpy ■ 5mol% (dtbpy)Ir(BPin)3(COE) ■ 2.5 mol%
[Ir(OMe)COD]2 with 5 mol% tmphen ■ 5mol% (tmphen)Ir(BPin)3(COE)

Solvent Effects on Catalyst Formation at Elevated Temperature.
In situ catalyst formation appears to be much more efficient at 80 ˚C, with isolated
complexes and in situ formed catalysts giving nearly equal conversions. IPAc appeared to
diminish reactivity with both sets of ligands and NMP appeared to hamper complexes formed
with the tmphen ligand (Figure 2.9). The diminished reactivity of NMP at 80 ˚C is not
completely surprising, since the very similar solvent DMF only afforded trace amounts of
borylation products at room temperature. Again, the best solvents for borylation with

37

(dtbpy)Ir(BPin)3(COE) and catalysts formed in-situ from [Ir(OMe)(COD)]2 and dtbpy were the
polar solvent THF and NMP, outperforming less polar solvents such as hexanes. Catalysts
formed from [Ir(OMe)(COD)]2

and tmphen in-situ and (tmphen)Ir(BPin)3(COE) gave

comparable conversions in both polar and non-polar solvents ranging from THF to Hünig's base
to hexanes. The lower conversions of the in-situ formed catalyst from [Ir(OMe)(COD)]2 and
tmphen in NMP and IPAc and for reactions using (tmphen)Ir(BPin)3(COE) in NMP and IPAc
maybe the result of side reactions between the active catalyst and the solvent similar to those
seen with (tmphen)Ir(BPin)3(COE) and DCM at room temperature. Comparing the reactivity of
(dtbpy)Ir(BPin)3(COE) and (tmphen)Ir(BPin)3(COE), we see the latter is much more reactive in
THF at higher temperatures. While this was a change from the room temperature results, it did
mirror reactivity seen with the elevated temperature reaction screens with 5a.

Elevated Temperature Reaction Screen Preformed on 5a in Multiple Solvents.
We thought it necessary to observe the effect solvent had on the multiple variables
screened in the elevated temperature reaction screen with 5a so portions of that screen using
conditions B were run in hexanes and Hünig's base. The data presented in Figure 2.10 shows all
precatalysts run with the dtbpy ligand and HBPin were more reactive in THF than in hexanes or
Hünig's base in agreement with the previous elevated solvent screen. However, hexane was the
preferred solvent when using B2Pin2 as the borylating reagent out preforming the analogous

38

Figure 2.10. Multivariable Solvent Screen.

39

reactions run with precatalysts [Ir(OMe)(COD)]2, [Ir(Cl)(COD)]2, and (Ind)Ir(COD). Solvent
had very little effect on reactions run with the tmphen ligand giving similar results with both
HBPin and B2Pin2. The only significant solvent effect observable with the tmphen catalyst was
with [Ir(Cl)(COD)]2 and B2Pin2, were the more non polar the solvent became, the higher the
realative reaction rates became.

Table 2.2. Temperature Effect on Catalyst Stability

Entry

ligand

T (˚C)

% yield

1

dtbpy

130

13

2

dtbpy

110

13

3

dtbpy

80

32

4

tmphen

130

38

5

tmphen

110

48

6

tmphen

80

94

7

dppbz

130

52

8

dppbz

110

15

9

dppbz

80

0

a

Reaction run in MeTHF.

40

a

Figure 2.11. Phosphine Ligand Screen.

Phosphine Ligated Iridium Borylation Catalysts.
A number of reports have utilized phosphine ligands for Ir catalyzed borylation reactions.
Although we desired to contain within this report, a head to head comparison of Ir catalysts with
bidentate phosphine ligands with those of bis nitrogen chelates it was found that the optimum
reaction conditions for each were drastically different. While nitrogen chelates such as dtbpy and
tmphen soundly outperform phosphine ligated Ir ctalysts at temperatures up to 80 ˚C, phosphine
complexes require higher temperatures to become catalytically viable. Table 2.2 shows that as
the reaction temperature is increased, reactivity for catalysts derived from dtbpy and tmphen

41

greatly decreases. Comparing entries 4 and 6 in Table 2.2, we see that as the reaction
temperature is raised from 80 ˚C to 130 ˚C, reactivity drops from 94% yield to 38% at identical
time points. Conversely, comparing Table 2.2 entry 9 with entry 7, reactivity increases from no
conversion at 80 ˚C to 52% conversion at 130 ˚C with catalysts derived from dppbz (1,2bis(diphenylphosphino)benzene) and [Ir(OMe)(COD)]2. The effects of heating reactions above
80 ˚C are not immediately clear but the reduction in catalytic reactivity with dtpby and tmphen Ir
complexes is most likely due to catalyst decomposition.

Figure 2.12. Elevated Temperature Phosphine Ligand Screen.

42

Ligand Effects; Electron Donating Ability and Constrained Geometry.
Reactivity or Ir catalysts has been shown to correlate with increasing donor ability of ligands
and Figure 2.11 shows the partial results from a reaction screen using the phosphine ligands
dmpe, dppe and dppbz. The lack of reactivity under these reaction conditions is surprising
considering that alkyl and aryl phosphines are both significantly strong donor ligands. More so,
the sterically smaller and more electron rich dmpe performs much worse than the sterically
larger, less electron rich dppbz. The fact that dmpe and dppe are known to form the catalytically
incompetent

2

1

(dmpe-κ P)Ir((BPin)3(dmpe-ĸ P)

and

2

1

11

(dppe-κ P)Ir((BPin)3(dppe-κ P)

complexes could account for the lack of reactivity. The constrained benzene backbone in dppbz
would prevent the two phosphine coordination sites from orientating themselves trans to each
2

1

other inhibiting the formation of an analogous (dppbz-κ P)Ir((BPin)3(dppbz-κ P) complex.
2

1

Figure 2.13. (dmpbz-κ P)Ir((BPin)3(dmpbz-κ P)

The results shown in Figure 2.12 of a similar phosphine reaction screen using dmpe, dmpbz
(1,2-bis(dimethylphosphino)benzene) and dppbz at 130 ˚C in Cpme show higher reactivity than
those done at 80 ˚C (Figure 2.10). An additional interesting result is the lower reactivity of the
dmpbz ligand relative to the dppbz ligand. As stated previously the lower steric bulk and
increased donor ability of ligands lead to more active catalysts. The dmpbz ligand should be both
43

less sterically hindering and more electron donating than dppbz, but reactions with the dmpbz
2

1

ligand gave lower yields. An explanation may be that a (dmpbz-κ P)Ir((BPin)3(dmpbz-κ P)
complex can be formed despite its constrained backbone because of its lower steric bulk (Figure
2.13).
Table 2.3. Borylation of 2,6-dimethylanisole (7a).

entry

ligand

% yield

1

dtbpy

46

2

dmabpy

55

3

phen

16

4

tmphen

86

In an attempt to probe whether the difference in reactivity of the tmphen ligated complex
and the dtbpy ligated complex was due the constrained dihedral angle in the chelate backbone or
due to the fact that tmphen is simply a stronger donor ligand than dtbpy, a set of experiments was
run with dmabpy (4,4’-bis(dimethylamino)-2,2’-bipyridine) and phen (1,10-phenanthroline)
ligands. The results shown in Table 2.3 suggest it is a combination of the two effects. While the
dmabpy ligand is more electron rich than the tmphen ligand,

12,13

the importance of the

conformational rigidity of tmphen is highlighted by its ability to give higher relative conversions
for the borylation of 2,6-dimethylanisole with HBPin. The constrained dihedral angle in the
chelate backbone of tmphen is a feature shared with the phen ligand, however, phen gave far
44

lower relative reaction rates than either the dtbpy or dmabpy ligands, ascribable to phen being
comparatively electron deficient.

Figure 2.14. Decay of 6a during the reaction with HBPin or B2pin2.

45

Kinetic Experiments with (tmphen)Ir(BPin)3(COE) and (dtbpy)Ir(BPin)3(COE).
As was noted in previous sections, the reactivity of reactions run at elevated temperatures
showed a clear dependence on the specific borylating reagent used (either HBPin or B2Pin2).
The

(tmphen)Ir(BPin)3(COE)

also

appeared

to

be

much

more

potent

than

the

(dtbpy)Ir(BPin)3(COE) analogue. The increased conversions observed for reactions with
(tmphen)Ir(BPin)3(COE) and B2Pin2 could be the result of either the complex being much more
reactive than the dtbpy analogue or (tmphen)Ir(BPin)3(COE) having a longer catalytic lifetime
and producing more TONs. Figure 2.14 shows the results of several NMR tube reactions run
with 5 mol% (dtbpy)Ir(BPin)3(COE) or (tmphen)Ir(BPin)3(COE), with either borylating reagent
B2Pin2 (0.260 M) or HBPin (0.260 M) and 6a (0.217 M) in THFd8 at 60 ˚C. For reactions run
with B2pin2, both (dtbpy)Ir(BPin)3(COE) and (tmphen)Ir(BPin)3(COE) gave comparable initial
rates for the intial two half-lives (Figure 2.15). Over this time period, the catalytic resting state
could

be

observed

as

that

of

the

initial

complexes

(dtbpy)Ir(BPin)3(COE)

or

(tmphen)Ir(BPin)3(COE) respectively. As the reaction progressed toward the inflection point
seen in Figure 2.14, HBPin formed as the byproduct of B2Pin2 and arene and the resting state
shifted from that of the 6-coordinate catalyst precurors to that of an unidentified species
accompanied by free COE (Figure 2.16). Free COE was observed with a shift in the aromatic
resonances

in

reactions

with

HBPin

and

either

(dtbpy)Ir(BPin)3(COE)

or

(tmphen)Ir(BPin)3(COE) at room temperature. The observation of different catalytic resting
46

states with different borylating reagents accounts for how different boron sources could give
different reactivity when the reaction has been determined to be zeroth order in borylating
reagent (Figure 2.17).

5

Figure 2.15. ln[arene] vs. time over two half-lives.

47

Figure 2.16. Catalytic resting states for kinetic experiments with (tmphen)Ir(BPin)3(COE) with
B2Pin2 (A) and HBPin (B).

Figure 2.17. Proposed catalytic cycle for (dtbpy)Ir(BPin)3(COE) from ref. 5.

rate = k2[(dtbpy)Ir(BPin)3(COE)][arene]
48

Figure 2.18. Kinetic Experiments with (tmphen)Ir(BPin)3(COE) at variable catalyst loadings.

2.5 mol% (tmphen)Ir(Bpin)3(COE)
5.0 mol% (tmphen)Ir(Bpin)3(COE)

0.2

10.0 mol% (tmphen)Ir(Bpin)3(COE)

0.15
0.1
0.05

21000

19500

18000

16500

15000

13500

12000

10500

9000

7500

6000

4500

3000

1500

0
0

[1,3-dimethoxybenzene] (mol L-1)

0.25

time (s)

Kinetic experiments done with varying amounts of (tmphen)Ir(BPin)3(COE) showed that
at higher catalyst loadings (10 mol% (tmphen)Ir(BPin)3(COE)), the reaction borylation of 6a
would initially proceed at a faster rate, but would also reach the inflection point quicker than
reactions

done

at

lower

loadings.

Conversely,

49

reactions

run

with

2.5

mol%

(tmphen)Ir(BPin)3(COE) had a slower initial reaction rate but would reach the inflection point at
a later time. These results are in agreement with the rate equations determined in ref 5.

C-H Borylation in Open vs. Closed Systems.
In this study the reactions were carried out in closed systems to prevent solvent and
reagent evaporation. Ir catalyzed C-H borylations with B2Pin2 generate HBPin as shown in Eq 1.
HBPin can react further to do a successive borylation and generate one equivalent of H 2 (Eq 2).
The H2 generated can react with Ir-BPin complexes to form hydrides according to Eq 3. Since
the effects of Ir-H complexes in the catalytic cycle are not well defined, a comparison between
open and closed systems with the borane reagents HBPin and B2Pin2 could offer insight into the
effect H2 concentration has on the reaction. For HBPin, borylations in open systems were
slightly more efficient than borylations in closed systems, while borylations with B2Pin2 were
essentially the same in open and closed systems (Figure 2.19).

50

Figure 2.19. C-H Borylation in Open vs. Closed Systems with 8a.

% conversion

100

HBPin

75

50

25

0
30

60

120

180

300

480

300

480

time (min)
100

B2Pin2

% conversion

75

50

25

0
30

60

120

180

time (min)
tmphen. closed

dtbpy, closed

tmphen, open

dtbpy, open
51

Table 2.4. Ligand to Metal Ratios and Catalyst Loading Study.

Ligand equivalents relative to Ir (data in % yield)
Entry

mol% Ir

Ligand

0.8

1.0

1.4

2.0

4.0

1

5.0

dtbpy

55

55

53

54

52

2

2.5

dtbpy

58

57

58

55

53

3

1.0

dtbpy

51

55

54

58

57

4

0.5

dtbpy

32

36

41

47

50

5

5.0

tmphen

75

74

68

61

43

6

2.5

tmphen

72

77

73

68

55

7

1.0

tmphen

57

69

78

78

72

8

0.5

tmphen

40

42

53

79

66

Ligand to Metal Ratio and Catalyst Loading Study.
Loading studies were conducted on the catalytic system to determine how concentration,
catalyst loadings, and ligand to metal ratios would affect the overall reaction rates. Table 2.4
displays results using [Ir(OMe)(COD)]2 at four catalyst loadings, with five ligand to Ir ratios
ranging from 0.8: 1.0 to 4.0: 1.0, in a 5 M reaction solution with respect to 5a. The results
highlight that reactivity can be maintained as you reduce catalyst loadings up to ten fold by
52

increasing the ligand to Ir ratio to 2.0: 1.0. This trend was observed for both dtbpy and tmphen
ligands, but is more dramatic with tmphen.
Since it is firmly established that mono ligated (dtbpy)IrBPin3 and (tmphen)IrBPin3 are
the active catalyst species in solution, the increased reactivity at lower concentrations of
[Ir(OMe)(COD)]2 suggest the extra equivalents of ligands aid in catalyst formation under these
conditions, which is not unusual for catalyst which require in-situ generation. Further increasing
the ligand to metal ratio was found to show diminishing reactivity.

Table 2.5. Ligand to Metal Ratio with preformed (tmphen)Ir(COE)BPin3.

entry

mol % (tmphen)Ir(COE)BPin3

mol % tmphen

Yield (%)

1

0.5

--

89

2

0.5

2.0

92

3

5.0

--

82

4

5.0

20

79

Table 2.5 shows the results of a similar ligand to metal ratio and catalyst loading study
run with preformed (tmphen)Ir(COE)BPin3. Reactions run with additional tmphen gave nearly
identical yields as those run without. This supports our hypothesis that the additional ligand aids
in active catalyst generation for in-situ generation from precatalyst [Ir(OMe)(COD)]2.
53

Decreasing the catalyst loading with the preformed (tmphen)Ir(COE)BPin3 gives a less
pronounced increase in conversion, similar to what was observed in the in-situ generated catalyst
loading studies.

Figure 2.20. Precatalyst Stability and Aging Study.

60
50

% Yield

40
1

30

2
3

20

7
10
0
0

25

50
Relative Hunidity (%)

54

75

100

Precatalyst Stability and Aging Studies.
In an effort to determine the various “shelf-life” of the precatalysts used in our
optimization study, we investigated how the reactivity would be effected by varying degrees of
humidity over time. Samples of precatalysts [Ir(OMe)(COD)]2, [Ir(Cl)(COD)]2, Ir(acac)(COD),
and (hexafluoroacetylacetonate)Ir(COD) were subdivided and stored in humidity chambers at
several humidities for 100 days and then tested against samples that were held in an inert
atmosphere (N2 filled glove box). The results are shown in Figure 2.20 and precatalysts
[Ir(OMe)(COD)]2, Ir(acac)(COD), and (hexafluoroacetylacetonate)Ir(COD) all show a gradual
drop in reactivity directly dependent on the conditions in which they were stored, with a more
moist environment leading to lower relative rates of reactivity. Precatalyst [Ir(Cl)(COD)]2, while
exhibiting a slight drop in reactivity from samples held in a glove box, shows that it is the most
“air stable” of the precatalysts commonly used for Ir catalyzed C-H borylation.

Due to [Ir(Cl)(COD)]2 superior bench top stability, lower cost and the fact that
precatalysts

[Ir(OMe)(COD)]2,

Ir(acac)(COD),

(Ind)Ir(COD),

and

(hexafluoroacetylacetonate)Ir(COD) are all prepared from [Ir(Cl)(COD)]2, we investigated the
effects various metal salt additives would have on the in-situ formation of these more active
precatalysts starting from [Ir(Cl)(COD)]2. Entries 1, 2, and 4 from Table 2.6 show that the
relative rates of C-H borylation could be increased by the combination of [Ir(Cl)(COD)]2 and K,
Na and Ti acetylacetonate salts to the point where they rivaled those seen with Ir(acac)(COD)
under reaction conditions B. Entry 8 demonstrates that [Ir(Cl)(COD)]2 with KOt-Bu can show
55

comparable reactivity to [Ir(OMe)(COD)]2 under reaction conditions B. Interestingly, the metal
salts Al(acac)3 and Mg(OMe)2 did not improve or inhibit reactivity with [Ir(Cl)(COD)]2, or
[Ir(OMe)(COD)]2. Such results raise the possibility that certain metal phenoxide or benzoate
salts may be able to undergo C-H borylation. Such a study is beyond the scope of the current
optimization work. Under order of addition A, when the HBPin is added before the ligand (dtbpy
for this experiment), reactions gave similar yields to reactions without metal salt additives
(entries 1-6 in Table 2.6).

56

Table 2.6. Metal Additive Screen for In-Situ Precatalyst Generation.

a

entry

precatalyst

additive

Condition A

Condition B

1

2

K(acac)

14

32

2

2

Na(acac)

13

28

3

2

Al(acac)3

13

0

4

2

Ti(O)(acac)2

14

27

5

2

--

14

0

6

2

Mg(OMe)2

14

2

7

2

KOMe

0

14

8

2

KOt-Bu

20

34

9

1

K(acac)

0

0

10

1

Na(acac)

5

6

11

1

Al(acac)3

33

33

12

1

Ti(O)(acac)2

30

31

13

1

--

33

33

14

1

Mg(OMe)2

33

32

15

1

KOMe

15

9

16

1

KOt-Bu

7

7

17

3

--

31

30

a

5 mol% metal additive added to reaction vial before all other reagents.

57

a

REFERENCES

58

REFERENCES
1) Mkhalid, I. A. I.; Barnard, J. H.; Marder, T. B.; Murphy, J. M.; Hartwig, J. F. Chem. Rev.
2010, 110, 890.
2) (a) The following articles on C–H borylation have been published since the review article
cited in ref. 1: Kallepalli, V. A.; Sanchez, L.; Li, H.; Gesmundo, N. J.; Turton, C. L.;
Maleczka, R. E., Jr.; Smith, M. R., III Heterocycles 2010, 80, 1429; (b) Liskey, C. W.;
Liao, X. B.; Hartwig, J. F. J. Am. Chem. Soc. 2010, 132, 11389; (c) Robbins, D. W.;
Boebel, T. A.; Hartwig, J. F. J. Am. Chem. Soc. 2010, 132, 4068; (d) Itoh, H.; Kikuchi,
T.; Ishiyama, T.; Miyaura, N. Chem. Lett. 2011, 40, 1007; (e) Li, G. Q.; Kiyomura, S.;
Yamamoto, Y.; Miyaura, N. Chem. Lett. 2011, 40, 702; (f) Liao, X. B.; Stanley, L. M.;
Hartwig, J. F. J. Am. Chem. Soc. 2011, 133, 2088; (g) Nguyen, D. H.; Perez-Torrente, J.
J.; Lomba, L.; Jimenez, M. V.; Lahoz, F. J.; Oro, L. A. Dalton Trans. 2011, 40, 8429; (h)
Norberg, A. M.; Smith, M. R., III; Maleczka, R. E., Jr. Synthesis 2011, 857; (i) Ozawa,
R.; Yoza, K.; Kobayashi, K. Chem. Lett. 2011, 40, 941; (j) Ros, A.; Estepa, B.; LopezRodriguez, R.; Alvarez, E.; Fernandez, R.; Lassaletta, J. M. Angew. Chem. Int. Ed. 2011,
50, 11724; (k) Teraoka, T.; Hiroto, S.; Shinokubo, H. Org. Lett. 2011, 13, 2532; (l)
Cheng, J. H.; Yi, C. L.; Liu, T. J.; Lee, C. F. Chem. Commun. 2012, 48, 8440; (m)
Crawford, A. G.; Liu, Z. Q.; Mkhalid, I. A. I.; Thibault, M. H.; Schwarz, N.; Alcaraz, G.;
Steffen, A.; Collings, J. C.; Batsanov, A. S.; Howard, J. A. K.; Marder, T. B. Chem. Eur.
J. 2012, 18, 5022; (n) Eliseeva, M. N.; Scott, L. T. J. Am. Chem. Soc. 2012, 134, 15169;
(o) Hartwig, J. F. Acc. Chem. Res. 2012, 45, 864; (p) Hitosugi, S.; Nakamura, Y.;
Matsuno, T.; Nakanishi, W.; Isobe, H. Tetrahedron Lett. 2012, 53, 1180; (q) Hume, P.;
Furkert, D. P.; Brimble, M. A. Tetrahedron Lett. 2012, 53, 3771; (r) Liskey, C. W.;
Hartwig, J. F. J. Am. Chem. Soc. 2012, 134, 12422; (s) Liu, T. F.; Shao, X. X.; Wu, Y.
M.; Shen, Q. L. Angew. Chem. Int. Ed. 2012, 51, 540; (t) Ohmura, T.; Torigoe, T.;
Suginome, M. J. Am. Chem. Soc. 2012, 134, 17416; (u) Robbins, D. W.; Hartwig, J. F.
Org. Lett. 2012, 14, 4266; (v) Roering, A. J.; Hale, L. V. A.; Squier, P. A.; Ringgold, M.
A.; Wiederspan, E. R.; Clark, T. B. Org. Lett. 2012, 14, 3558; (w) Roosen, P. C.;
Kallepalli, V. A.; Chattopadhyay, B.; Singleton, D. A.; Maleczka, R. E., Jr.; Smith, M.
R., III J. Am. Chem. Soc. 2012, 134, 11350; (x) Ros, A.; Lopez-Rodriguez, R.; Estepa,
B.; Alvarez, E.; Fernandez, R.; Lassaletta, J. M. J. Am. Chem. Soc. 2012, 134, 4573; (y)
Wang, C.; Sperry, J. J. Org. Chem. 2012, 77, 2584. (z) Lopez-Rodríguez, R.; Ros, A.;
Fernandez, R.; Lassaletta, J. M. J. Org. Chem. 2012, 77, 9915.
3) Ishiyama, T.; Takagi, J.; Hartwig, J. F.; Miyaura, N. Angew. Chem. Int. Ed. 2002, 41,
3056.
4) Kikuchi, T.; Takagi, J.; Isou, H.; Ishiyama, T.; Miyaura, N. Chem Asian J 2008, 3, 208290.
5) Boller, T. M.; Murphy, J. M.; Hapke, M.; Ishiyama, T.; Miyaura, N.; Hartwig, J. F. J Am
Chem Soc 2005, 127, 14263-78.
6) Mestroni, G.; Camus, A.; Zassinovich, G. J. Organomet. Chem. 1974, 73, 119.
59

7) Filipuzzi, S.; Farnetti, E. J. Mol. Catal. A: Chem. 2005, 238, 111.
8) Liskey, C. W.; Wei, C. S.; Pahls, D. R.; Hartwig, J. F. Chem Commun 2009, 5603-5605.
9) Vanchura, B. A., II; Preshlock, S. M.; Roosen, P. C.; Kallepalli, V. A.; Staples, R. J.;
Maleczka, R. E., Jr; Smith, M. R., III Chem. Commun. 2010, 46, 7724.
10) Iwadate, N.; Suginome, M. J Organomet Chem 2009, 694, 1713-1717.
11) Vanchura, B. A., II Ph. D. Thesis, Mich. State University, 2010.
12) The electron-donating ability of dipyridyl (dpy) ligands to transition metals can be
estimated from relative ʋCO frequencies in dpy metal carbonyl complexes or by
evaluating their effects on redoxpotentials in dpy complexes. From the average ʋCO
2+/3+
frequencies in (dpy)Cr(CO)4 complexes(refs 13a and d) and E° values for Ru
in
2+

Ru(dpy)3 compounds (refs 13b and c), the electron-donor ability increases in the order
dtbpy < tmphen ≪ dmabpy.
13) (a) Connor, J. A.; Overton, C. J. Organomet. Chem. 1983, 249, 165. (b) Leidner, C. R.;
Murray, R. W. J. Am. Chem. Soc. 1984, 106, 1606. (c) Nazeeruddin, M. K.; Zakeeruddin,
S. M.; Kalyanasundaram, K. J. Phys. Chem. 1993, 97, 9607. (d) Johnson, R.; Madhani,
H.; Bullock, J. P. Inorg. Chim. Acta 2007, 360, 3414.

60

CHAPTER 3
CHELATE DIRECTED C-H BORYLATIONS

Figure 3.1. Ester directed C-H borylation.

Ester directed C-H borylation.
As mentioned in Chapter 1, the regioselectivities of products formed from Ir catalyzed CH borylation of arenes are primarily controlled by steric effects. We have seen examples in
Chapter 1 were substantial electronic effects can influence regioselectivity and in Chapter 4 we
will discuss outer sphere directing effects. There have been several examples where borylation
occurs ortho to a carbonyl via inner sphere chelate directed C-H borylation. In 2008, Miyaura
reported the ortho-borylation of a number methyl benzoates using the catalyst system
F

1

[Ir(OMe)COD]2 with 4 equivalents of P(3,5-bis(CF3)2-C6H3)3 (PAr 3) ligand (Figure 3.1).

More recently, silica-supported mono(phosphine)-Ir systems have been shown to give similar
selectivities with various benzoate derivatives and even great selectivity for borylation ortho to
2

chlorine in chlorobenzene. The selectivity of the silica-supported chemistry is believed to occur
61

-

as a result of the silica-supported SMAP ligands ability to generate 14 e intermediates. It is of
significant note that HBPin was ineffective for catalysis in both cases. Sawamura has since
extended the silica-supported phosphine chemistry to ortho directed phenol surrogates utilizing
3

HBPin as borylating reagent and primary and secondary bonds in 2-substituted alkyl pyridines.

4

F

Figure 3.2. Cis and Trans-(Ar 3P)2Ir(BPin)3.

F

Synthesis of Discrete 5 Coordinate (Ar 3P)2Ir(BPin)3 Trisboryl Complex
5

Using the procedure first reported by Smith and coworkers, we attempted to isolate Ir
1

complexes relevant to the ester directed C-H borylation reported by Miyaura. Attempts to

62

F

6

isolate (Ar 3P)2Ir(BPin)3 in the reaction between (η -C6Me3H3)Ir(BPin)3 and two equivalents
F

of PAr 3 , the 6 electron arene ligand is displaced to give two products in a 2 : 1 ratio believed to
F

F

be cis-(Ar 3P)2Ir(BPin)3 (9a) and trans-(Ar 3P)2Ir(BPin)3 (9b), (Figure 3.2).

F

Figure 3.3. Trans-(Ar 3P)2Ir(BPin)3 (9b). The following are 50% thermal ellipsoidal drawings
of the molecule in the asymmetric cell with various amount of labeling.

63

A crystal structure of the 9b isomer was obtained by recrystallization from THF / pentane
at -35 °C (Figure 3.3). The structure of 9b is of note as being the first and only known example
of a metal complex containing trans boryl ligands. The trans boryl geometry is generally
disfavored due to strong ligand-to-metal σ-donation for metal boryl ligands. It is generally
excepted that for complexes of the type M-B(OR)2 the metal(d)-to-ligand(p) π-back-bonding is
relatively weak compared to the π-interaction between B atom and its diol substituents (pinacol
in the case of BPin complexes). The σ-donor strength of the boryl ligands is extremely potent
due to boron being even more electropositive than carbon and causes it to have a strong trans
6

F

influence. Ultimately, the trans-(Ar 3P)2Ir(BPin)3 geometry of 9b is most likely the result of
F

F

the large steric bulk of the two (PAr 3) ligands, while the structure of the cis-(Ar 3P)2Ir(BPin)3)
isomer 9a would be the electronically favored product.
1

The proposed structures of the two isomers were supported by integration from H and
31

F

P NMR. Addition of excess PAr 3 ligand did not perturb the isomer ratio and no coordination
F

F

of a third PAr 3 ligand to form a (Ar 3P)3Ir(BPin)3 species was observed most likely due to the
F

PAr 3 ligand’s steric bulk. Variable temperature

31

P NMR demonstrated that the major isomer

F

had two inequivalent PAr 3 ligands at lower temperatures, broadening into the baseline at 0 °C
to -20 °C and sharpening considerably at -80 °C (Figure 3.4). The single peak observed at room
temperature suggests that at ambient temperature the phosphine ligands undergo rapid exchange
on the NMR time scale. At higher temperatures (55 °C) the signal sharpens substantially.

64

Unfortunately the complex undergoes decomposition at higher temperatures after prolonged
heating.

Figure 3.4. Variable temperature

31

F

P NMR of Cis and Trans-(Ar 3P)2Ir(BPin)3.

Multiple attempts to crystallize the major isomer have so far proven futile and it appears
that the complex may only crystallize as 9b. Behnaz Ghaffari has shown that samples dissolved
at low temperature are of the single isomer 9b and that they equilibrate over time.

65

F

Mechanistic Insights into (Ar 3P)2Ir(BPin)3 Catalytic Cycle

Having isolated and identified the

31

P NMR resonances of the cis and trans-

F

(Ar 3P)2Ir(BPin)3 mixture, we varified that these catalysts were formed using the standard
F

catalytic conditions. Indeed, heating a mixture of [Ir(OMe)COD]2 with 4 equivalents of PAr 3
F

ligand in the presence of 4 equivalents of B2Pin2 formed the cis and trans-(Ar 3P)2Ir(BPin)3
mixture as the major products, confirming that the complexes were present during catalysis.
F

Figure 3.5. Ester coordination to (Ar 3P)2Ir(BPin)3 complex.

We next attempted to determine which of the isomers was responsible for ester directed
F

C-H borylation. Dissolving (Ar 3P)2Ir(BPin)3 in THFd8 with 10 equivalents methyl benzoate
F

(10a) did not produce any observable reaction and no free PAr 3 ligand was observed in

31

P

NMR at room temperature. We hypothesize that initial ester coordination to the iridium catalyst
is the source of the ester directing effect (Figure 3.5). The fact that the resulting intermediate is
not observed, suggests ester coordination may be the rate limiting step. However, such
experiments have not been done to rule out phosphine dissociation. An NMR tube experiment
F

F

with (Ar 3P)2Ir(BPin)3 and 10 equivalents of tetrahydrothiophene (THT) did produce free PAr 3
66

ligand and a new phosphine iridium species at 4 ppm in

31

P NMR in a 1 : 1 ratio. After 30 min,

the major isomer 9a had disappeared while 9b remained, suggesting the former was the reactive
species. After 24h the reaction mixture had gone completely to the new species at 4 ppm and free
F

PAr 3 suggesting 9b reacts at a much slower rate than 9a or 9a must first undergo isomerization
to the active isomer and then reacts.
Figure 3.6. Stiochiometric borylation of methyl 3-(trifluoromethyl)benzoate (11a).

F

Reacting (Ar 3P)2Ir(BPin)3 directly with methyl 3-(trifluoromethyl)benzoate (11a) at 65
°C for 45 min in THFd8 led to the formation of methyl 2-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)-5-(trifluoromethyl)benzoate (11b) in 70% yield (Figure 3.6).

31

P NMR

showed two major phosphorous containing compounds, which accounted for a combined 80% of
the products formed from the stoichiometric borylation of 11a. Crystals obtained from the
F

reaction mixture gave the X-Ray structure for a trans-(Ar 3P)2Ir(H)(BPin)2 (12) complex
(Figure 3.7) which was in agreement with a minor product with the chemical formula Ir(H)BPin2
and had a

31

P resonance at 33 ppm and pinacol resonances at 0.47 and 0.25 ppm and hydride

peak at -7.95 ppm (t, J = 18.6 Hz, 1H).

67

F

Figure 3.7. Trans-(Ar 3P)2Ir(H)(BPin)2 (12). The following are 50% thermal ellipsoidal
drawings of the molecule in the asymmetric cell with various amount of labeling.

68

F

Figure 3.8. Borylation of methyl benzoate (10a) with excess (Ar 3P)2Ir(BPin)3.

F

Reacting (Ar 3P)2Ir(BPin)3 directly with 0.33 equivalents of methyl benzoate (10a) at
room temperature for 15 min in THFd8 led to the formation of methyl 2-(4,4,5,5-tetramethyl1,3,2-dioxaborolan-2-yl)benzoate (10b) (Figure 3.8).

31

P NMR showed the formation of three

new phosphorous containing compounds, which corresponded to three hydride peaks observed in
1

the H NMR. A 1H-31P gHMQC experperiment determined there was a coorelation between the
31

P resonances at 21.6 ppm and a hydride peak at -8.29 ppm (d, J = 10.0 Hz). This compound
F

was the major product formed from reaction of (Ar 3P)2Ir(BPin)3 and 10a. A second correlation
between

31

P resonances at 26.4 ppm and a hydride resonance at -6.55 ppm (dd, J = 141.8, 24

Hz) was identified. This compound was the second most abundant product formed, the major
was present in a 2:1 ratio with respect to this species and the hydride without a 1H-31P gHMQC
correlation was present in a 1:0.7 ratio. The

31

P resonances at 25.8 ppm and a hydride resonance

at -8.49 ppm showed no evidence of coupling in the 1H-31P gHMQC, but there integarations
relative to the other

31

P resonances and hydride resonances were roughly equivalent, so there is a

possibility they belong to the same species. It should also be noted that none of these were major
species observed in the experiment depicted in Figure 3.6.
69

F

Figure 3.9. Trans-(Ar 3P)2Ir(H2BPin)(BPin)2 (13).

With the aid and hard work of Behnaz Ghaffari we were able to obtain an X-Ray crystal
F

structure of a trans-(Ar 3P)2Ir(H2BPin)(BPin)2 (13) complex (Figure 3.9) formed from the
F

reaction of (Ar 3P)2Ir(BPin)3 with 11a in THF. This compound was independently synthesized
F

from (Ar 3P)2Ir(BPin)3 and HBPin in nearly quantitative yields with mild heating. This structure
had a single

31

P NMR resonance at 16 ppm and pinacol resonances at 0.62 (s, 12H), 0.54 (br s,
1

24H) and a hydride resonance at -7.00 ppm (br s, 2H) in the H NMR which were identical to a
F

species formed during the stoichiometric reaction of (Ar 3P)2Ir(BPin)3 and 11a.

A putative catalytic cycle is shown in Figure 3.10 for the chelate directed borylation of
F

aryl esters with (Ar 3P)2Ir(BPin)3 based on the results from our previous experiments. Initially,
F

the methyl benzoate coordinates to 9a via its carbonyl. This is proceeded by PAr 3 ligand
dissociation and directed oxidative addition or sigma bond metathesis of an ortho C-H bond,
ligand rearrangement and subsequent reductive elimination to give a TS 4 complex. Ligand
F

displacement by a PAr 3 ligand could lead to complex 12 we obtained an X-Ray crystal structure
F

for. This intermediate could react with B2Pin2 to regenerate the (Ar 3P)2Ir(BPin)3 active catalyst
or react with HBPin to form the 13 complex.
70

F

Figure 3.10. Proposed catalytic cycle for the chelate directed borylation of aryl esters with (Ar 3P)2Ir(BPin)3.

71

Table 3.1. Borane effects on ortho-directed borylation of 10a.

entry

equiv HBpin

equiv B2Pin2

ortho (%)

bis (%)

1

1.0

0.0

0

0

2

1.0

1.0

7

0

3

0.0

1.0

55

8

4

0.0

2.0

56

21

A series of experiments was done to determine the effect borane had on the reactivity of
F

these (Ar 3P)2Ir(BPin)3 catalysts. Table 3.1 shows that there were no borylation products
formed when HBPin was used as borylating reagent and that HBPin had a deleterious effect
when B2Pin2 was used as borylatign reagent (entries 2 and 4). These results corroborated what
was presented in the initial report by Miyaura

1b

and suggest the 13 complex is a thermodynamic

sink, although further experimentation has not been done to confirm this.

72

Figure 3.11. Designing more reactive Iridium catalysts.

It was identified early in the development of iridium catalyzed C-H borylation chemistry
that more electron rich ligands generate catalysts that are more reactive than catalysts containing
electron deficient ligands (Figure 3.11). An early example which illustrates this well is the
comparison of catalysts derived from [Ir(OMe)COD]2 and 4,4’di-chloro-2,2’bipydine which
7

show far lower reactivity than catalysts utilizing dtbpy and [Ir(OMe)COD]2. Steric hindrance
can also effect a catalysts reactivity as has been demonstrated with the isolated five-coordinate
iridium trisboryl complexes, (dippe)Ir(BPin)3 and (dtbpe)Ir(BPin)3 were dtbpe is (1,2-bis(di-tertbutylphosphino)ethane. A comparison of the stoichiometric borylation of 2-methylthiophene
occurred much faster with (dippe)Ir(BPin)3 than with (dtbpe)Ir(BPin)3 due to the decrease in
steric hindrance of the phosphine ligands .

8

73

Changing the ancillary boryl ligands proved to have a tremendous effect on the the
reactivity of the similar iridium catalysts (dtbpy)Ir(BPin)3(COE) and (dtbpy)Ir(BCat*)3(COE)
were BCat* is 4-tert-butylcatecholboryl.

9

Comparisons of the reactivity of those catalyst

complexes with benzene highlight the effect the structural changes have on reactivity, with the
former reacting at room temperature to produce three equivalents of PhBPin and the latter being
stable for several hours at room temperature in a benzene solution. Additionally, the carbonyl
analogues were prepared, (dtbpy)Ir(BPin)3(CO) and (dtbpy)Ir(BCat*)3(CO), and the ƲCO value
corresponding to the CO stretch was 30 wavenumbers greater for the tris-BCat* complex than
that for the tris-BPin complex.

Figure 3.12. Synthesis of silylboranes.

Given that the trend of increasing electron density at the iridium center leads to catalysts
that are more active towards C-H borylation reactions and silyl ligands are calculated to have
6

even stronger σ-donor abilities than boryl ligands, we sought to design ligands that would
incorporate Si-Ir into the catalyst system. The Hartwig group has reported the synthesis of mixed
R3SiBPin complexes from the reaction of various R3SiH and B2Pin2 (Figure 3.12)

74

10

meaning

reductive elimination of Si-B compounds could be a potential decomposition pathway.
i

Interestingly, when the bulky Pr3SiH are used no silylboranes form. In addition, HBPin did not
yield any silylboranes while identical reactions with B2Pin2 would produce the corresponding
silylboranes.

Figure 3.13. Silyl-directed ortho borylation of alkylamines.

The Hartwig group was then able to do silyl-directed borylations using silated phenols,
arylamines, alkylamines

11,12

and N-H containing heterocycles.

13

In these reactions, the silyl

group would serve as a chelating ligand to direct the C-H borylation and then undergo reductive
elimination and regenerate the Si-H bond (Figure 3.13). The facile reductive elimination of the
ArEt2Si-H bond by iridium proved useful for catalytic reactions because it allowed for catalytic
turnovers. Without such reversibility, the iridium catalyst would become saturated with silyl
ligands or it would require additional equivalents of B2Pin2 to generate ArEt2Si-BPin.

75

Figure 3.14. N-(dimethylsilyl)-N,N-bis(2-pyridyl)amine (14b).

In our initial attempt to create silyl chelate ligands, we synthesized a N-(dimethylsilyl)N,N-bis(2-pyridyl)-amine (14b) from di(2-pyridyl)amine (14a) and dimethylchlorosilane (Figure
3.14). We chose 14b as a target because dipyridine ligands are among the most reactive ligands
for iridium catalyzed C-H borylation reactions. We also speculated that the two chelating pyridal
ligands would maintain Si-Ir coordination by preventing ligand disassociation since Si-H bond
breaking and formation has proven reversible. We also concluded the Me2Si(H)Cl was an
appropriate silane because excessive steric balk impedes catalytic reactivity.
2

Figure 3.15. Synthesis of Ir(κ -SiNpy2)3

76

8

Work by a co-researcher, Behnaz Ghaffari, showed the 14b ligand reacted with
2

(MesH)Ir(BPin)3 to form a coordinately saturated Ir(κ -SiNpy2)3 complex (Figure 3.15).
Catalytic reactions with 14b and [Ir(OMe)COD]2 showed poor reactivity as well.

Figure 3.16. Synthesis of SiPbz ligands.

Realizing our first attempt at silyl ligands failed because of the dual calamities of being
too sterically small, enabling multiple ligands to bond to the iridium center, and the ligands
having an unconstrained backbone, allowing the tridentate 14b to bind as a bidentate ligand. Our
next generation of silyl ligands focused on a structural motif that would have a bulky p-Tolyl2P
i

and Pr2Si- coordination sites and a constrained benzene backbone (Figure 3.16). The (2(diisopropylsilyl)phenyl)di-p-tolylphosphane (SiPbz) ligand could be made in two steps from
commercially available starting materials and its synthesis (as well as that for the 14b ligand)
allowed for a platform that could be applied to analogues.

77

Table 3.2. Ligand effects on ortho-directed borylation of methyl benzoate (10a).

entry

ligand

equiv HBpin

equiv B2Pin2

ortho (%)

bis (%)

1

PAr 3

1.0

0.0

0

0

2

P(C6F5)3

1.0

0.0

0

0

3

AsPh3

1.0

0.0

0

0

4

SbPh3

1.0

0.0

0

0

5

P(OCH(CF3)2)3

1.0

0.0

0

0

6

tppp

1.0

0.0

0

0

7

P(odtbz)3

1.0

0.0

0

0

8

Me-Verkade

1.0

0.0

0

0

9

SiPBz

1.0

0.0

40 + 27*

0

F

a

* 13% meta isomer and 14% para isomer. a5 mol% ligand used.
Ligand Key for Table 3.2.

78

Table 3.3. Borane effects on ortho-directed borylation of methyl benzoate (10a).

entry

ligand

equiv HBpin

equiv B2Pin2

ortho (%)

bis (%)

1

PAr 3

1.0

1.0

7

0

2

PAr 3

0.0

1.0

55

8

3

P(C6F5)3

1.0

1.0

24

0

4

P(C6F5)3

0.0

1.0

43

4

5

AsPh3

1.0

1.0

6

0

6

AsPh3

0.0

1.0

26

0

7

SbPh3

1.0

1.0

0

0

8

SbPh3

0.0

1.0

0

0

9

P(OCH(CF3)2)3

1.0

1.0

7

0

10

P(OCH(CF3)2)3

0.0

1.0

30

3

11

tppp

1.0

1.0

0

0

12

tppp

0.0

1.0

0

0

13

P(odtbz)3

1.0

1.0

0

0

14

P(odtbz)3

0.0

1.0

45

11

15

Me-Verkade

1.0

1.0

0

0

F
F

79

Table 3.3 (cont’d)
16

Me-Verkade

17

SiPBz

18

SiPBz

0.0

0

1.0

45

55

0.0

a

0

1.0

a

1.0

1.0

58

42

a

5 mol% ligand used.

An initial reaction screen (Table 3.2) with 10a showed that the SiPbz ligand out
preformed the best ligands reported in the literature for ester directed C-H borylation with
1

homogenous iridium catalysts. It was also the least susceptible to the deleterious effects of
HBPin and was the only ligand screened that produced product with HBPin as borane source.
F

When reactions run with PAr 3 and P(C6F5)3 and 1 equivalent B2Pin2 respectable amounts of
10b were produced (Table 3.3, entry 2 and entry 4 respectively). However, when reactions were
run under identical conditions with 1 equivalent HBPin and 1 equivalent B2Pin2 (Table 3.3,
entries 1 and 3) the yields of borylated products dropped substantially. This trend was also seen
with AsPh3 and the phosphite ligands P(OCH(CF3)2)3 and P(odtbz)3.
SiPbz and 14b silyl ligands represent a novel approach to designing more reactive
iridium catalysts for C-H borylation reactions. Both offer frame works that can be easily
modified to optimize the sterics and donor ability of future analogues. I believe these silyl
ligands will offer exciting new reactivity for future homogeneous iridium catalyzed C-H
borylation reactions.

80

REFERENCES

81

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Kikuchi, T.; Miyaura, N. Chem. Commun. 2010, 46, 159.
2) (a) Kawamorita, S.; Ohmiya, H.; Hara, K.; Fukuoka, A.; Sawamura, M. J. Am. Chem.
Soc. 2009, 131, 5058; (b) Kawamorita, S.; Ohmiya, H.; Sawamura, M. J. Org. Chem.
2010, 75, 3855.
3) Yamazaki, K.; Kawamorita, S.; Ohmiya, H.; Sawamura, M. Org. Lett. 2010, 12, 3978.
4) Kawamorita, S.; Murakami, R.; Iwai, T.; Sawamura, M. J. Am. Chem. Soc. 2013, 135,
2947.
5) Chotana, G. C.; Vanchura, B. A., II; Tse, M. K.; Staples, R. J.; Maleczka, R. E., Jr;
Smith, M. R., III Chem. Commun., 2009, 5731.
6) Dang, L.; Lin, Z.; Marder, T. B. Chem. Commun. 2009, 3987.
7) Ishiyama, T.; Takagi, J.; Hartwig, J. F.; Miyaura, N. Angew. Chem. Int. Ed. 2002, 41,
3056.
8) Chotana, G. C.; Vanchura, B. A., II; Tse, M. K.; Staples, R. J.; Maleczka, R. E., Jr;
Smith, M. R., III Chem. Commun., 2009, 5731.
9) Liskey, C. W.; Wei, C. S.; Pahls, D. R.; Hartwig, J., F. Chem. Commun., 2009, 5603.
10) Boebel, T. B.; Hartwig, J. F. Organometallics, 2008, 27, 6013.
11) Boebel, T. B.; Hartwig, J. F. J. Am. Chem. Soc. 2008, 130, 7534.
12) Cho, S. H.; Hartwig, J. F. J. Am. Chem. Soc. 2013, 135, Ahead of Print.
13) Robins, D. A.; Boebel, T. B.; Hartwig, J. F. J. Am. Chem. Soc. 2010, 132, 4068.

82

CHAPTER 4
BPIN AS A TRACELESS DIRECTING GROUP FOR C-H BORYLATIONS

Traceless BPin protected borylation of heterocycles.
It has been demonstrated that tert-butoxycarbonyl (Boc) protected heterocycles such as
pyrroles and indoles

1

can lead to different borylated regioisomers than their respective
2

unprotected counterparts when subjugated to Ir-catalyzed C-H borylation conditions. Figure 4.1
shows that Ir-catalyzed C-H borylation with indole gives the 2-borylated regioisomer. However,
NBoc protected indole gives the 3-borylated regioisomer due to the steric bulk of the Boc
protecting group when exposed to similar Ir catalyzed C-H borylation conditions.
Figure 4.1. Borylation of indole.

We envisioned a protocol that would allow for the in-situ protection of heterocycles with
HBPin. The strategy of using N-BPin as a directing group has the advantage of N-BPin bonds
being extremely easy to hydrolyze and therefore remove. Unfortunately, pyrrole and indole do
83

not react with HBPin to give N-borylation despite the reaction being thermodynamically favored.
i

We hypothesized that the addition of a base such as NEt3 or NEt Pr2 would make the HBPin
sufficiently hydridic for such a reaction to occur. Indeed, the use of Lewis bases to enhance the
hydride transfer character of HBPin for the reduction of imines has recently been reported.

3

Using this strategy, we were able to do a one pot in-situ protection/ borylation/ deprotection on
indole and pyrrole giving the same regiochemistry as the Boc protected compounds (Figure 4.2).
It should be noted that borenium cations give the regioselective product by electrophilic arene
borylation, however, such chemistry is incompatible with unprotected heteroarenes.

4

Figure 4.2. Base assisted protection of heterocycles with HBPin.

When a basic functionality is inherent in the heterocyclic substrate, no additional base is
needed and we observed a spontaneous reaction between HBPin and an array of heterocycles
including pyrazole, 4-azaindole and 7-azaindoles. It should also be noted that the pKas are lower
for pyrozole and azaindoles relative to pyrrole and indole. Application of Ir-catalyzed C-H
84

borylation conditions gave products identical to those observed with NBoc protected analogues
(Figure 4.3). It is noteworthy that for the diborylation of 7-azaindole, that in-situ NBPin
protection occurred with B2Pin2.

Figure 4.3. In-situ protection of heterocycles with HBPin.

A comparison of isolated yields of borylated products produced via the traceless BPin
directing group versus those obtained through NBoc direction/deprotection from reference 2
highlights the efficiency that the traceless BPin directing group provides. Let it be noted that the
Boc yields were calculated based on N-Boc protected heterocycles, therefore yields from the
85

parent heterocycles would be lower for the Boc-directed route. As shown in Figure 4.4, traceless
BPin direction offers a distinct advantage, not only in minimizing purification/isolation steps, but
also in improving isolated yields of borylated parent heterocycles. For example, the greater than
30% improvement of borylated 17 is found when the traceless route is employed. The case for
azaindoles is even more striking as the traceless direction provides 18a and 19 in good yield,
whereas the parent compounds are inaccessible via the Boc-directed route because extensive
decomposition to unidentified products occurred during attempted thermal deprotection.
Figure 4.4. Comparison of Boc and traceless directed borylation of heterocycles.

86

Application of BPin as traceless protecting group with primary anilines.
It has recently been shown that N-Boc anilines undergo an outer-sphere directed ortho5

borylation. Theory and experiment support a mechanism where the selectivity results from
transition state stabilization attributed to a hydrogen bonding interaction between the aniline N-H
and a BPin oxygen (Figure 4.5A). In principle, unsubstituted anilines could engage in this
reaction through a transition state shown as Figure 4.5B or through an N-BPin protected aniline
created from the reaction of HBPin and aniline shown as Figure 4.5C.

Figure 4.5. Outer-sphere ortho directed iridium catalyzed C-H borylation of aniline.

NMR experiments were conducted to determine what species are present in reaction
mixtures containing HBPin and 3-(trifluoromethyl)aniline (20a). Vigorous bubbling occurs when
HBPin is added to a solution containing 20a.

1

H,

11

B and

19

F NMR indicate that a

monoborylated N-BPin-3-(trifluoromethyl)aniline (20b) forms when 20a is treated with excess
HBPin (Figure 4.6). No N,N-bis(BPin)-3-(trifluoromethyl)aniline was observed indicating outersphere ortho directed C-H borylation was feasible in which a polarized N-H bond is needed to
function as the directing group. The requirement of only one additional equivalent of HBPin to
serve as a traceless directing group enhances the atom economy of this methodology. Addition of
87

Figure 4.6. Synthesis of N-BPin-3-(trifluoromethyl)aniline (20b).

Ir catalyst and additional HBPin produced a mixture of ortho and meta borylated products in a
2:1 ratio when heated at 80°C (Figure 4.7). It should be pointed out that no N,N-bis(BPin)-3(trifluoromethyl)aniline compounds were observed even after prolonged heating. The N-BPin
bonds formed in-situ could be easily hydrolyzed with MeOH during work up without
degradation of C-BPin bonds formed during catalysis. The net reaction provides a simple one pot
procedure where the directing group is installed in-situ and subsequently removed upon work up
without requiring any extra steps or isolation.
Figure 4.7. Ortho borylation of N-BPin-3-(trifluoromethyl)aniline (20b).

Considering that the reaction is believed to rely on H-bonding between the N-H hydrogen
on the substrate and the oxygen of the Ir-boryl ligand (Figure 4.8) this reaction should not be
applicable for secondary anilines. This was indeed found to be true when Ir-catalyzed C-H
borylation reaction conditions were applied to 3-chloro-N-mehtylaniline (21a) only the N-

88

methyl-3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)-benzenamine meta product was
observed (21b Figure 4.9).
Figure 4.8. Proposed Reaction Mechanism.

Figure 4.9. Borylation of 3-chloro-N-methylaniline (21a).

Optimization.
Solvent, borane and ligand effects were screened in an attempt to optimize
regioselectivity and reactivity for the borylation of 3-chloroaniline (22a) (Tables 4.1 & 4.2). The
general trends that can be drawn from the reaction screen are that as solvent polarity increases
from cyclohexane to Hünig’s Base to THF to NMP the ortho directing effect decreases and more
of the meta products are formed. Secondly, higher concentrations of B2Pin2 give more meta
borylated products. This can be significantly blunted by addition of HBPin. Lastly, the more
electron rich tmphen ligand gives more ortho directed products in agreement with our

89

Table 4.1. Borane and Solvent Effects on Borylation of 3-chloroaniline (22a) with tmphen.

entry

solvent.

equiv borane
1.1 B2Pin2

yield
(%)
79

meta
(%)
23

ortho
(%)
51

diboryl
(%)
5

meta : ortho +
diborylated
1.0 : 2.4

1

Cyclohexane

2

Hünig’s Base

1.1 B2Pin2

71

25

45

1

1.0 : 1.8

3

THF

1.1 B2Pin2

77

32

35

10

1.0 : 1.4

4

NMP

1.1 B2Pin2

24

16

8

1

1.8 : 1.0

5

Cyclohexane

2.2 B2Pin2

99

38

29

32

1.0 : 1.6

6

Hünig’s Base

2.2 B2Pin2

99

50

32

18

1.0 : 1.0

7

THF

2.2 B2Pin2

99

58

21

21

1.4 : 1.0

8

NMP

2.2 B2Pin2

74

45

22

8

1.5 : 1.0

9

Cyclohexane

1.1 B2Pin2 + 1.1 HBPin

99

26

39

34

1.0 : 2.8

10

Hünig’s Base

1.1 B2Pin2 + 1.1 HBPin

99

27

40

31

1.0 : 2.6

11

THF

1.1 B2Pin2 + 1.1 HBPin

99

43

31

25

1.0 : 1.3

12

NMP

1.1 B2Pin2 + 1.1 HBPin

96

56

31

8

1.4 : 1.0

90

Table 4.2. Borane and Solvent Effects on Borylation of 3-chloroaniline (22a) with dtbpy.

entry

solvent.

equiv borane

yield
(%)

meta
(%)

ortho
(%)

diboryl
(%)

meta : ortho +
diborylated

1

Cyclohexane

1.1 B2Pin2

58

27

31

0

1.0 ; 1.2

2

Hünig’s Base

1.1 B2Pin2

34

16

18

0

1.0 : 1.1

3

THF

1.1 B2Pin2

67

43

23

1

1.8 : 1.0

4

NMP

1.1 B2Pin2

38

27

11

0

2.6 : 1.0

5

Cyclohexane

2.2 B2Pin2

99

65

31

3

2.0 : 1.0

6

Hünig’s Base

2.2 B2Pin2

99

65

33

2

1.9 : 1.0

7

THF

2.2 B2Pin2

99

71

18

10

2.5 : 1.0

8

NMP

2.2 B2Pin2

84

65

17

2

3.3 : 1.0

9

Cyclohexane

1.1 B2Pin2 + 1.1 HBPin

74

37

36

1

1.0 : 1.0

10

Hünig’s Base

1.1 B2Pin2 + 1.1 HBPin

71

33

39

0

1.0 : 1.2

11

THF

1.1 B2Pin2 + 1.1 HBPin

95

57

36

2

1.5 : 1.0

12

NMP

1.1 B2Pin2 + 1.1 HBPin

77

56

19

2

2.6 : 1.0

91

hypothesized mechanism that increasing the Lewis basicity of the oxygen on the boryl ligand
should promote the ortho directing effect.

Solvent Effects on Regioselectivity.
The decreased directing effect in polar solvents can be attributed to suppression of Hbonding between the aniline and the Ir catalyst which proceeds formation of the ortho directed
products. The rate of formation of the meta isomer would not be as susceptible to the change in
solvent polarity, therefore you would see a relative increase in the meta : ortho product ratio.

Table 4.3. Solvent Screen for 3-(trifluoromethyl)anilines (20a).

entry

solvent

yield (%)

meta (%)

ortho (%)

meta : ortho

1

Sulfolane

0

--

--

NA

2

NMP

89

62

27

2.3 : 1.0

6

DMA

36

26

10

2.6 : 1.0

92

Further attempts to push the meta selectivity in 3-substituted anilines utilizing solvents
with even greater dielectric constants met with little success. Table 4.3 shows the results of
several experiments carried out on the Ir catalyzed C-H borylation of 20a in solvents with high
dielectric constants (ɛ); sulfolane (43), NMP (33) and DMA (38). While DMA did give greater
regioselectivity for the meta borylation isomer then NMP, there was a significant drop in yield.
Other solvents with high dielectric constants (ɛ), DMSO (47) and DMF (37), were precluded
because previous studies showed they are largely incompatible with Ir catalyzed C-H borylation
chemistry (see chapter 2).

Ligand Effects on Regioselectivity.
The origin of the ligand effects on selectivity was also observed with the outer-sphere
5

directed borylation of N-Boc protected primary anilines. It was postulated that the basicity on
the pinacolate oxygens with more electron-rich ligands attached to the iridium, you favor a
stronger NH-O H-bond (Figure 4.5A), which would favor ortho borylated products. Several
experiments run on 20a with various ligands (Table 4.4) support what had been seen with the NBoc directed borylation report. The more electron donating the ancillary ligands became, the
greater the ortho : meta ratio became. The most electron donating ligand screened, dmadpy
(4,4’-bis(dimethylamino)-2,2’-bipyridine), gave the greatest ortho : meta

selectivity. The

unsubstitued phen (1,10-phenanthroline) ligand showed the lowest ortho : meta selectivity. The
diimine type ligands diim (2,3,5,6,8,9-hexahydrodiimidazo[1,2-a:2',1'-c]pyrazine) and box
(4,4',5,5'-tetrahydro-2,2'-bioxazole) ligands showed poor ortho : meta
however the reaction yields were far lower than all other ligands screened.

93

selectivity as well,

Table 4.4. Ligand effects on borylation of 3-(trifluoromethyl)anilines (20a).

entry

ligand

yield (%)

meta (%)

ortho (%)

meta : ortho

1

dtbpy

80

38

42

1.0 : 1.1

2

dmabpy

86

33

53

1.0 : 1.6

3

phen

73

42

30

1.4 : 1.0

4

tmphen

86

36

50

1.0 : 1.4

5

diim

17

8

8

1.0 : 1.0

6

box

10

4

6

1.0 : 1.5

Ligand Key for Table 4.4.

94

Table 4.5. Traceless BPin protected borylation of anilines.

a

1

8% 2-borylated isomer observed by H NMR.

b

c

4.0 equivalents HBPin used. Conditions: 1.5

mol% [Ir(OMe)COD]2, 3.0 mol% dmabpy with 2.0 equivalents HBPin in n-hexane as reaction
d
solvent. Conditions: 2.5 mol% [Ir(OMe)COD]2, 5.0 mol% tmphen.

95

Applications.
This methodology was then applied to a number of 4-substituted anilines (Table 4.5). 4substituted halo anilines provide ortho borylated products in excellent isolated yields. 2borylated products were obtained with 4-chloroaniline, 4-bromoaniline, 4-bromo-5-chloroaniline
and 4-(trifluoromethyl)aniline in 93%, 88%, 92%, and 91% isolated yields respectively.
Purification and isolation of the unprotected aniline products was achieved by passing the crude
material through a short plug of SiO2 and crystallization from a MeOH/ H2O solution. 4methoxy-2-BPin-benzamine (24) and 5-chloro-4-methoxy-2-BPin-benzamine (27) were isolated
in a similar fashion albeit in lower yields (63% and 74% respectively).
Aminophenols required an additional equivalent of HBPin to undergo O-BPin protection
in addition to N-BPin protection. Isolation of analytically pure 4-amino-3-BPin-phenol (32) and
4-amino-2-chloro-5-BPin-phenol (33) products was achieved by crystallization from DCM/
hexanes in 70% and 63% isolated yields respectively.
When the para-substituent was of low steric bulk, as in 4-amino benzonitrile, standard
conditions led to the diborylated products 4-amino-2,5-bisBPin-benzonitrile (30). By altering
the reaction conditions and using the more electron donating ligand dmabpy, less polar hexanes
as solvent and 2.0 equivalents of HBPin, the monoborylated 4-amino-3-BPin-benzonitrile (34)
could be isolated in 83% yield. The same procedure was used to obtain 4-fluoro-2-BPin1

benzamine in 74% isolated yield (35). H and

19

F NMR of the crude reaction mixture showed 35 in

a 12.5: 1.0 ratio with 4-fluoro-3-BPin-benzamine.

96

Although borylation of 4-aminobenzonitrile with less equivalents of HBPin gave small
amounts of bisborylated products, excellent selectivity could be achieved for 4-amino-2substituted benzonitriles. The borylation of 4-amino-2-chloro-5-BPin-benzonitrile was achieved
using standard conditions in 90% isolated yield with no observable amount of borylation
occurring ortho to the cyano functionality. Similarly, borylation ortho to a fluoro substituent was
a nonfactor when the fluoro substituent was meta to the amino group in a 4-chloro-3fluoroaniline. 4-chloro-5-fluoro-2-BPin-benzamine (31) was isolated in 90% yield with only
trace amounts of the 4-chloro-3-fluoro-2-BPin-benzamine using standard conditions.
The borylation of 3-substituted anilines led to mixtures of ortho and meta products. The
ratio of ortho and meta products is largely dependent on nature of the 3-substituent with electron
withdrawing substituents such as chloro or trifluoromethyl giving 22c to 22b and 20f to 20e in a
2: 1 ratio from the respective anilines. However, electron donating substituents such as a
methoxy group in the meta position gave a product ratio of 5-methoxy-2-BPin-aniline (36a) to 3methoxy-5-BPin-aniline (36b) of 1.0: 1.4 in favor of the meta isomer.
Figure 4.10. Borylation of o-anisidine.

Unfortunately 2-substituted anilines did not give ortho directing borylation products.
Nevertheless, borylation of o-anisidine gave the 2-methoxy-4-BPin-benzenamine (37) isomer
with surprisingly high regioselectivity (Figure 4.10). The reason for a lack of directing effect in
97

2-sustituted aniline is most likely the result of steric repulsion between the ortho substituent and
NBPin protecting group (Figure 4.11). The regioselectivity of the 2-methoxy-4-BPin1

benzenamine over the 2-methoxy-5-BPin-benzenamine (<5% observed in crude H NMR) was
surprising and most likely is the result of electronic effects, albeit non-obvious ones.

Figure 4.11. Putative transition state for ortho-borylation of 2-substituted anilines.

Borylation of Aminopyridines.
Attempts to borylate aminopyridines were unsuccessful for aminopyridines with an
unhindered pyridine N atom. Indeed no products were observed in reactions with 2aminopyriinde, 3-aminopyridine or 4-aminopyridine. Pyridines with substitution ortho to the
pyridine N did however prove themselves to be compatible with our borylation conditions.
Indeed 6-chloropyridin-3-amine and 6-methylpyridin-3-amine and 2-chloropyridin-4-amine and
2-methoxypyridin-4-amine gave ortho directed borylation products in moderate to good yields
(Figure 4.12). Identical reaction conditions applied to 6-chloropyridin-2-amine and 6(trifluoromethyl)pyridin-2-amine gave only the sterically determined borylation products. The
rationale for this is competing coordination of the H-NBPin with the pyridine N ortho in the 298

1

aminopyridines. H NMR of 6-(trifluoromethyl)pyridine-2-amine and 1.5 equivalents of HBPin
showed only mono NHBPin borylated pyridin-2-amine and no N(BPin)2 protected pyridine-2amine.

Figure 4.12. Traceless BPin protected borylation of amino pyridines.

99

REFERENCES

100

REFERENCES
1) Kallepalli, V. A.; Shi, F.; Paul, S.; Onyeozili, E. N.; Maleczka, R. E., Jr.; Smith, M. R.,
III J. Org. Chem. 2009, 74, 9199.
2) Takagi, J.; Sato, J.; Hartwig, J. F.; Ishiyama, T.; Miyaura, N. Tetrahedron Lett. 2002, 43, 5649.
3) Eisenberger, P; Bailey, A. M.; Crudden, C. M. J. Am. Chem. Soc. 2012, 134, 17384.
4) Bagutski, V.; Del Grosso, A.; Carrillo, J. A.; Cade, I. A.; Helm, M. D.; Lawson, J. R.; Singleton,
P. J.; Solomon, S. A.; Marcelli, T.; Ingleson, M. J. J. Am. Chem. Soc. 2013, 135, 474.

5) Roosen, P. C.; Kallepalli, V. A.; Chattopadhyay, B.; Singleton, D. A.; Maleczka, R. E.,
Jr.; Smith, M. R., III J. Am. Chem. Soc. 2012, 134, 11350.

101

CHAPTER 5
EXPERIMENTAL

General Methods.
All reactions were conducted in a nitrogen filled glove-box. THF was distilled from sodium
benzophenone solutions. All other solvents were used as received from Sigma-Aldrich
(Sure/SealTM) and were stored in the glove-box. All other commercially available materials were
used as received. 1H and

13

C NMR spectra were recorded on a Varian Inova-300 (300.11 and

75.47 MHz respectively), Varian VXR-500 or Varian Unity-500-Plus spectrometer (499.74 and
125.67 MHz respectively) and referenced to residual solvent signals.

11

B spectra were recorded

on Varian VXR-500 or Varian Inova-300 operating at 160.41 and 96.29 MHz respectively, and
were referenced to neat BF3·Et2O as the external standard. Elemental analyses were performed at
Michigan State University using a Perkin Elmer Series II 2400 CHNS/O Analyzer. Melting
points were measured on a MEL-TEMP® capillary melting apparatus and are uncorrected.

Stoichiometric borylation of veratrole with (dippe)Ir(BPin)3
(dippe)Ir(BPin)3 (20 mg, 0.024 mmol, 1 equiv) was weighed into a small vial. Veratrole (24.5
µL, 0.19 mmol, 8 equiv) was added to the vial via microliter syringe. Cyclohexane (2.4 mL) was
added to the vial and the solution was divided four J. Young NMR tubes (600 µL per tube). The
tubes were heated in an oil bath at 100 °C and monitored by GC. After 15 min, 0.20 equiv of
veratrole were converted to the 4- and 3-substituted boronic esters in a ratio greater than 99:1.

102

Borylation of veratrole (1) with catalysts generated in situ from (Ind)Ir(COD) and dippe
(Ind)Ir(COD) (2.0 mg, 0.005 mmol, 0.02 equiv) was weighed in a test tube and was transferred
to a J. Young NMR tube using C6H12 (100 μL × 4). A standard solution of dippe (13.2 mg, 0.05
mmol, 0.2 equiv) in C6H12 (500 μL) was prepared in a small vial. A 50 µL portion of this
solution was then transferred to the J. Young NMR tube (0.02 equiv dippe). Veratrole (255 μL,
2.0 mmol, 8 equiv) and HBPin (36 μL, 0.25 mmol, 1 equiv) were syringed into the J. Young
NMR tube, which was then was capped and heated in an oil bath at 130 °C. After 4 h, GC
analysis showed that 0.26 equiv. of veratrole were converted to the 4- and 3-substituted boronic
esters in a 98:2 ratio.

Stoichiometric borylation of veratrole (1) with (dtbpy)Ir(BPin)3COE

(dtbpy)Ir(BPin)3COE (30 mg, 0.0315 mmol, 1 equiv) was weighed in a test tube and was
dissolved in C6D12 (300 μL). Veratrole (34.8 mg, 0.252 mmol, 8 equiv) was weighed in a test
tube and mixed with the solution containing (dtbpy)Ir(BPin)3COE. The mixture was then
transferred via pipette into a J. Young NMR tube. The J. Young NMR tube was capped and the
1

reaction was monitored by H NMR. The reaction was quenched at 1h (19 % conversion by
NMR) with wet EtOAc and the product ratios were determined by GC/FID (99:1 4-isomer to 3isomer.)

103

Catalytic borylation of veratrole (1) with (dtbpy)Ir(BPin)3COE

(dtbpy)Ir(BPin)3COE (19 mg, 0.02 mmol) was weighed in a test tube and was dissolved in
C6H12 (2 mL) in a 20 mL scintillation vial containing a magnetic stir bar. 145 μL HBPin (1
mmol, 1 equiv) was added to the solution via syringe. Veratrole (127 μL, 1 mmol, 1 equiv) was
added via syringe to the mixture and the vial was loosely sealed. Reaction was quenched at 9h
with wet EtOAc and product ratios determined by GC/FID (98:2 4-isomer to 3-isomer at 26%
conversion.)

Stoichiometric borylation of 1,3-benzodioxole (2) with (dippe)Ir(BPin)3
(dippe)Ir(BPin)3 (20 mg, 0.024 mmol, 1 equiv) was weighed into a small vial. 1,3-benzodioxole
(22.1 µL, 0.19 mmol, 8 equiv) was added to the vial via microliter syringe. Cyclohexane (2.4
mL) was added to the vial and the solution was divided four J. Young NMR tubes (600 µL per
tube). The tubes were heated in an oil bath at 100 °C and monitored by GC. After 15 min, 1.3
equiv of 1,3-benzodioxole were converted to the 5- and 4-substituted boronic esters in a 2:98
ratio.

104

Catalytic Borylation of 1,3-benzodioxole (2) with (dippe)Ir(BPin)3
(dippe)Ir(BPin)3 (4.2 mg, 0.005 mmol, 0.02 equiv) was weighed in a test tube and was
transferred to a J. Young NMR tube using C6H12 (100 μL × 4). 1,3-benzodioxole (230 μL, 2.0
mmol, 8 equiv) and HBPin (36 μL, 0.25 mmol, 1 equiv) were syringed into the J. Young NMR
tube, which was then was capped and heated in an oil bath at 130 °C. After 4 h, GC analysis
showed that 0.34 equiv. of 1,3-benzodioxole were converted to the 5- and 4-substituted boronic
esters in a 4:96 ratio.

Stoichiometric borylation of 1,3-benzodioxole (2) with (dtbpy)Ir(BPin)3COE

(dtbpy)Ir(BPin)3COE (30 mg, 0.0315 mmol, 1 equiv) was weighed in a test tube and was
dissolved in C6D12 (300 μL). 1,3-benzodioxole (30.8 mg, 0.252 mmol, 8 equiv) was weighed in
a test tube and mixed with the solution containing (dtbpy)Ir(BPin)3COE. The mixture was then
transferred via pipette into a J. Young NMR tube. The J. Young NMR tube was capped and the
1

reaction was monitored by H NMR. The reaction was quenched at 15 min at room temperature
(51 % conversion by NMR) with wet EtOAc and the product ratios were determined by GC/FID
(95:5 4-isomer to 5-isomer.)

105

Catalytic borylation of 1,3-benzodioxole (2) with (dtbpy)Ir(BPin)3COE

(dtbpy)Ir(BPin)3COE (19 mg, 0.02 mmol) was weighed in a test tube and was dissolved in
C6H12 (2 mL) in a 20 mL scintillation vial containing a magnetic stir bar. 145 μL HBPin (1
mmol, 1 equiv) was added to the solution via syringe. 1,3-benzodioxole (122 mg, 1 mmol, 1
equiv) was added to the mixture and the vial was loosely sealed. Reaction was quenched at 1h
with wet EtOAc and product ratios determined by GC/FID (91:3 4-isomer to 5-isomer with 6%
diborylation at 30% conversion.)

General Procedures for Screening Iridium Catalyzed C-H Borylation Conditions with
Varying Ligands, Iridium Precatalyst, Borane and Order of Addition.
All reactions were conducted in a nitrogen filled glove-box. THF and MeTHF were distilled
from sodium benzophenone solutions. All other solvents were used as received from SigmaAldrich (Sure/Seal

TM

) and were stored in the glove-box. All other commercially available

materials were used as received. Reactions for high through-put screening were conducted in 8 ×
30 mm borosilicate glass shell vials arranged in 96 well metal blocks (Symyx) with magnetic
stirring. Materials were dispensed to the vials whenever possible as solutions in the reaction
solvent, otherwise in suitable solvents (in which the material was soluble in) via micro pippetters
followed by evaporation of the solvent in vacuuo in a Genevac

TM

centrifugal evaporator in the

glove box. The reactions were heated via the metal 96 well blocks after sealing with a
106

perfluoroelastomeric backed metal top plate screwed to the metal block. Analysis was
accomplished by reversed phase HPLC (Zorbax Eclipse Plus C18, 1.8 micron, 4.6 × 50 mm
column eluted with 0.1% aq H3PO4 and acetonitrile) using an internal standard such as
dodecahydrotriphenylene to facilitate quantitative HPLC solution assay yield determination.

General Procedure for Microscale Reactions Utilizing Conditions A.
In a nitrogen filled glovebox, 50 μL of solution containing 0.5 μmol iridium precatalyst dimer
(0.01 M stock solution) or 1.0 μmol iridium monomer (0.02 M stock solution) in the reaction
solvent was added to a 1 mL reaction vial containing a magnetic stir bar. To this solution, 50 μL
of stock solution containing 30 μmol HBPin (0.6 M) or 15 μmol B2Pin2 (0.3 M) was added to
the 1 mL reaction vial. 50 μL of a solution containing 1.0 μmol ligand (0.02 M) was added via
micropipette followed by 50 μL of a stock solution containing 20 μmol arylsubstrate (0.4 M) and
2 μmol dodecahydrotripheneylene internal standard. The reaction vessel was then sealed and the
reaction mixture stirred at the desired temperature for an allotted amount of time, at which point
the reaction was cooled to room temperature and quenched by exposure to atmospheric O2 and
dilution with MeCN.

107

General Procedure for Microscale Reactions Utilizing Conditions B.
In a nitrogen filled glovebox, 50 μL of a solution containing 0.5 μmol iridium precatalyst dimer
(0.01 M stock solution) or 1.0 μmol iridium monomer (0.02 M stock solution) in the reaction
solvent was added to a 1 mL reaction vial containing a magnetic stir bar. To this solution, 50 μL
of stock solution containing 1.0 μmol ligand (0.02 M was added to the 1 mL reaction vial. 50 μL
of a solution containing 30 μmol HBPin (0.6 M) or 15 μmol B2Pin2 (0.3 M) was added via micro
pipette followed by 50 μL of stock solution containing 20 μmol arylsubstrate (0.4 M) and 2 μmol
dodecahydrotripheneylene internal standard. The reaction vessel was then sealed and stirred at
the desired temperature for an allotted amount of time, at which point the reaction was cooled to
room temperature and quenched by exposure to atmospheric O2 and dilution with MeCN.

Room Temperature Reaction Screen on 3-bromotoluene (3a).

The 96 reactor wells consist of 1mL glass vials equipped with a micro-magnetic stir bar arrayed
in a 12x8 reaction plate, 12 columns labeled 1-12 and 8 rows labeled A-H. In a nitrogen filled
glove box, 0.01 M stock solutions of [Ir(COD)Cl]2 in THF and [Ir(OMe)COD]2 in THF and 0.02
M stick solutions of (Ind)Ir(COD) in THF and Ir(acac)COD in THF were prepared. 50 μL of
[Ir(OMe)COD]2 (0.5 μmol) stock solution were added to each well across rows A and E (wells
108

A1-A12 and E1-E12) via micro pipette. 50 μL of [Ir(COD)Cl]2 (0.5 μmol) stock solution were
added to each well across rows B and F (wells B1-B12 and F1-F12) via micro pipette. 50 μL of
Ir(acac)COD (1.0 μmol) stock solution were added to each well across rows C and G (wells C1C12 and G1-G12) via micro pipette. 50 μL of (Ind) Ir(COD) (1.0 μmol) stock solution were
added to each well across rows D and H (wells D1-D12 and H1-H12) via micro pipette. 50 μL of
a 0.02 M stock solution of dtbpy (1.0 μmol) in THF was added down columns 7 and 10 (wells
A7-H7 and A10-H10) via micro pipette. 50 μL of a 0.02 M stock solution of tmphen (1.0 μmol)
in THF was added down columns 8 and 11 (wells A8-H8 and A11-H11) via micro pipette. 50 μL
of a 0.02 M stock solution of box (1.0 μmol) in THF was added down columns 9 and 12 (wells
A9-H9 and A12-H12) via micro pipette. 50 μL of a 0.6 M stock solution of HBPin (30 μmol) in
THF was added across rows A, B, C, and D (wells A1-D12) via micro pipette. 50 μL of a 0.3 M
stock solution of B2Pin2 (15 μmol) in THF was added across rows E, F, G, and H (wells E1H12) via micro pipette. The reaction plate was then capped and stirred for 5 min at room
temperature resulting in catalyst generation under Conditions B for wells A7-H12. 50 μL of a
0.02 M stock solution of dtbpy (1.0 μmol) in THF was added down columns 1 and 4 (wells A1H1 and A4-H4) via micro pipette. 50 μL of a 0.02 M stock solution of tmphen (1.0 μmol) in THF
was added down columns 2 and 5 (wells A2-H2 and A5-H5) via micro pipette. 50 μL of a 0.02
M stock solution of box (1.0 μmol) in THF was added down columns 3 and 6 (wells A3-H3 and
A6-H6) via micro pipette, resulting in catalyst generation under Conditions A for wells A7-H12.
Finally,

50

μL

of

a

0.4

M

stock

solution

of

3-bromotoluene

containing

dodecahydrotripheneylene internal standard (0.04 M) was added to all 96 wells via micro pipette
and the reaction plate was sealed and stirred for 4h at room temperature. The reaction was then
quenched by exposure to air and dilution with MeCN.
109

Elevated Temperature Reaction Screen on N,N-dimethyl-m-toluidine (5a).

The 96 reactor wells consist of 1mL glass vials equipped with a micro-magnetic stir bar arrayed
in a 12x8 reaction plate, 12 columns labeled 1-12 and 8 rows labeled A-H. In a nitrogen filled
glove box, 0.01 M stock solutions of [Ir(COD)Cl]2 in THF and [Ir(OMe)COD]2 in THF and 0.02
M stick solutions of (Ind)Ir(COD) in THF and Ir(acac)COD in THF were prepared. 50 μL of
[Ir(OMe)COD]2 (0.5 μmol) stock solution were added to each well across rows A and E (wells
A1-A12 and E1-E12) via micro pipette. 50 μL of [Ir(COD)Cl]2 (0.5 μmol) stock solution were
added to each well across rows B and F (wells B1-B12 and F1-F12) via micro pipette. 50 μL of
Ir(acac)COD (1.0 μmol) stock solution were added to each well across rows C and G (wells C1C12 and G1-G12) via micro pipette. 50 μL of (Ind) Ir(COD) (1.0 μmol) stock solution were
added to each well across rows D and H (wells D1-D12 and H1-H12) via micro pipette. 50 μL of
a 0.02 M stock solution of dtbpy (1.0 μmol) in THF was added down columns 7 and 10 (wells
A7-H7 and A10-H10) via micro pipette. 50 μL of a 0.02 M stock solution of tmphen (1.0 μmol)
in THF was added down columns 8 and 11 (wells A8-H8 and A11-H11) via micro pipette. 50 μL
of a 0.02 M stock solution of box (1.0 μmol) in THF was added down columns 9 and 12 (wells
A9-H9 and A12-H12) via micro pipette. 50 μL of a 0.6 M stock solution of HBPin (30 μmol) in
THF was added across rows A, B, C, and D (wells A1-D12) via micro pipette. 50 μL of a 0.3 M
stock solution of B2Pin2 (15 μmol) in THF was added across rows E, F, G, and H (wells E1-

110

H12) via micro pipette. The reaction plate was then capped and stirred for 5 min at room
temperature resulting in catalyst generation under Conditions B for wells A7-H12. 50 μL of a
0.02 M stock solution of dtbpy (1.0 μmol) in THF was added down columns 1 and 4 (wells A1H1 and A4-H4) via micro pipette. 50 μL of a 0.02 M stock solution of tmphen (1.0 μmol) in THF
was added down columns 2 and 5 (wells A2-H2 and A5-H5) via micro pipette. 50 μL of a 0.02
M stock solution of box (1.0 μmol) in THF was added down columns 3 and 6 (wells A3-H3 and
A6-H6) via micro pipette, resulting in catalyst generation under Conditions A for wells A7-H12.
Finally, 50 μL of a 0.4 M stock solution of N,N-dimethyl-m-toluidine (20 μmol) in THF,
containing dodecahydrotripheneylene internal standard (0.04 M, 2.0 μmol), was added to all 96
wells via micro pipette and the reaction plate was sealed and stirred for 8h at 80 °C. The reaction
was then quenched by exposure to air and dilution with MeCN.

General Procedure for Borylation of 1,2,3-trimethoxybenzene (4a).

In a nitrogen filled glovebox, 500 μL of solution containing 5.0 μmol of [Ir(OMe)COD] 2 (0.01
M stock solution) in THF was added to a 8 mL scintillation vial containing a magnetic stir bar.
To this solution, 500 μL of stock solution containing 10.0 μmol ligand (0.02 M) in THF was
added to the 8 mL scintillation vial. 500 μL of solution containing 300 μmol HBPin (0.6 M) in
THF or 150 μmol B2Pin2 (0.3 M) in THF was added via micro pipette followed by 500 μL of
111

stock solution containing 200 μmol arylsubstrate (0.4 M) in THF and 20 μmol
dodecahydrotripheneylene internal standard. The reaction vessel was then sealed and stirred at
the desired temperature for 2.5h, at which point the reaction was cooled to room temperature and
quenched by exposure to atmospheric O2 and dilution with MeCN.

Solvent Effects on Catalyst Formation at Room Temperature (3a).

The 96 reactor wells consist of 1mL glass vials equipped with a micro-magnetic stir bar arrayed
in a 12x8 reaction plate, 12 columns labeled 1-12 and 8 rows labeled A-H. In a nitrogen filled
glove box, 0.01 M stock solutions of [Ir(OMe)COD]2 in THF and 0.02 M stick solutions of
(dtbpy)Ir(BPin)3COE in THF and (tmphen)Ir(BPin)3COE in THF were prepared. 50 μL of
[Ir(OMe)COD]2 (0.5 μmol) stock solution were added to each well across rows A, C, E and G
(wells A1-A12, C1-C12, E1-E12 and G1-G12) via micro pipette. 50 μL of (dtbpy)Ir(BPin)3COE
(1.0 μmol) stock solution were added to each well across rows B and F (wells B1-B12 and F1F12) via micro pipette. 50 μL of (tmphen)Ir(BPin)3COE (1.0 μmol) stock solution were added to
each well across rows D and H (wells D1-D12 and H1-H12) via micro pipette. 50 μL of a 0.02 M
stock solution of dtbpy (1.0 μmol) in THF was added to each well across rows A and E (wells
A1-A12 and E1-E12) via micro pipette. 50 μL of a 0.02 M stock solution of tmphen (1.0 μmol)

112

in THF was to each well across rows C and G (wells C1-C12 and G1-G12) via micro pipette.
Volatile solvent were removed under reduced pressure. 100 μL of a 0.3 M stock solution of
HBPin (30 μmol) in THF was added down column 1 (wells A1 through H1) via micro pipette.
100 μL of a 0.3 M stock solution of HBPin (30 μmol) in MeTHF was added down column 2
(wells A2-H2) via micro pipette. 100 μL of a 0.3 M stock solution of HBPin (30 μmol) in Cpme
was added down column 3 (wells A3-H3) via micro pipette. 100 μL of a 0.3 M stock solution of
HBPin (30 μmol) in MTBE was added down column 4 (wells A4-H4) via micro pipette. 100 μL
of a 0.3 M stock solution of HBPin (30 μmol) in hexanes was added down column 5 (wells A5H5) via micro pipette. 100 μL of a 0.3 M stock solution of HBPin (30 μmol) in Hünig’s base was
added down column 6 (wells A6-H6) via micro pipette. 100 μL of a 0.3 M stock solution of
HBPin (30 μmol) in NEt3 was added down column 7 (wells A7-H7) via micro pipette. 100 μL of
a 0.3 M stock solution of HBPin (30 μmol) in NMP was added down column 8 (wells A8-H8)
via micro pipette. 100 μL of a 0.3 M stock solution of HBPin (30 μmol) in IPAc was added down
column 9 (wells A9-H9) via micro pipette. 100 μL of a 0.3 M stock solution of HBPin (30 μmol)
in 1,4-dioxane was added down column 10 (wells A10-H10) via micro pipette. 100 μL of a 0.3
M stock solution of HBPin (30 μmol) in DCM was added down column 11 (wells A11-H11) via
micro pipette. 100 μL of a 0.3 M stock solution of HBPin (30 μmol) in MeCN was added down
column 12 (wells A12-H12) via micro pipette. 100 μL of a 0.2 M stock solution of 3bromotoluene (20 μmol) with 2.0 μmol dodecahydrotriphenylene internal standard in THF was
added down column 1 (wells A1 through H1) via micro pipette. 100 μL of a 0.2 M stock solution
of 3-bromotoluene (20 μmol) with 2.0 μmol dodecahydrotriphenylene internal standard in
MeTHF was added down column 2 (wells A2-H2) via micro pipette. 100 μL of 0.2 M stock
solution of 3-bromotoluene (20 μmol) with 2.0 μmol dodecahydrotriphenylene internal standard
113

in Cpme was added down column 3 (wells A3-H3) via micro pipette. 100 μL of a 0.2 M stock
solution of 3-bromotoluene (20 μmol) with 2.0 μmol dodecahydrotriphenylene internal standard
in MTBE was added down column 4 (wells A4-H4) via micro pipette. 100 μL of 0.2 M stock
solution of 3-bromotoluene (20 μmol) with 2.0 μmol dodecahydrotriphenylene internal standard
in hexanes was added down column 5 (wells A5-H5) via micro pipette. 100 μL of a 0.2 M stock
solution of 3-bromotoluene (20 μmol) with 2.0 μmol dodecahydrotriphenylene internal standard
in Hünig’s base was added down column 6 (wells A6-H6) via micro pipette. 100 μL of a 0.2 M
stock solution of 3-bromotoluene (20 μmol) with 2.0 μmol dodecahydrotriphenylene internal
standard in NEt3 was added down column 7 (wells A7-H7) via micro pipette. 100 μL of a 0.2 M
stock solution of 3-bromotoluene (20 μmol) with 2.0 μmol dodecahydrotriphenylene internal
standard in NMP was added down column 8 (wells A8-H8) via micro pipette. 100 μL of a 0.2 M
stock solution of 3-bromotoluene (20 μmol) with 2.0 μmol dodecahydrotriphenylene internal
standard in IPAc was added down column 9 (wells A9-H9) via micro pipette. 100 μL of a 0.2 M
stock solution of 3-bromotoluene (20 μmol) with 2.0 μmol dodecahydrotriphenylene internal
standard in 1,4-dioxane was added down column 10 (wells A10-H10) via micro pipette. 100 μL
of a 0.2 M stock solution of 3-bromotoluene (20 μmol) with 2.0 μmol dodecahydrotriphenylene
internal standard in DCM was added down column 11 (wells A11-H11) via micro pipette. 100
μL of

a 0.2 M

stock solution

of 3-bromotoluene (20 μmol) with

2.0 μmol

dodecahydrotriphenylene internal standard in MeCN was added down column 12 (wells A12H12) via micro pipette. The reaction plate was then sealed and stirred for 4h at room
temperature. The reaction was then quenched by exposure to air and dilution with MeCN.

114

Solvent Effects on Catalyst Formation at Elevated Temperature (6a).

The 96 reactor wells consist of 1mL glass vials equipped with a micro-magnetic stir bar arrayed
in a 12x8 reaction plate, 12 columns labeled 1-12 and 8 rows labeled A-H. In a nitrogen filled
glove box, 0.01 M stock solutions of [Ir(OMe)COD]2 in THF and 0.02 M stick solutions of
(dtbpy)Ir(BPin)3COE in THF and (tmphen)Ir(BPin)3COE in THF were prepared. 50 μL of
[Ir(OMe)COD]2 (0.5 μmol) stock solution were added to each well across rows A, C, E and G
(wells A1-A6, C1-C6, E1-E6 and G1-G6) via micro pipette. 50 μL of (dtbpy)Ir(BPin)3COE (1.0
μmol) stock solution were added to each well across rows B and F (wells B1-B6 and F1-F6) via
micro pipette. 50 μL of (tmphen)Ir(BPin)3COE (1.0 μmol) stock solution were added to each
well across rows D and H (wells D1-D6 and H1-H6) via micro pipette. 50 μL of a 0.02 M stock
solution of dtbpy (1.0 μmol) in THF was added to each well across rows A and E (wells A1-A6
and E1-E6) via micro pipette. 50 μL of a 0.02 M stock solution of tmphen (1.0 μmol) in THF
was to each well across rows C and G (wells C1-C6 and G1-G6) via micro pipette. Volatile
solvent were removed under reduced pressure. 100 μL of a 0.3 M stock solution of HBPin (30
μmol) in THF was added down column 1 (wells A1 through H1) via micro pipette. 100 μL of a
0.3 M stock solution of HBPin (30 μmol) in hexanes was added down column 2 (wells A2-H2)
via micro pipette. 100 μL of a 0.3 M stock solution of HBPin (30 μmol) in Hünig’s base was
added down column 3 (wells A3-H3) via micro pipette. 100 μL of a 0.3 M stock solution of

115

HBPin (30 μmol) in NMP was added down column 4 (wells A4-H4) via micro pipette. 100 μL of
a 0.3 M stock solution of HBPin (30 μmol) in IPAc was added down column 5 (wells A5-H5)
via micro pipette. 100 μL of a 0.3 M stock solution of HBPin (30 μmol) in MeCN was added
down column 6 (wells A6-H6) via micro pipette. 100 μL of a 0.2 M stock solution of N,Ndimethyl-m-toluidine (20 μmol) with 2.0 μmol dodecahydrotriphenylene internal standard in
THF was added down column 1 (wells A1 through H1) via micro pipette. 100 μL of a 0.2 M
stock solution of N,N-dimethyl-m-toluidine (20 μmol) with 2.0 μmol dodecahydrotriphenylene
internal standard in hexanes was added down column 2 (wells A2-H2) via micro pipette. 100 μL
of 0.2 M stock solution of N,N-dimethyl-m-toluidine (20 μmol) with 2.0 μmol
dodecahydrotriphenylene internal standard in Hünig’s base was added down column 3 (wells
A3-H3) via micro pipette. 100 μL of a 0.2 M stock solution of N,N-dimethyl-m-toluidine (20
μmol) with 2.0 μmol dodecahydrotriphenylene internal standard in NMP was added down
column 4 (wells A4-H4) via micro pipette. 100 μL of 0.2 M stock solution of N,N-dimethyl-mtoluidine (20 μmol) with 2.0 μmol dodecahydrotriphenylene internal standard in IPAc was added
down column 5 (wells A5-H5) via micro pipette. 100 μL of a 0.2 M stock solution of N,Ndimethyl-m-toluidine (20 μmol) with 2.0 μmol dodecahydrotriphenylene internal standard in
MeCN was added down column 6 (wells A6-H6) via micro pipette. The reaction plate was then
sealed and stirred for 8h at 80 °C. The reaction was then quenched by exposure to air and
dilution with MeCN.

116

Extended Solvent Screen at Room Temperature.
In a nitrogen filled glovebox, 16.6 mg [Ir(OMe)COD]2 (2.5 μmol, 2.5 mol%) and 13.3 mg 4,4'di-tert-butyl-2,2'-bipyridine (5.0 μmol, 5.0 mol%) was dissolved in 1 mL reaction solvent in a 15
mL pressure tube containing a magnetic stir bar. 1.5 equiv HBPin (1.5 mmol, 218 μL), 1.0 equiv
3-bromotoluene (1.0 mol, 121 μL) and 0.1 equiv dodecahydrotripheneylene (0.1 mmol, 24 mg)
internal standard were added to the reaction vessel. The reaction vessel was then sealed and
allowed to stir at room temp for 4h, at which point the reaction was cooled to room temperature
and the reaction mixture quenched by exposure to atmospheric O2. Volitiles were removed under
1

reduced pressure and product yields were determined by H NMR in CDCl3 with respect to
dodecahydrotripheneylene internal standard. For DMSO as solvent, 0% product was observed.
For DMF as solvent, 4% product was observed.

Elevated Temperature Reaction Screen Preformed on N,N-dimethyltoluidine (5a) in
Multiple Solvents.

The 96 reactor wells consist of 1mL glass vials equipped with a micro-magnetic stir bar arrayed
in a 12x8 reaction plate, 12 columns labeled 1-12 and 8 rows labeled A-H. In a nitrogen filled

117

glove box, 0.01 M stock solutions of [Ir(COD)Cl]2 in THF and [Ir(OMe)COD]2 in THF and 0.02
M stick solutions of (Ind)Ir(COD) in THF and Ir(acac)COD in THF were prepared. 50 μL of
[Ir(OMe)COD]2 (0.5 μmol) stock solution were added to wells across rows A and E (wells A1A2, A7-A8 and E1-E2, E7-E8) via micro pipette. 50 μL of [Ir(COD)Cl]2 (0.5 μmol) stock
solution were added to wells across rows B and F (wells B1-B2, B7-B8 and F1-F2, F7-F8) via
micro pipette. 50 μL of Ir(acac)COD (1.0 μmol) stock solution were added to wells across rows
C and G (wells C1-C2, C7-C8 and G1-G2, G7-G8) via micro pipette. 50 μL of (Ind) Ir(COD)
(1.0 μmol) stock solution were added to wells across rows D and H (wells D1-D2, D7-D8 and
H1-H2, H7-H8) via micro pipette. 0.01 M stock solutions of [Ir(COD)Cl]2 in hexanes and
[Ir(OMe)COD]2 in hexanes and 0.02 M stick solutions of (Ind)Ir(COD) in hexanes and
Ir(acac)COD in hexanes were prepared. 50 μL of [Ir(OMe)COD]2 (0.5 μmol) stock solution
were added to wells across rows A and E (wells A3-A4, A9-A10 and E3-E4, E9-E10) via micro
pipette. 50 μL of [Ir(COD)Cl]2 (0.5 μmol) stock solution were added to wells across rows B and
F (wells B3-B4, B9-B10 and F3-F4, F9-F10) via micro pipette. 50 μL of Ir(acac)COD (1.0
μmol) stock solution were added to wells across rows C and G (wells C3-C4, C9-C10 and G3G4, G9-G10) via micro pipette. 50 μL of (Ind) Ir(COD) (1.0 μmol) stock solution were added to
wells across rows D and H (wells D3-D4, D9-D10 and H3-H4, H9-H10) via micro pipette. 0.01
M stock solutions of [Ir(COD)Cl]2 in Hünig’s base and [Ir(OMe)COD]2 in Hünig’s base and
0.02 M stick solutions of (Ind)Ir(COD) in Hünig’s base and Ir(acac)COD in Hünig’s base were
prepared. 50 μL of [Ir(OMe)COD]2 (0.5 μmol) stock solution were added to wells across rows A

118

and E (wells A5-A6, A11-A12 and E5-E6, E11-E12) via micro pipette. 50 μL of [Ir(COD)Cl]2
(0.5 μmol) stock solution were added to wells across rows B and (wells B5-B6, B11-B12 and F5F6, F11-F12) via micro pipette. 50 μL of Ir(acac)COD (1.0 μmol) stock solution were added to
wells across rows C and G (wells C5-C6, C11-C12 and G5-G6, G11-G12) via micro pipette. 50
μL of (Ind) Ir(COD) (1.0 μmol) stock solution were added to wells across rows D and H (wells
D5-D6, D11-D12 and H5-H6, H11-H12) via micro pipette. 50 μL of a 0.02 M stock solution of
dtbpy (1.0 μmol) in THF was added down columns 1 and 7 (wells A1-H1 and A7-H7) via micro
pipette. 50 μL of a 0.02 M stock solution of tmphen (1.0 μmol) in THF was added down
columns 2 and 8 (wells A2-H2 and A8-H8) via micro pipette. 50 μL of a 0.02 M stock solution
of dtbpy (1.0 μmol) in hexanes was added down columns 3 and 9 (wells A3-H3 and A9-H9) via
micro pipette. 50 μL of a 0.02 M stock solution of tmphen (1.0 μmol) in hexanes was added
down columns 4 and 10 (wells A4-H4 and A10-H10) via micro pipette. 50 μL of a 0.02 M stock
solution of dtbpy (1.0 μmol) in Hünig’s base was added down columns 5 and 11 (wells A5-H5
and A11-H11) via micro pipette. 50 μL of a 0.02 M stock solution of tmphen (1.0 μmol) in
Hünig’s base was added down columns 6 and 12 (wells A6-H6 and A12-H12) via micro pipette.
50 μL of a 0.6 M stock solution of HBPin (30 μmol) in THF was added to wells A1-D2 and A7D8 via micro pipette. 50 μL of a 0.3 M stock solution of B2Pin2 (15 μmol) in THF was added to
wells E1-H2 and E7-H8 via micro pipette. 50 μL of a 0.6 M stock solution of HBPin (30 μmol)
in hexanes was added to wells A3-D4 and A9-D10 via micro pipette. 50 μL of a 0.3 M stock
solution of B2Pin2 (15 μmol) in hexanes was added to wells E3-H4 and E9-H10 via micro
pipette. 50 μL of a 0.6 M stock solution of HBPin (30 μmol) in Hünig’s base was added across to
wells A5-D6 and A11-D12 via micro pipette. 50 μL of a 0.3 M stock solution of B2Pin2 (15

119

μmol) in Hünig’s base was added to wells E5-H6 and E11-H12 via micro pipette. The reaction
plate was then capped and stirred for 5 min at room temperature resulting in catalyst generation
under Conditions B. Finally, 50 μL of a 0.4 M stock solution of N,N-dimethyl-m-toluidine (20
μmol) in THF, containing dodecahydrotripheneylene internal standard (0.04 M, 2.0 μmol), was
added to wells A1-H2 and A7-H8 via micro pipette. 50 μL of a 0.4 M stock solution of N,Ndimethyl-m-toluidine (20 μmol) in hexanes, containing dodecahydrotripheneylene internal
standard (0.04 M, 2.0 μmol), was added to wells A3-H4 and A9-H10 via micro pipette. 50 μL of
a 0.4 M stock solution of N,N-dimethyl-m-toluidine (20 μmol) in Hünig’s base, containing
dodecahydrotripheneylene internal standard (0.04 M, 2.0 μmol), was added to wells A5-H6 and
A11-H12 via micro pipette and the reaction plate was sealed and stirred for 8h at 80 °C. The
reaction was then quenched by exposure to air and dilution with MeCN.

Temperature Effect on Catalyst Stability
In a nitrogen filled glovebox, 16.6 mg [Ir(OMe)COD]2 (2.5 μmol, 2.5 mol%) and 5.0 μmol
dtbpy, tmphen or dppbz, (5.0 mol%) of ligand was dissolved in 1 mL Cpme in a 15 mL pressure
tube containing a magnetic stir bar. 1.5 equiv HBPin (1.5 mmol, 218 μL), 1.0 equiv N,Ndimethyl-m-toluidine (1.0 mol, 145 μL) and 0.1 equiv dodecahydrotripheneylene (0.1 mmol, 24
mg) internal standard were added to the reaction vessel. The reaction vessel was then sealed and
allowed to stir at the indicated temperature (80, 110 or 130 °C) for 12h, at which point the
reaction was cooled to room temperature and the reaction mixture quenched by exposure to
atmospheric O2. Volitiles were removed under reduced pressure and product yields were
1

determined by H NMR in CDCl3 with respect to dodecahydrotripheneylene internal standard.
120

Elevated Temperature Reaction Screen on N,N-dimethyl-m-toluidine (5a) with Phosphine
Ligands

The 96 reactor wells consist of 1mL glass vials equipped with a micro-magnetic stir bar arrayed
in a 12x8 reaction plate, 12 columns labeled 1-12 and 8 rows labeled A-H. In a nitrogen filled
glove box, 0.01 M stock solutions of [Ir(COD)Cl]2 in THF and [Ir(OMe)COD]2 in THF and 0.02
M stick solutions of (Ind)Ir(COD) in THF and Ir(acac)COD in THF were prepared. 50 μL of
[Ir(OMe)COD]2 (0.5 μmol) stock solution were added to each well across rows A and E (wells
A1-A12 and E1-E12) via micro pipette. 50 μL of [Ir(COD)Cl]2 (0.5 μmol) stock solution were
added to each well across rows B and F (wells B1-B12 and F1-F12) via micro pipette. 50 μL of
Ir(acac)COD (1.0 μmol) stock solution were added to each well across rows C and G (wells C1C12 and G1-G12) via micro pipette. 50 μL of (Ind) Ir(COD) (1.0 μmol) stock solution were
added to each well across rows D and H (wells D1-D12 and H1-H12) via micro pipette. 50 μL of
a 0.02 M stock solution of dmpe (1.0 μmol) in THF was added down columns 7 and 10 (wells
A7-H7 and A10-H10) via micro pipette. 50 μL of a 0.02 M stock solution of dppe (1.0 μmol) in
THF was added down columns 8 and 11 (wells A8-H8 and A11-H11) via micro pipette. 50 μL of
a 0.02 M stock solution of dppbz (1.0 μmol) in THF was added down columns 9 and 12 (wells
A9-H9 and A12-H12) via micro pipette. 50 μL of a 0.6 M stock solution of HBPin (30 μmol) in
THF was added across rows A, B, C, and D (wells A1-D12) via micro pipette. 50 μL of a 0.3 M

121

stock solution of B2Pin2 (15 μmol) in THF was added across rows E, F, G, and H (wells E1H12) via micro pipette. The reaction plate was then capped and stirred for 5 min at room
temperature resulting in catalyst generation under Conditions B for wells A7-H12. 50 μL of a
0.02 M stock solution of dmpe (1.0 μmol) in THF was added down columns 1 and 4 (wells A1H1 and A4-H4) via micro pipette. 50 μL of a 0.02 M stock solution of dppe (1.0 μmol) in THF
was added down columns 2 and 5 (wells A2-H2 and A5-H5) via micro pipette. 50 μL of a 0.02
M stock solution of dppbz (1.0 μmol) in THF was added down columns 3 and 6 (wells A3-H3
and A6-H6) via micro pipette, resulting in catalyst generation under Conditions A for wells A7H12. Finally, 50 μL of a 0.4 M stock solution of N,N-dimethyl-m-toluidine (20 μmol) in THF,
containing dodecahydrotripheneylene internal standard (0.04 M, 2.0 μmol), was added to all 96
wells via micro pipette and the reaction plate was sealed and stirred for 8h at 80 °C. The reaction
was then quenched by exposure to air and dilution with MeCN.

130 °C Reaction Screen on N,N-dimethyl-m-toluidine (5a) with Phosphine Ligands

The 96 reactor wells consist of 1mL glass vials equipped with a micro-magnetic stir bar arrayed
in a 12x8 reaction plate, 12 columns labeled 1-12 and 8 rows labeled A-H. In a nitrogen filled
glove box, 0.01 M stock solutions of [Ir(COD)Cl]2 in Cpme and [Ir(OMe)COD]2 in Cpme and
0.02 M stick solutions of (Ind)Ir(COD) in Cpme and Ir(acac)COD in Cpme were prepared. 50 μL
122

of [Ir(OMe)COD]2 (0.5 μmol) stock solution were added to each well across rows A and E
(wells A1-A12 and E1-E12) via micro pipette. 50 μL of [Ir(COD)Cl]2 (0.5 μmol) stock solution
were added to each well across rows B and F (wells B1-B12 and F1-F12) via micro pipette. 50
μL of Ir(acac)COD (1.0 μmol) stock solution were added to each well across rows C and G
(wells C1-C12 and G1-G12) via micro pipette. 50 μL of (Ind) Ir(COD) (1.0 μmol) stock solution
were added to each well across rows D and H (wells D1-D12 and H1-H12) via micro pipette. 50
μL of a 0.02 M stock solution of dmpe (1.0 μmol) in Cpme was added down columns 7 and 10
(wells A7-H7 and A10-H10) via micro pipette. 50 μL of a 0.02 M stock solution of dmpbz (1.0
μmol) in Cpme was added down columns 8 and 11 (wells A8-H8 and A11-H11) via micro
pipette. 50 μL of a 0.02 M stock solution of dppbz (1.0 μmol) in Cpme was added down columns
9 and 12 (wells A9-H9 and A12-H12) via micro pipette. 50 μL of a 0.6 M stock solution of
HBPin (30 μmol) in Cpme was added across rows A, B, C, and D (wells A1-D12) via micro
pipette. 50 μL of a 0.3 M stock solution of B2Pin2 (15 μmol) in Cpme was added across rows E,
F, G, and H (wells E1-H12) via micro pipette. The reaction plate was then capped and stirred for
5 min at room temperature resulting in catalyst generation under Conditions B for wells A7H12. 50 μL of a 0.02 M stock solution of dmpe (1.0 μmol) in Cpme was added down columns 1
and 4 (wells A1-H1 and A4-H4) via micro pipette. 50 μL of a 0.02 M stock solution of dmpbz
(1.0 μmol) in Cpme was added down columns 2 and 5 (wells A2-H2 and A5-H5) via micro
pipette. 50 μL of a 0.02 M stock solution of dppbz (1.0 μmol) in Cpme was added down columns
3 and 6 (wells A3-H3 and A6-H6) via micro pipette, resulting in catalyst generation under
Conditions A for wells A7-H12. Finally, 50 μL of a 0.4 M stock solution of N,N-dimethyl-mtoluidine (20 μmol) in Cpme, containing dodecahydrotripheneylene internal standard (0.04 M,

123

2.0 μmol), was added to all 96 wells via micro pipette and the reaction plate was sealed and
stirred for 8h at 130 °C. The reaction was then quenched by exposure to air and dilution with
MeCN.

Borylation of 2,6-dimethylanisole (7a).
In a nitrogen filled glovebox, 16.6 mg [Ir(OMe)COD]2 (2.5 μmol, 2.5 mol%) and 5.0 μmol
dtbpy, dmabpy, phen or tmphen, (5.0 mol%) of ligand was dissolved in 1 mL THF in a 15 mL
pressure tube containing a magnetic stir bar. 1.0 equiv B2Pin2 (1.0 mmol, 254 mg), 1.0 equiv
2,6-dimethylanisole (1.0 mol, 141 μL) and 0.1 equiv dodecahydrotripheneylene (0.1 mmol, 24
mg) internal standard were added to the reaction vessel. The reaction vessel was then sealed and
allowed to stir at 80 °C for 4h, at which point the reaction was cooled to room temperature and
the reaction mixture quenched by exposure to atmospheric O2. Volitiles were removed under
1

reduced pressure and product yields were determined by H NMR in CDCl3 with respect to
dodecahydrotripheneylene internal standard.

124

Kinetic Experiments with (tmphen)Ir(BPin)3(COE) and (dtbpy)Ir(BPin)3(COE).
37 µL of HBPin or 66 mg B2Pin2 (0.260 mmol, 1.2 equiv) was weighed into a test tube and
dissolved in 1 mL THFd8. This solution was then transferred to a test tube containing 5.84 mg of
(tmphen)Ir(BPin)3(COE) or 6.04 mg of (dtbpy)Ir(BPin)3(COE) (6.35 µmol, 5.0 mol%) and
10.68 mg 1,3,5-tri-tert-butylbenzene (43 µmol, 0.20 equiv). 1,3-dimethoxybenzene (27.8 µL,
0.217 mmol, 1 equiv) was added to the vial via microliter syringe. The solution was then
transferred to a screw cap NMR tube. The tubes were heated in the NMR probe and monitored
1

by H NMR.

Precatalyst Aging Study
Batches

of

[Ir(OMe)COD]2,

[Ir(Cl)COD]2,

Ir(acac)COD,

and

Ir(1,1,1,3,3,3-

hexafluoroacetylacetonate)COD were bought from multiple commercial suppliers, subdivided
and stored in closed containers over solid Mg(SO4) (21% relative humidity), saturated aqueous
Mg(NO3) (51% relative humidity) and deionized H2O (100% relative humidity) for 100 days
and then tested with General Procedure for Microscale Reactions Utilizing Conditions A.
The relative humidities were determined by an internal hydrometer.

125

Kinetic Experiments with (tmphen)Ir(BPin)3(COE) at higher and lower catalyst loadings.

66 mg B2Pin2 (0.260 mmol, 1.2 equiv) was weighed into a test tube and dissolved in 1 mL
THFd8. This solution was then transferred to a test tube containing 2.92 or 11.68 mg of
(tmphen)Ir(BPin)3(COE) (3.18 µmol, 2.5 mol% or 12.7 µmol, 10.0 mol%) and 10.68 mg 1,3,5tri-tert-butylbenzene (43 µmol, 0.20 equiv) internal standard. 1,3-dimethoxybenzene (27.8 µL,
0.217 mmol, 1 equiv) was added to the vial via microliter syringe. The solution was then
transferred to a screw cap NMR tube. The tubes were heated in the NMR probe and monitored
1

by H NMR.

126

Open and Closed System C-H Borylation of 1,3-diisopropylbenzene (8a).
In a nitrogen filled glovebox, a 250 µL of a 0.010 M stock solution containing [Ir(OMe)COD]2
in THF was dispensed into an 8 mL scintillation vial equipped with a magnetic stir bar. To this
solution, 250 µL of a 0.020 M stock solution containing tmphen in THF, followed by 250 µL of
a 0.60 M stock solution containing HBPin in THF. Finally, 250 µL of a 0.40 M stock solution
containing 1,3-diisopropylbenzene substrate and dodecahydrotriphenylene (0.040 M with respect
to DHT) as internal standard in THF was added to the reaction vial and the vial was sealed with
an open top screw cap fitted with a Teflon seal. 12 such reaction vials were made of which six
were fitted with an 18G 1½ PrecisionGlide® Needle. 12 additional reaction vials were made with
a 0.30 M stock solution containing B2Pin2 in THF in place of the 0.60 M HBPin/THF solutions.
Again 6 of these were fitted with an 18G 1½ PrecisionGlide® Needle. 24 reaction vials identical
to those previously described with the exception of a 0.020 M stock solution containing dtbpy
instead of tmphen were prepared, again 12 made with a 0.60 M stock solution containing HBPin
in THF and 12 with a 0.30 M stock solution containing B2Pin2 in THF. Half of each 12 were
likewise, fitted with an 18G 1½ PrecisionGlide® Needle. The reaction vials were then placed on
to two 4x6 reactor well plates and heated to 70 °C in the glove box. At each of the six time
points (30 min, 1, 2, 3, 5, and 8h) 8 reaction vials (1 of each ligand, borylating reagent and open
vs. closed combination) were removed and quenched by exposure to atmospheric O2 and
conversions were determined by HPLC. The weight of the reaction mixture was then measured
to determine if there was any significant loss of solvent. In all cases the weight of the reaction
mixtures was the same showing there was no appreciable loss of solvent.
127

Catalyst Loading Study

Reaction was set-up in a nitrogen filled glove box, in a 96 reactor well plate consisting of 1mL
glass vials equipped with a micro-magnetic stir bar arrayed in a 12x8 reaction plate, 12 columns
labeled 1-12 and 8 rows labeled A-H. A 0.02 M stock solution of dtbpy in THF was prepared and
40 μL (0.8 μmol) was added to wells A1 and A7, 50 μL (1.0 μmol) was added to wells A2 and
A8, 70 μL (1.4 μmol) was added to wells A3 and A9, 100 μL (2.0 μmol) was added to wells A4
and A10, 200 μL (4.0 μmol) was added to wells A5 and A11, and 400 μL (8.0 μmol) was added
to wells A6 and A12 via micro pipette. A 0.01 M stock solution of dtbpy in THF was prepared
and 40 μL (0.4 μmol) was added to wells B1 and B7, 50 μL (0.5 μmol) was added to wells B2
and B8, 70 μL (0.7 μmol) was added to wells B3 and B9, 100 μL (1.0 μmol) was added to wells
B4 and B10, 200 μL (2.0 μmol) was added to wells B5 and B11, and 400 μL (4.0 μmol) was
added to wells B6 and B12 via micro pipette. A 0.004 M stock solution of dtbpy in THF was
prepared and 40 μL (0.16 μmol) was added to wells C1 and C7, 50 μL (0.2 μmol) was added to
wells C2 and C8, 70 μL (0.28 μmol) was added to wells C3 and C9, 100 μL (0.4 μmol) was
added to wells C4 and C10, 200 μL (0.8 μmol) was added to wells C5 and C11, and 400 μL (1.6
μmol) was added to wells C6 and C12 via micro pipette. A 0.002 M stock solution of dtbpy in
THF was prepared and 40 μL (0.08 μmol) was added to wells D1 and D7, 50 μL (0.1 μmol) was
added to wells D2 and D8, 70 μL (0.14 μmol) was added to wells D3 and D9, 100 μL (0.2 μmol)
was added to wells D4 and D10, 200 μL (0.4 μmol) was added to wells D5 and D11, and 400 μL
(0.8 μmol) was added to wells D6 and D12 via micro pipette. A 0.02 M stock solution of tmphen
128

in THF was prepared and 40 μL (0.8 μmol) was added to wells E1 and E7, 50 μL (1.0 μmol) was
added to wells E2 and E8, 70 μL (1.4 μmol) was added to wells E3 and E9, 100 μL (2.0 μmol)
was added to wells E4 and E10, 200 μL (4.0 μmol) was added to wells E5 and E11, and 400 μL
(8.0 μmol) was added to wells E6 and E12 via micro pipette. A 0.01 M stock solution of tmphen
in THF was prepared and 40 μL (0.4 μmol) was added to wells F1 and F7, 50 μL (0.5 μmol) was
added to wells F2 and F8, 70 μL (0.7 μmol) was added to wells F3 and F9, 100 μL (1.0 μmol)
was added to wells F4 and F10, 200 μL (2.0 μmol) was added to wells F5 and F11, and 400 μL
(4.0 μmol) was added to wells F6 and F12 via micro pipette. A 0.004 M stock solution of tmphen
in THF was prepared and 40 μL (0.16 μmol) was added to wells G1 and G7, 50 μL (0.2 μmol)
was added to wells G2 and G8, 70 μL (0.28 μmol) was added to wells G3 and G9, 100 μL (0.4
μmol) was added to wells G4 and G10, 200 μL (0.8 μmol) was added to wells G5 and G11, and
400 μL (1.6 μmol) was added to wells G6 and G12 via micro pipette. A 0.002 M stock solution
of tmphen in THF was prepared and 40 μL (0.08 μmol) was added to wells H1 and H7, 50 μL
(0.1 μmol) was added to wells H2 and H8, 70 μL (0.14 μmol) was added to wells H3 and H9,
100 μL (0.2 μmol) was added to wells H4 and H10, 200 μL (0.4 μmol) was added to wells H5
and H11, and 400 μL (0.8 μmol) was added to wells H6 and H12 via micro pipette. The THF
was then removed under reduced pressure. 500 μL of a 0.001 M stock solution of
[Ir(OMe)COD]2 (0.5 μmol) in THF was added to each well across rows A and E (wells A1-A12
and E1-E12) via micro pipette. 250 μL of a 0.001 M stock solution of [Ir(OMe)COD] 2 (0.25
μmol) in THF was added to each well across rows A and E (wells B1-B12 and F1-F12) via micro
pipette. 100 μL of a 0.001 M stock solution of [Ir(OMe)COD]2 (0.1 μmol) in THF was added to
each well across rows C and G (wells C1-C12 and G1-G12) via micro pipette. 50 μL of a 0.001

129

M stock solution of [Ir(OMe)COD]2 (0.05 μmol) in THF was added to each well across rows D
and H (wells D1-D12 and H1-H12) via micro pipette. The THF was then removed under reduced
pressure. 100 μL of 0.75 M stock solution of B2Pin2 (0.75 μmol) in THF was added to all 96
wells. 100 μL of

1.0 M stock solution of N,N-dimethyl-m-toluidine (100 μmol) and 10 μmol

dodecahydrotripheneylene internal standard in THF was added to all 96 wells. The well plate
was sealed and heated to 80 °C for 8h, at which point the reaction was cooled to room
temperature and quenched by exposure to atmospheric O2 and dilution with MeCN.

Ligand to Metal Ratio with preformed (tmphen)Ir(COE)BPin3

In a nitrogen filled glovebox, 190 mg (0.75 mmol) B2Pin2, 24 mg (0.10 mmol)
dodecahydrotripheneylene, 4.6 or 46 mg (0.005 or 0.05 mmol) (tmphen)Ir(COE)BPin3, and 4.7
or 47 mg (0.02 or 0.2 mmol) tmphen (if used) where weighed into test tubes and then dissolved
in 1mL THF and transferred to a 15 mL pressure tube containing a magnetic stir bar. 145 μL (1.0
mmol) of N,N-dimethyl-m-toluidine was added to the pressure tube. The reaction vessel was
sealed and the reaction mixture heated to 80 °C for 8h, at which point the reaction was cooled to

130

room temperature and quenched by exposure to atmospheric O2 and MeOH. Volatiles were
removed under reduced pressure and reaction yields were determined by 1H NMR.

Table 5.1. Ligand to Metal Ratio with preformed (tmphen)Ir(COE)BPin3.
entry

mol % (tmphen)Ir(COE)BPin3

mol % tmphen

Yield (%)

1

0.5

--

89

2

0.5

2.0

92

3

5.0

--

82

4

5.0

20

79

Additive Screen.

The 96 reactor wells consist of 1mL glass vials equipped with a micro-magnetic stir bar arrayed
in a 12x8 reaction plate, 12 columns labeled 1-12 and 8 rows labeled A-H. In a nitrogen filled
glove box, 0.02 M stock solutions of K(acac) in MeOH, Na(acac) in MeOH, KOMe in MeOH
t

and K BuO in THF and 0.01 M stock solutions of Ti(acac)2(O) in MeOH and Mg(acac)2 in
MeOH and 0.66 M stock solution of Al(acac)3 in MeOH were prepared. Volatile solvent were
131

removed under reduced pressure. 50 μL of [Ir(COD)Cl]2 (0.5 μmol) stock solution were added to
each well down columns 1, 2, 5, 6, 9, and 10 (wells A1-H2, A5-H6, and A9-H10) via micro
pipette. 50 μL of [Ir(OMe)COD]2 (0.5 μmol) stock solution were added to each well down
columns 3, 4, 7, 8, 11, and 12 (wells A3-H4, A7-H8, and A11-H12) via micro pipette. 50 μL of
(dtbpy)Ir(BPin)3COE (1.0 μmol) stock solution were added to each well across rows B and F
(wells B1-B12 and F1-F12) via micro pipette. 50 μL of a 0.02 M stock solution of dtbpy (1.0
μmol) in THF was added down columns 1, 3, 5, 7, 9, and 11 (wells A1-H1, A3-H3, A5-H5, A7H7, A9-H9 and A11-H11) via micro pipette. 50 μL of a 0.6 M stock solution of HBPin (30
μmol) in THF was added to all 96 reaction wells. 50 μL of a 0.02 M stock solution of dtbpy (1.0
μmol) in THF was added down columns 2, 4, 6, 8, 10, and 12 (wells A2-H2, A4-H4, A6-H6, A8H8, A10-H10 and A12-H12) via micro pipette. Finally, 50 μL of a 0.4 M stock solution of 3bromotoluene containing dodecahydrotripheneylene internal standard (0.04 M) was added to all
96 wells via micro pipette and the reaction plate was sealed and stirred for 4h at room
temperature. The reaction was then quenched by exposure to air and dilution with MeCN.

Precatalyst and Ligand NMR reactions. In a nitrogen filled glovebox, 25 μmol iridium
precatalyst dimer or 50 μmol Iridium monomer was dissolved in 750 μL in THFd8 in a test tube.
This solution was then transferred to a test tube containing 50 μmol ligand and 5 μmol 1,3,5-tri-tbutylbenzene via pipette. The resulting mixture was then transferred to a screw cap NMR tube
and sealed.

132

Synthesis of (tmphen)Ir(BPin)3(COE)

In a 100 mL flask, equipped with a magnetic stir bar, 500 mg [Ir(OMe)COD]2 (0.75 mmol) was
dissolved in 80 mL cyclohexane. 1.2 mL cis-cyclooctene (9 mmol) was added via micropipette.
1.3 mL of HBPin (9 mmol) was added dropwise by syringe to a vigorously stirred solution. A
solution of 3,4,7,8-tetramethyl-1,10-phenanthroline (354 mg, 1.5 mmol) dissolved in DCM (10
mL) was added via pipette and the solution was stirred for 30 min. Volatiles were removed by
evaporation and (tmphen)Ir(BPin)3(COE) was purified by trituration with petroleum ether as a
1

yellow solid (yield 510 mg, 37% yield); decomposition 114-120 °C. H NMR (500 MHz,
THFd8, -35 °C) δ 9.62 (s, 2H), 8.18 (s, 2H), 3.86 (d, J = 7 Hz, 2H), 2.76 (s, 6H) 2.55 (s, 6H),
1.27 (br m, 12H), 1.22 (s, 12H), 1.19 (s, 12H), 0.54 (s, 12H);

13

C NMR (125 MHz, THFd8, -35

°C) δ 154.2, 146.9, 140.5, 131.2, 128.3, 122.3, 79.0, 78.6, 75.4, 31.1, 26.3, 24.9, 24.2, 23.9;

11

B

NMR (160 MHz, THFd8) δ 37 (br s); Anal. Calcd for C44H66IrB3N2O6: C, 54.85; H, 7.23; N,
3.05. Found: C, 54.63; H, 6.98; N, 2.99.

133

3-Bromo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborlan-2-yl)toluene (3b)

General procedure A was scaled up to the 1.0 mmol scale for isolation using [Ir(OMe)COD] 2 as
catalyst, dtbpy as ligand and 0.75 equiv B2Pin2 as borylating reagent. Product was isolated by
passing the reaction mixture through SiO2 and evaporation of the volatiles. Off-white solid; 217
1

mg, 73% yield; mp 74-76 °C. NMR data reported matched that in ref 1. H NMR (500 MHz,
CDCl3) δ 7.73 (s, 1H), 7.53 (s, 1H), 7.41 (s, 1H), 2.32 (s, 3H), 1.34 (s, 12H);
MHz, CDCl3) δ 140.1, 133.8, 133.3, 121.5, 84.0, 24.5, 20.3;
(br s).

134

11

13

C NMR (125

B NMR (160 MHz, CDCl3) δ 30

1,2,3-Trimethoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborlan-2-yl)benzene (4b)

General procedure A was scaled up to the 1.0 mmol scale for isolation using [Ir(OMe)COD] 2 as
catalyst, dtbpy as ligand and 0.75 equiv B2Pin2 as borylating reagent. Product was isolated by
passing the reaction mixture through SiO2 and evaporation of the volatiles, followed by
recrystallization from 1:1 MeOH:H2O. White solid; 270 mg, 92% yield; mp 104-106 °C. NMR
1

data reported matched that in ref 2. H NMR (500 MHz, CDCl3) δ 7.03 (s, 2H), 3.90 (s, 6H),
3.87 (s, 3H), 1.34 (s, 12H);
56.1, 24.8;

13

C NMR (125 MHz, CDCl3) δ 152.9, 140.9, 111.3, 83.9, 60.8,

11

B NMR (160 MHz, CDCl3) δ 30 (br s).

135

N,N-Dimethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborlan-2-yl)-5-methyl benzamine (5b)

General procedure A was scaled up to the 1.0 mmol scale for isolation using [Ir(OMe)COD]2 as
catalyst, dtbpy as ligand and 0.75 equiv B2Pin2 as borylating reagent. Product was isolated by
passing the reaction mixture through SiO2 and evaporation of the volatiles. Off-white solid; 245
1

mg, 94% yield; mp 82-84 °C. H NMR (500 MHz, CDCl3) δ 7.03 (s, 1H), 7.02 (s, 1H), 6.68 (s,
1H), 2.95 (s, 6H), 2.32 (s, 3H), 1.34 (s, 12H);
124.1, 116.7, 116.0, 83.5, 40.8, 24.8, 21.6;

11

13

C NMR (125 MHz, CDCl3) δ 150.4, 138.0,

B NMR (160 MHz, CDCl3) δ 31 (br s). Anal. Calcd

for C15H24BNO2: C, 68.98; H, 9.26; N, 5.36. Found: C, 69.18; H, 9.26; N, 5.36.

136

1,3-Dimethoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborlan-2-yl) benzene (6b)

General procedure A was scaled up to the 1.0 mmol scale for isolation using [Ir(OMe)COD]2 as
catalyst, dtbpy as ligand and 0.75 equiv B2Pin2 as borylating reagent. Product was isolated by
passing the reaction mixture through SiO2 and evaporation of the volatiles. White solid; 216 mg,
1

82% yield; mp 87-88 °C. NMR data matched that reported in ref 1. H NMR (500 MHz, CDCl3)
δ 6.95 (d, J = 2.4 Hz, 2H), 6.56 (t, J = 2.4 Hz, 1H), 3.81 (s, 6H), 1.34 (s, 12H);
MHz, CDCl3) δ 160.4, 111.6, 104.5, 83.9, 55.4, 24.8;

137

11

13

C NMR (125

B NMR (160 MHz, CDCl3) δ 30 (br s).

2,5-Dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborlan-2-yl) anisole (7b)

General procedure A was scaled up to the 1.0 mmol scale for isolation using [Ir(OMe)COD] 2 as
catalyst, dtbpy as ligand and 0.75 equiv B2Pin2 as borylating reagent. Product was isolated by
passing the reaction mixture through SiO2 and evaporation of the volatiles. White solid; 230 mg,
1

88% yield; mp 84-86 °C. NMR data matched that reported in ref 3. H NMR (500 MHz, CDCl3)
δ 7.49 (s, 2H), 3.73 (s, 3H), 2.29 (s, 6H), 1.33 (s, 12H);
135.6, 130.3, 83.6, 59.6, 24.8, 15.8;

11

13

C NMR (125 MHz, CDCl3) δ 159.8,

B NMR (160 MHz, CDCl3) δ 31 (br s).

138

1,3-Diisopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborlan-2-yl) benzene (8b)

General procedure A was scaled up to the 1.0 mmol scale for isolation using [Ir(OMe)COD] 2 as
catalyst, dtbpy as ligand and 0.75 equiv B2Pin2 as borylating reagent. Product was isolated by
passing the reaction mixture through SiO2 and evaporation of the volatiles. White solid; 239 mg,
1

83% yield; mp 118-120 °C. NMR data matched that reported in ref 4. H NMR (500 MHz,
CDCl3) δ 7.51 (d, J = 1.5 Hz, 2H), 7.19 (t, J = 1.5 Hz, 1H), 2.93 (m, 2H), 1.35 (s, 12H), 1.28 (m,
12 H);

13

C NMR (125 MHz, CDCl3) δ 148.1, 132.6, 130.4, 127.7, 83.6, 34.2, 24.8, 24.0;

NMR (160 MHz, CDCl3) δ 31 (br s).

139

11

B

Synthesis of cis- and trans-((3,5-bis(trifluoromethyl)benzene)3P)2Ir(BPin)3 (9a) and (9b).

6

In a 20 mL vial, equipped with a magnetic stirring bar, (η -MesH)Ir(BPin)3 (280 mg,
0.40

mmol,

1

equiv)

was

dissolved

in

THF

(4

mL).

Tris(3,5-

F

bis(trifluoromethyl)benzene)3phosphine (PAr 3) (570 mg, 0.81 mmol, 2 equiv) was weighed out
in a test tube and was transferred to the reaction vial by dissolving in THF (2 mL). The reaction
was stirred at room temperature for 4 h. The crude reaction mixture was pumped down under
high vacuum to give a mixture of the desired complex and its cis isomer as a light yellow solid
F

1

(yield 580 mg, 76%). cis-(Ar 3P)2Ir(BPin)3 H NMR (THFd8, 500 MHz): δ 8.37 (s, 6H), 8.04
(br, 12H), 1.02 (s, 36H);
36.86;

11

B NMR (THFd8, 160 MHz): δ 39;

19

F

31

P NMR (THFd8, 202 MHz): δ
1

F NMR (THFd8, 470 MHz) δ -58.72. trans-(Ar 3P)2Ir(BPin)3 H NMR (THFd8, 500

MHz): δ 8.19 (s, 6H), 8.13 (s, 12H), 0.78 (s, 36H);
NMR (THFd8, 202 MHz): δ 28.81;

19

11

B NMR (THFd8, 160 MHz): δ 39;

F NMR (THFd8, 470 MHz) δ -58.53.

140

31

P

methyl 2,6-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (10c)

In a nitrogen filled glovebox, 126 µL methyl benzoate (1.0 mmol, 1.0 equiv) was dissolved in 1
mL THF in a 15 mL pressure tube containing a magnetic stir bar. 2.0 equiv B2Pin2 (218 μL) was
added and the reaction vessel was sealed and stirred at room temperature for 1h. 2.5 μmol
[Ir(OMe)COD]2 (2.5 mol%) and 5.0 μmol SiPbz (5.0 mol%) were added and the reaction
vessel was sealed and heated at 80 °C for 16h. The reaction mixture was allowed to return to
room temperature and the reaction mixture was exposed to air and diluted with 1 mL MeOH.
The volatiles were then removed under reduced pressure and the product was purified by passing
it through a short plug of SiO2 in MTBE. The product was isolated by recrystallization from
1

MeOH/H2O. White solid (244 mg); H NMR (500 MHz, CDCl3) δ 7.70 (d, J = 7.4 Hz, 2H),
7.43 (d, J = 7.3 Hz, 1H), 3.89 (s, 3H), 1.35 (s, 24H);
141.7, 135.4, 128.9, 84.0, 52.0, 24.8;

11

13

C NMR (125 MHz, CDCl3) δ 170.6,

B NMR (160 MHz, CDCl3) δ 31 (br s). ; HRMS (ESI)

+

m/z calcd for C20H31B2O6 [M + H] 389.2307, found 389.2307.

141

Ligand and Borane Effects Screen on the Borylation of methyl benzoate (10a).
Reaction was conducted in 8 × 30 mm borosilicate glass shell vials arranged in 96 well metal
blocks (Symyx) with magnetic stirring. In a nitrogen filled glove box, a 50 μL of 0.01 M stock
solutions of [Ir(OMe)COD]2 (0.5 µmol) in THF were added to a 1 mL reaction vial containing a
magnetic stir bar. 50 μL of a 0.04 M stock solution of ligand (2.0 μmol) in THF was added to
reaction vials containing [Ir(OMe)COD]2. 50 μL of a solution of either 30 μmol HBPin (0.6 M),
30 μmol B2Pin2 (0.6 M), 30 μmol HBPin and 30 μmol B2Pin2 (0.6 M), or 60 μmol B2Pin2 (1.2
M) in THF was added via micropipette. Finally, 50 μL of a 0.2 M stock solution containing
methyl benzoate (20 μmol) and 2.0 μmol dodecahydrotriphenylene internal standard in THF was
added to the reaction mixture. The reaction vessel was then sealed and stirred at 80 °C for 16h.
The reaction was then cooled to room temperature and quenched by exposure to atmospheric O2
1

and dilution with MeCN. Volatiles were removed and assay yields were determined by H NMR.

142

F

Stoichiometric borylation of (11a) with (Ar 3P)2Ir(BPin)3

F

(Ar 3P)2Ir(BPin)3 (80 mg, 0.0418 mmol, 1 equiv) was weighed in a test tube and was dissolved
in THFd8 (750 μL). Methyl 3-trifluoromethylbenzoate (6.5 mg, 0.0418 mmol, 1 equiv) was
F

weighed in a test tube and mixed with the solution containing (Ar 3P)2Ir(BPin)3. The mixture
was then transferred via pipette into a J. Young NMR tube. The J. Young NMR tube was capped
1

and the reaction was monitored by H and

31

P NMR.

F

NMR reaction of (Ar 3P)2Ir(BPin)3 with excess THT.
F

(Ar 3P)2Ir(BPin)3 (40 mg, 0.0209 mmol, 1 equiv) was weighed in a test tube and was dissolved
in THF (1.0 mL). THT (18 µL, 0.209 mmol, 10 equiv) was added to the solution containing
F

(Ar 3P)2Ir(BPin)3 via micro syringe. The mixture was then transferred via pipette into a J.
Young NMR tube. The J. Young NMR tube was capped and the reaction was monitored
NMR.

143

31

P

Synthesis of (2-(diisopropylsilyl)phenyl)di-p-tolylphosphane (SiPbz).

In a nitrogen filled glovebox, 333 mg (2-bromophenyl)di-p-tolylphosphine (0.9 mmol was
n

dissolved in 10 mL ether in a 20 mL scintillation vial and cooled to -30 °C. 396 μL of BuLi
(2.5M in hexanes, 1.1 equiv) was further diluted in 5 mL ether and added to the solution
containing (2-bromophenyl)di-p-tolylphosphine drop wise. The reaction was sealed and stirred
for 30 min while it was allowed to come to room temperature. Volatiles were removed under
reduced

pressure

and

the

residue

was

dissolved

in

10

mL

toluene.

162

mg

diisopropylshlorosilane (1.08 mmol, 1.2 equiv) was added to the solution and the reaction was
sealed and stirred at room temperature for 4 h. The mixture was then filtered and the precipitate
washed with toluene. Volatiles were removed under reduced pressure and the product was
1

isolated as a pure white solid (365 mg, 99% yield). ); H NMR (500 MHz, C6D6) δ 7.62-7.58
(m, 1H), 7.36-7.33 (m, 1H), 7.31 (t, J = 7.8, 7.4 Hz, 4H), 7.08-7.02 (m, 2H), 6.90 (d, J = 7.8 Hz,
4H), 4.57 (m, 1H), 1.98 (s, 6H0, 1.47 (m, 2H), 1.17 (d, J = 7.3 Hz, 6H), 1.01 (d, J = 7.4 Hz, 6H);
13

C NMR (125 MHz, C6D6) δ 144.7 (d, J = 11.5 Hz), 143.3, 142.9, 137.9, 136.9 (d, J = 5.3 Hz),

134.9 (s, J = 10.5 Hz), 134.3, 133.7 (d, J = 19.1 Hz), 129.3, 129.2, 20.7, 19.4, 12.3 (d, J = 5.7
Hz);

31

P NMR (202 MHz, C6D6) δ -9.74 (s).

144

3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole (15)

In a nitrogen filled glovebox, 69 µL pyrrole (1 mmol) was dissolved in 1 mL THF in a 15 mL
pressure tube containing a magnetic stir bar. 3.0 equiv HBPin (435 μL) and 1.0 equiv NEt3 (140
µL) was added and the reaction vessel was sealed and stirred at room temperature for 12h. 0.25
μmol [Ir(OMe)COD]2 (0.25 mol%) and 1.0 μmol 3,4,7,8-tetramethyl-1,10-phenanthroline (1.0
mol%) were added and the reaction vessel was sealed and heated at 80 °C for 4h. The reaction
mixture was allowed to return to room temperature and the reaction mixture was exposed to air
and diluted with 5 mL MeOH. The volatiles were then removed under reduced pressure and the
product was purified by passing it through a short plug of SiO2 in MTBE. The product was
1

isolated by recrystallization from MeOH/H2O. White solid (185 mg, 76% isolated yield); H
NMR (500 MHz, CDCl3) δ 8.62 (br s, 1H), 7.24 (d, 2H), 6.85 (dd, J = 4.4, 2.5 Hz, 1H), 6.57 (d,
J = 1.4 Hz, 1H), 1.33 (s, 12H);
11

13

C NMR (125 MHz, CDCl3) δ 127.0, 118.5, 113.8, 83.0, 24.9;
5,6

B NMR (160 MHz, CDCl3) δ 29 (br s).

145

3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)-indole (16)

In a nitrogen filled glovebox, 117 mg indole (1 mmol) was dissolved in 1 mL THF in a 15 mL
pressure tube containing a magnetic stir bar. 2.0 equiv HBPin (290 μL) and 1.0 equiv NEt3 (140
µL) was added and the reaction vessel was sealed and heated at 80 °C for 10 min. 0.25 μmol
[Ir(OMe)COD]2

(0.25 mol%)

and

1.0 μmol 3,4,7,8-tetramethyl-1,10-phenanthroline (1.0

mol%) were added and the reaction vessel was sealed and heated at 80 °C for 4h. The reaction
mixture was allowed to return to room temperature and the reaction mixture was exposed to air
and diluted with 5 mL MeOH. The volatiles were then removed under reduced pressure and the
product was purified by passing it through a short plug of SiO2 in MTBE. The product was
1

isolated by recrystallization from MeOH/H2O. White solid (139 mg, 57% isolated yield); H
NMR (500 MHz, CDCl3) δ 8.47 (br s, 1H), 8.08 (dd, J = 7.3, 2.4 Hz, 2H), 7.65 (d, J = 2.4 Hz,
1H), 7.40 (dd, J = 7.4, 1.9 Hz, 1H), 7.23-7.18 (m, 2H), 1.37 (s, 12H) );
CDCl3) δ 136.0, 133.5, 131.9, 122.8, 83.0, 24.9;

11

146

13

C NMR (125 MHz,

B NMR (160 MHz, CDCl3) δ 30 (br s).

5

In Situ generation of 1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole

In a nitrogen filled glovebox 117 mg indole (1 mmol) was dissolved in 1 mL C6D6 in a screw
cap NMR tube. 2.0 equiv HBpin (290 μL) and 1.0 equiv NEt3 (140 µL) was added and the tube
1

was sealed and heated at 80 °C for 30 min. Quantitative conversion was observed by NMR. H
NMR (500 MHz, C6D6) δ 8.24 (d, J = 8.4 Hz, 1H), 7.56 (d, J = 7.8 Hz, 1H), 7.48 (d, J = 3.5 Hz,
1H), 7.25 (dd, J = 8.4, 6.8 Hz, 1H), 7.15 (dd, J = 7.8, 6.8 Hz, 1H), 0.96 (s, 12H) );
(160 MHz, C6D6) δ 24 (br s).

147

11

B NMR

4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)-pyrazole (17)

In a nitrogen filled glovebox, 68 mg pyrazole (1 mmol) was dissolved in 1 mL THF in a 15 mL
pressure tube containing a magnetic stir bar. 0.25 μmol [Ir(OMe)COD]2 (0.25 mol%), 1.0 μmol
3,4,7,8-tetramethyl-1,10-phenanthroline (1.0 mol%) and 2.0 equiv HBPin (290 μL) were added
and the reaction vessel was sealed and heated at 80 °C for 4h. The reaction mixture was allowed
to return to room temperature and the reaction mixture was exposed to air and diluted with 5 mL
MeOH. The volatiles were then removed under reduced pressure and the product was purified by
passing it through a short plug of SiO2 in MTBE. The product was isolated by recrystallization
1

from MeOH/H2O. White solid (171 mg, 88% isolated yield); H NMR (500 MHz, CDCl3) δ
7.90 (s, 1H), 7.81 (s, 1H), 4.75 (br s, 1H), 1.35 (s, 12H);
83.8, 24.9;

11

B NMR (160 MHz, CDCl3) δ 30 (br s).

148

5

13

C NMR (125 MHz, CDCl3) δ 133.9,

3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)-7-azaindole (18a)

In a nitrogen filled glovebox, 188 mg 7-azaindole (1 mmol) was dissolved in 1 mL THF in a 15
mL pressure tube containing a magnetic stir bar. 0.25 μmol [Ir(OMe)COD]2 (0.25 mol%), 1.0
μmol 3,4,7,8-tetramethyl-1,10-phenanthroline (1.0 mol%) and 2.0 equiv HBPin (290 μL) were
added and the reaction vessel was sealed and heated at 80 °C for 4h. The reaction mixture was
allowed to return to room temperature and the reaction mixture was exposed to air and diluted
with 5 mL MeOH. The volatiles were then removed under reduced pressure and the product was
purified by passing it through a short plug of SiO2 in MTBE. The product was isolated by
1

recrystallization from MeOH/H2O. White solid (185 mg, 76% isolated yield); H NMR (500
MHz, CDCl3) δ 11.36 (br s, 1H), 8.32 (m, 2H), 7.84 (s, 1H), 7.14 (dd, J = 7.3, 4.9 Hz, 1H), 1.37
(s, 12H);

13

C NMR (125 MHz, CDCl3) δ 149.9, 142.5, 134.8, 130.9, 124.4, 116.5, 83.0, 24.9;

11

B NMR (160 MHz, CDCl3) δ 29 (br s).

149

3,5-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)-7-azaindole (18b)

In a nitrogen filled glovebox, 188 mg 7-azaindole (1 mmol) was dissolved in 1 mL THF in a 15
mL pressure tube containing a magnetic stir bar. 0.25 μmol [Ir(OMe)COD]2 (0.25 mol%), 1.0
μmol 3,4,7,8-tetramethyl-1,10-phenanthroline (1.0 mol%) and 2.0 equiv B2Pin2 (508 mg) were
added and the reaction vessel was sealed and heated at 80 °C for 4h. The reaction mixture was
allowed to return to room temperature and the reaction mixture was exposed to air and diluted
with 5 mL MeOH. The volatiles were then removed under reduced pressure and the product was
purified by passing it through a short plug of SiO2 in MTBE. The product was isolated by
recrystallization from MeOH/H2O. White solid (332 mg, 91% isolated yield); mp: 209-210 °C;
1

H NMR (500 MHz, CDCl3) δ 11.7 (s, 1H), 8.73 (d, J = 1.5 Hz, 1H), 8.68 (d, J = 1.5 Hz, 1H),

7.83 (s, 1H), 1.40 (s, 12H), 1.38 (s, 12H);
134.9, 123.4, 83.8, 83.1, 24.9;

13

C NMR (125 MHz, CDCl3) δ 151.5, 149.3, 137.6,

11

B NMR (160 MHz, CDCl3) δ 31; HRMS (ESI) m/z calcd for

+

C19H28B2N2O4 [M + H] 371.2320, found 371.2509.

150

3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)-4-azaindole (19)

In a nitrogen filled glovebox, 188 mg 4-azaindole (1 mmol) was dissolved in 1 mL THF in a 15
mL pressure tube containing a magnetic stir bar. 0.25 μmol [Ir(OMe)COD]2 (0.25 mol%), 1.0
μmol 3,4,7,8-tetramethyl-1,10-phenanthroline (1.0 mol%) and 2.0 equiv HBPin (290 μL) were
added and the reaction vessel was sealed and heated at 80 °C for 4h. The reaction mixture was
allowed to return to room temperature and the reaction mixture was exposed to air and diluted
with 5 mL MeOH. The volatiles were then removed under reduced pressure and the product was
purified by passing it through a short plug of SiO2 in MTBE. The product was isolated by
1

recrystallization from MeOH/H2O. White solid (202 mg, 83% isolated yield); H NMR (500
MHz, DMSO-d6) δ 11.39 (br s, 1H), 8.51 (s, 1H), 7.97 (s, 1H), 7.71 (dd, J = 5.9, 3.0 Hz, 1H),
6.54 (s, 1H), 1.30 (s, 12H);

13

C NMR (125 MHz, DMSO-d6) δ 148.5, 148.0, 131.3, 128.3,
+

124.8, 102.2, 84.0, 25.1; HRMS (ESI) m/z calcd for C13H17BN2O2 [M + H] 245.1461, found
245.1456.

151

Borane and Solvent Effects Screen on Borylation of 3-chloroaniline (22a). In a nitrogen filled
glove box, a 50 μL of 0.01 M stock solutions of [Ir(OMe)COD]2 in THF were added to a 1 mL
reaction vial containing a magnetic stir bar. 50 μL of a 0.02 M stock solution of dtbpy (1.0 μmol)
or tmphen (1.0 μmol) in DCM was added to reaction vials containing [Ir(OMe)COD] 2. Volatiles
were removed under reduced pressure. The reaction vials were then subjected to one set of three
following conditions using stock solutions made up in THF, cyclohexane, N,Ndiisopropylethylamine, or NMP:
1) 100 μL of a solution of 22 μmol B2Pin2 (0.22 M) in the reaction solvent was added via
micropipette.
2) 100 μL of a solution of 44 μmol B2Pin2 (0.44 M) in the reaction solvent was added via
micropipette.
3) 100 μL of a solution containing 22 μmol HBPin (0.22 M) and 22 μmol B2Pin2 (0.22 M) in the
reaction solvent was added via micropipette.
Then, 100 μL of a 0.2 M stock solution containing 3-chloroaniline (20 μmol) and 2.0 μmol
dodecahydrotriphenylene internal standard in reaction solvent was added to the reaction mixture.
The reaction vessel was then sealed and the reaction mixture stirred at 80 °C for 8h. The reaction
was then cooled to room temperature and quenched by exposure to atmospheric O2 and dilution
1

with MeOH. Volatiles were removed and assay yields were determined by H NMR.

152

Extended Solvent Screen for 3-(trifluoromethyl)anilines (20a). In a nitrogen filled glove box,
1 mmol 3-(trifluoromethyl)aniline was dissolved in 1 mL NMP, DMA or 1.26 g sulfolane in a 15
mL pressure tube containing a magnetic stir bar. 1.5 equiv HBPin (218 μL) was added and the
reaction vessel was sealed and stirred at room temperature for 1h. 0.25 μmol [Ir(OMe)COD]2
(0.25 mol%), 1.0 μmol 3,4,7,8-tetramethyl-1,10-phenanthroline (1.0 mol%), and 100 μmol
dodecahydrotriphenylene (24 mg) internal standard and an additional 1.5 mmol HBPin (218 μL)
and the reaction vessel was sealed and heated at 80 °C for 16h. The reaction mixture was allowed
to return to room temperature and the reaction mixture was exposed to air and diluted with 5 mL
H2O. The product was extracted with DCM and dried under reduced pressure and the product
was purified by passing it through a short plug of SiO2 in MTBE.

Table 5.2. Solvent Screen for 3-(trifluoromethyl)anilines (20)
entry

solvent

yield (%)

meta (%)

ortho (%)

meta : ortho

1

Sulfolane

0

--

--

NA

2

NMP

89

62

27

2.3 : 1.0

6

DMA

36

26

10

2.6 : 1.0

153

Ligand Effects Screen on Borylation of 3-(trifluoromethyl)aniline (20). Reaction was
conducted in 8 × 30 mm borosilicate glass shell vials arranged in 24 well metal blocks (Symyx)
with magnetic stirring. In a nitrogen filled glove box, a 50 μL of 0.01 M stock solutions of
[Ir(OMe)COD]2 (0.5 µmol) in THF were added to a 1 mL reaction vial containing a magnetic
stir bar. 50 μL of a 0.02 M stock solution of ligand (1.0 μmol) in THF was added to reaction
vials containing [Ir(OMe)COD]2. 50 μL of a solution of 30 μmol B2Pin2 (0.6 M) in THF was
added via micropipette. Finally, 50 μL of a 0.2 M stock solution containing 3(trifluoromethyl)aniline (20 μmol) and 2.0 μmol dodecahydrotriphenylene internal standard in
THF was added to the reaction mixture. The reaction vessel was then sealed and stirred at 80 °C
for 16h. The reaction was then cooled to room temperature and quenched by exposure to
atmospheric O2 and dilution with MeOH. Volatiles were removed and assay yields were
1

determined by H NMR.

154

In Situ generation and borylation of 4,4,5,5-tetramethyl-N-(3-(trifluoromethyl)phenyl)1,3,2-dioxaborolan-2-amine. In a nitrogen filled glovebox, 62 µL 3-(trifluoromethyl)aniline
(0.5 mmol) and 21 mg 1,4-bis(trifluoromethyl)-benzene (0.1 mmol) was dissolved in 1 mL
THFd8 and transferred to a screw cap NMR tube. 109 µL HBPin (0.75 mmol) was added via
micro pipette and the tube was loosely sealed. After 30 min, the cap was firmly tightened and
1

H and

19

F NMR were recorded. The NMR tube was returned to the glove box and 1.7 mg

[Ir(OMe)COD]2 (0.25 mol%), 2.4 mg 3,4,7,8-tetramethyl-1,10-phenanthroline (1.0 mol%) and
an additional 109 µL HBPin (0.75 mmol 1.5 equiv HBPin (218 μL) was added and the reaction
vessel was sealed and heated at 80 °C for 8h.

1

H and

19

F NMR of 4,4,5,5-tetramethyl-N-(3-(trifluoromethyl)phenyl)-1,3,2-dioxaborolan-

2-amine (20b)

1

H NMR (500 MHz, THFd8) δ 7.39 (s, 1H), 7.33 (d, J = 8.3 Hz, 1H), 7.24 (t, J = 8.3, 7.8 Hz,

1H), 7.00 (d, J = 7.8 Hz, 1H), 6.32 (br s, 1H), 1.27 (s, 12H);
(s).

155

19

F NMR (470 MHz, THFd8) δ 63.6

1

H and

19

F NMR of 4,4,5,5-tetramethyl-N-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-

5-(trifluoromethyl)phenyl)-1,3,2-dioxaborolan-2-amine (20c)

1

H NMR (500 MHz, THFd8) δ 7.96 (s, 1H), 7.73 (d, J = 7.8 Hz, 1H), 7.00 (d, J = 8.3 Hz, 1H),

6.88 (s, 1H), 1.35 (s, 12H), 1.29 (s, 12H);

1

H and

19

F NMR (470 MHz, THFd8) δ 64.1 (s).

19

F NMR of 4,4,5,5-tetramethyl-N-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-

5-(trifluoromethyl)phenyl)-1,3,2-dioxaborolan-2-amine (20d)

1

H NMR (500 MHz, THFd8) δ 7.67 (s, 1H), 7.57 (s, 1H), 7.42 (s, 1H), 6.26 (s, 1H), 1.31 (s,

12H), 1.27 (s, 12H);

19

F NMR (470 MHz, THFd8) δ 63.4 (s).

156

2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)-5-(trifluoromethyl)-benzenamine (20f)

In a nitrogen filled glovebox, 124 µL 3-(trifluoromethyl)aniline (1.0 mmol, 1.0 equiv) was
dissolved in 1 mL THF in a 15 mL pressure tube containing a magnetic stir bar. 1.5 equiv HBPin
(218 μL) was added and the reaction vessel was sealed and stirred at room temperature for 1h.
2.5 μmol [Ir(OMe)COD]2 (2.5 mol%) and 5.0 μmol 3,4,7,8-tetramethyl-1,10-phenanthroline
(5.0 mol%) were added followed by an additional 1.5 equiv HBPin (218 μL) and the reaction
vessel was sealed and heated at 80 °C for 16h. The reaction mixture was allowed to return to
room temperature and the reaction mixture was exposed to air and diluted with 5 mL MeOH.
The volatiles were then removed under reduced pressure and the product was purified by passing
it through a short plug of SiO2 in MTBE. Purified by column chromatography; heptane: MTBE
1

(90: 10). White solid (153 mg); mp: 64-65 °C; H NMR (500 MHz, CDCl3) δ 7.70 (d, J = 7.9
Hz, 1H), 6.88 (d, J = 7.9 Hz, 1H), 6.80 (s, 1H), 4.92 (br s, 2H), 1.35 (s, 12H);

13

C NMR (125

MHz, CDCl3) δ 153.6, 137.4, 134.4 (q, J = 31.5 Hz), 125.2 (q, J = 272.8 Hz), 112.8 (q, J = 3.8
Hz), 110.9 (q, J = 3.8 Hz), 84.0, 24.9;

19

F NMR (470 MHz, CDCl3) δ 63.6;

11

B NMR (160
+

MHz, CDCl3) δ 30 (br s); HRMS (ESI) m/z calcd for C13H17BF3NO2 [M + H] 288.1383,
7

found 288.1378.

157

3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)-5-(trifluoromethyl)-benzenamine (20e)

Purified by column chromatography; heptane: MTBE (90: 10). White solid (62 mg); mp: 61-62
1

°C; H NMR (500 MHz, CDCl3) δ 7.43 (s, 1H), 7.26 (s, 1H), 6.96 (s, 1H), 3.82 (br s, 2H), 1.34
(s, 12H);

13

C NMR (125 MHz, CDCl3) δ 146.1, 131.2 (q, J = 31.5 Hz), 125.3 (q, J = 272.7 Hz),

124.1, 121.1 (q, J = 3.8 Hz), 113.8 (q, J = 3.8 Hz), 84.2, 24.9;
62.8;

11

19

F NMR (470 MHz, CDCl3) δ

B NMR (160 MHz, CDCl3) δ 31 (br s); HRMS (ESI) m/z calcd for C13H17BF3NO2 [M

+

+ H] 288.1383, found 288.1376.

158

N-methyl-3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)-benzenamine (21b)

In a nitrogen filled glovebox, 122 µL 3-chloro-N-methylaniline (1.0 mmol, 1.0 equiv) was
dissolved in 1 mL THF in a 15 mL pressure tube containing a magnetic stir bar. 2.0 equiv HBPin
(290 μL) was added and the reaction vessel was sealed and stirred at room temperature for 1h.
0.25 μmol [Ir(OMe)COD]2 (0.25 mol%) and 1.0 μmol 3,4,7,8-tetramethyl-1,10-phenanthroline
(1.0 mol%) was added and the reaction vessel was sealed and heated at 80 °C for 16h. The
reaction mixture was allowed to return to room temperature and the reaction mixture was
exposed to air and diluted with 5 mL MeOH. The volatiles were then removed under reduced
pressure and the product was purified by passing it through a short plug of SiO2 in MTBE.
Product isolated by recrystallization from MeOH/H2O. White solid (230 mg, 86% isolated
1

yield); mp: 75-76 °C; H NMR (500 MHz, CDCl3) δ 7.11 (d, J = 2.0 Hz, 1H), 6.90 (d, J = 2.5
Hz, 1H), 6.66 (t, J = 2.4, 2.0 Hz, 1H), 3.77 (br s, 1H), 2.82 (s, 3H), 1.33 (s, 12H);
(125 MHz, CDCl3) δ 133.9, 122.9, 117.0, 114.4, 84.0, 30.6, 24.9;
+

11

13

C NMR

B NMR (160 MHz, CDCl3)

δ 30 (br s); HRMS (ESI) m/z calcd for C13H19BClNO2 [M + H] 268.1276, found 268.1270.

159

5-chloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)-benzenamine (22c)

In a nitrogen filled glovebox, 106 µL 3-(chloro)aniline (1.0 mmol, 1.0 equiv) was dissolved in 1
mL THF in a 15 mL pressure tube containing a magnetic stir bar. 1.5 equiv HBPin (218 μL) was
added and the reaction vessel was sealed and stirred at room temperature for 1h. 2.5 μmol
[Ir(OMe)COD]2 (2.5 mol%) and 5.0 μmol 3,4,7,8-tetramethyl-1,10-phenanthroline (5.0 mol%)
were added followed by an additional 1.5 equiv HBPin (218 μL) and the reaction vessel was
sealed and heated at 80 °C for 16h. The reaction mixture was allowed to return to room
temperature and the reaction mixture was exposed to air and diluted with 5 mL MeOH. The
volatiles were then removed under reduced pressure and the product was purified by passing it
through a short plug of SiO2 in MTBE. Purified by column chromatography; heptane: MTBE
1

(90: 10). White solid (105 mg, 42% isolated yield); mp: 64-65 °C; H NMR (500 MHz, CDCl3)
δ 7.50 (d, J = 7.8 Hz, 1H), 6.63 (dd, J = 7.8, 1.9 Hz, 1H), 6.58 (d, J = 2.0 Hz, 1H), 4.80 (br s,
2H), 1.35 (s, 12H);
24.9;

13

C NMR (125 MHz, CDCl3) δ 154.6, 138.6, 138.0, 117.1, 114.2, 83.6,

11

B NMR (160 MHz, CDCl3) δ 30 (br s); HRMS (ESI) m/z calcd for C12H17BClNO2 [M

+

+ H] 254.1121, found 254.1129.

160

3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (22b)

Purified by column chromatography; heptane: MTBE (90: 10). Yellow solid (43 mg, 17%
1

isolated yield); mp: 54-55 °C; H NMR (500 MHz, CDCl3) δ 7.17 (d, J = 1.0 Hz, 1H), 6.98 (d, J
= 1.9 Hz, 1H) 6.76 (dd, J = 1.9, 1.0 Hz, 1H), 3.70 (br s, 2H), 1.34 (s, 12H);
CDCl3) δ 147.1, 146.3, 124.4, 119.2, 115.4, 84.0, 24.8;

11

13

C NMR (125 MHz,

B NMR (160 MHz, CDCl3) δ 30 (br

+

s); HRMS (ESI) m/z calcd for C12H17BClNO2 [M + H] 254.1121, found 254.1134.

1

13

H and

C NMR of 5-chloro-2,4-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline

(22d)

1

H NMR (500 MHz, CDCl3) δ 7.96 (s, 1H), 6.56 (s, 1H), 4.97 (br s, 2H), 1.34 (s, 12H), 1.33 (s,

12H);

13

C NMR (125 MHz, CDCl3) δ 156.5, 146.3, 144.6, 114.9, 83.6, 83.4, 24.9, 24.8.
161

4-bromo-5-chloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)-benzamine (23)

In a nitrogen filled glovebox, 206 mg 4-bromo-3-chloroaniline (1.0 mmol, 1.0 equiv) was
dissolved in 1 mL THF in a 15 mL pressure tube containing a magnetic stir bar. 1.5 equiv HBPin
(218 μL) was added and the reaction vessel was sealed and stirred at room temperature for 1h.
0.25 μmol [Ir(OMe)COD]2 (0.25 mol%) and 1.0 μmol 3,4,7,8-tetramethyl-1,10-phenanthroline
(1.0 mol%) were added followed by an additional 1.5 equiv HBPin (218 μL) and the reaction
vessel was sealed and heated at 80 °C for 16h. The reaction mixture was allowed to return to
room temperature and the reaction mixture was exposed to air and diluted with 5 mL MeOH.
The volatiles were then removed under reduced pressure and the product was purified by passing
it through a short plug of SiO2 in MTBE. Product isolated by recrystallization from MeOH/H2O.
1

White solid (305 mg, 92% isolated yield); mp: 79-81 °C; H NMR (500 MHz, CDCl3) δ 7.76 (s,
1H), 6.70 (s, 1H), 4.80 (br s, 2H), 1.33 (s, 12H);
138.0, 116.0, 108.4, 84.0, 24.9;

13

C NMR (125 MHz, CDCl3) δ 153.3, 141.0,

11

B NMR (160 MHz, CDCl3) δ 30 (br s); HRMS (ESI) m/z
+

calcd for C12H17BBrClNO2 [M + H] 332.0224, found 332.0222.

162

4-methoxy-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)-benzenamine (24)

In a nitrogen filled glovebox, 115 µL p-anisidine (1.0 mmol, 1.0 equiv) was dissolved in 1 mL
THF in a 15 mL pressure tube containing a magnetic stir bar. 1.5 equiv HBPin (218 μL) was
added and the reaction vessel was sealed and stirred at room temperature for 1h. 0.25 μmol
[Ir(OMe)COD]2

(0.25 mol%)

and

1.0 μmol 3,4,7,8-tetramethyl-1,10-phenanthroline (1.0

mol%) were added followed by an additional 1.5 equiv HBPin (218 μL) and the reaction vessel
was sealed and heated at 80 °C for 16h. The reaction mixture was allowed to return to room
temperature and the reaction mixture was exposed to air and diluted with 5 mL MeOH. The
volatiles were then removed under reduced pressure and the product was purified by passing it
through a short plug of SiO2 in MTBE. Product isolated by recrystallization from MeOH/H2O.
1

Pale red solid (157 mg, 63% isolated yield); mp: 73-74 °C; H NMR (500 MHz, C6D6) δ 7.60
(d, J = 2.9 Hz, 1H), 6.94 (dd, J = 8.3, 2.9 Hz, 1H), 6.53 (d, J = 8.8 Hz, 1H), 4.31 (br s, 2H), 3.37
(s, 3H), 1.03 (s, 12H);
56.0, 24.9;

13

C NMR (125 MHz, CDCl3) δ 147.9, 133.9, 120.6, 119.6, 116.5, 83.8,

11

B NMR (160 MHz, CDCl3) δ 31 (br s); HRMS (ESI) m/z calcd for C13H20BNO3

+

[M + H] 250.1617, found 250.1616.

163

4-chloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)-benzenamine (25)

In a nitrogen filled glovebox, 128 mg 4-chloroaniline (1.0 mmol, 1.0 equiv) was dissolved in 1
mL THF in a 15 mL pressure tube containing a magnetic stir bar. 1.5 equiv HBPin (218 μL) was
added and the reaction vessel was sealed and stirred at room temperature for 1h. 0.25 μmol
[Ir(OMe)COD]2

(0.25 mol%)

and

1.0 μmol 3,4,7,8-tetramethyl-1,10-phenanthroline (1.0

mol%) were added followed by an additional 1.5 equiv HBPin (218 μL) and the reaction vessel
was sealed and heated at 80 °C for 16h. The reaction mixture was allowed to return to room
temperature and the reaction mixture was exposed to air and diluted with 5 mL MeOH. The
volatiles were then removed under reduced pressure and the product was purified by passing it
through a short plug of SiO2 in MTBE. Product isolated by recrystallization from MeOH/H2O.
1

White solid (236 mg, 93% isolated yield); mp: 91-93 °C; H NMR (500 MHz, CDCl3) δ 7.54 (d,
J = 2.5 Hz, 1H), 7.14 (dd, J = 8.8, 2.5 Hz, 1H), 6.53 (d, J = 8.8 Hz, 1H), 4.69 (br s, 2H), 1.33 (s,
12H);

13

C NMR (125 MHz, CDCl3) δ 152.0, 135.8, 132.4, 121.6, 116.2, 83.9, 24.9;
+

11

B NMR

(160 MHz, CDCl3) δ 30 (br s); HRMS (ESI) m/z calcd for C12H17BClNO2 [M + H] 254.1119,
found 254.1116.

164

4-amino-2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)-benzonitrile (26)

In a nitrogen filled glovebox, 152 mg 4-amino-2-2chlorobenzonitrile (1.0 mmol, 1.0 equiv) was
dissolved in 1 mL THF in a 15 mL pressure tube containing a magnetic stir bar. 1.5 equiv HBPin
(218 μL) was added and the reaction vessel was sealed and stirred at room temperature for 1h.
0.25 μmol [Ir(OMe)COD]2 (0.25 mol%) and 1.0 μmol 3,4,7,8-tetramethyl-1,10-phenanthroline
(1.0 mol%) were added followed by an additional 1.5 equiv HBPin (218 μL) and the reaction
vessel was sealed and heated at 80 °C for 16h. The reaction mixture was allowed to return to
room temperature and the reaction mixture was exposed to air and diluted with 5 mL MeOH.
The volatiles were then removed under reduced pressure and the product was purified by passing
it through a short plug of SiO2 in MTBE. Product isolated by recrystallization from MeOH/H2O.
1

White solid (250 mg, 90% isolated yield); mp: 123-125 °C; H NMR (500 MHz, CDCl3) δ 7.87
(s, 1H), 6.61 (s, 1H), 5.32 (br s, 2H), 1.34 (s, 12H);

13

C NMR (125 MHz, CDCl3) δ 157.1,

11

B NMR (160 MHz, CDCl3) δ 30 (br s); HRMS

143.37, 140.4, 117.3, 114.5, 100.1, 84.4, 24.9;
+

(ESI) m/z calcd for C13H16BClN2O2 [M + H] 279.1072, found 279.1068.

165

5-chloro-4-methoxy-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)-benzamine (27)

In a nitrogen filled glovebox, 154 mg 3-chloro-4-methoxyaniline (1.0 mmol, 1.0 equiv) was
dissolved in 1 mL THF in a 15 mL pressure tube containing a magnetic stir bar. 1.5 equiv HBPin
(218 μL) was added and the reaction vessel was sealed and stirred at room temperature for 1h.
0.25 μmol [Ir(OMe)COD]2 (0.25 mol%) and 1.0 μmol 3,4,7,8-tetramethyl-1,10-phenanthroline
(1.0 mol%) were added followed by an additional 1.5 equiv HBPin (218 μL) and the reaction
vessel was sealed and heated at 80 °C for 16h. The reaction mixture was allowed to return to
room temperature and the reaction mixture was exposed to air and diluted with 5 mL MeOH.
The volatiles were then removed under reduced pressure and the product was purified by passing
it through a short plug of SiO2 in MTBE. Product isolated by recrystallization from MeOH/H2O.
1

White solid (210 mg, 74% isolated yield); mp: 133-134 °C; H NMR (500 MHz, CDCl3) δ 7.15
(s, 1H), 6.67 (s, 1H), 4.49 (br s, 2H), 3.84 (s, 3H), 1.34 (s, 12H);
δ 148.4, 146.8, 127.6, 119.9, 116.9, 83.8, 57.0, 24.9;
+

11

13

C NMR (125 MHz, CDCl3)

B NMR (160 MHz, CDCl3) δ 31 (br s);

HRMS (ESI) m/z calcd for C13H19BClNO3 [M + H] 284.1225, found 284.1220.

166

4-bromo-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)-benzenamine (29)

In a nitrogen filled glovebox, 170 mg 4-bromoaniline (1.0 mmol, 1.0 equiv) was dissolved in 1
mL THF in a 15 mL pressure tube containing a magnetic stir bar. 1.5 equiv HBPin (218 μL) was
added and the reaction vessel was sealed and stirred at room temperature for 1h. 0.25 μmol
(0.25 mol%)

[Ir(OMe)COD]2

and

1.0 μmol 3,4,7,8-tetramethyl-1,10-phenanthroline (1.0

mol%) were added followed by an additional 1.5 equiv HBPin (218 μL) and the reaction vessel
was sealed and heated at 80 °C for 16h. The reaction mixture was allowed to return to room
temperature and the reaction mixture was exposed to air and diluted with 5 mL MeOH. The
volatiles were then removed under reduced pressure and the product was purified by passing it
through a short plug of SiO2 in MTBE. Product isolated by recrystallization from MeOH/H2O.
White solid (246 mg, 88% isolated yield); mp: 101-102 °C;

1

H NMR (500 MHz, CD2Cl2) δ

7.62 (d, J = 2.5 Hz, 1H), 7.27 (dd, J = 8.8, 2.5 Hz, 1H), 6.53 (d, J = 8.3 Hz, 1H), 4.85 (br s, 2H),
1.34 (s, 12H);

13

C NMR (125 MHz, CD2Cl2) δ 152.5, 138.5, 135.0, 116.5, 108.1, 83.9, 24.6;

11

B NMR (160 MHz, CD2Cl2) δ 30 (br s); HRMS (ESI) m/z calcd for C12H17BBrNO2 [M +
+

H] 298.0614, found 298.0609.

167

4-chloro-5-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)-benzamine (31)

In a nitrogen filled glovebox, 145 mg 4-chloro-3-fluoroaniline (1.0 mmol, 1.0 equiv) was
dissolved in 1 mL THF in a 15 mL pressure tube containing a magnetic stir bar. 1.5 equiv HBPin
(218 μL) was added and the reaction vessel was sealed and stirred at room temperature for 1h.
0.25 μmol [Ir(OMe)COD]2 (0.25 mol%) and 1.0 μmol 3,4,7,8-tetramethyl-1,10-phenanthroline
(1.0 mol%) were added followed by an additional 1.5 equiv HBPin (218 μL) and the reaction
vessel was sealed and heated at 80 °C for 16h. The reaction mixture was allowed to return to
room temperature and the reaction mixture was exposed to air and diluted with 5 mL MeOH.
The volatiles were then removed under reduced pressure and the product was purified by passing
1

it through a short plug of SiO2 in MTBE. 8% 2-borylated isomer was observed by H NMR but
not isolated. Product isolated by recrystallization from MeOH/H2O. White solid (244 mg, 90%
1

isolated yield); mp: 95-96 °C; H NMR (500 MHz, CDCl3) δ 7.58 (d, J = 9.3 Hz, 1H), 6.36 (d, J
= 11.2 Hz, 1H), 4.84 (br s, 2H), 1.33 (s, 12H);

13

C NMR (125 MHz, CDCl3) δ 161.9 (d, J =

249.8 Hz), 154.0 (d, J = 10.5 Hz), 138.4 (d, J = 2.9 Hz), 125.5, 102.4 (d, J = 23.9 Hz), 83.9,
24.9;

19

F NMR (470 MHz, CDCl3) δ 110.9 (t, J = 10 Hz);

11

B NMR (160 MHz, CDCl3) δ 30

+

(br s); HRMS (ESI) m/z calcd for C12H16BClFNO2 [M + H] 272.1025, found 272.1019.

168

4-amino-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)-phenol (32)

In a nitrogen filled glovebox, 109 mg 4-aminophenol (1.0 mmol, 1.0 equiv) was dissolved in 1
mL THF in a 15 mL pressure tube containing a magnetic stir bar. 4.0 equiv HBPin (580 μL) was
added and the reaction vessel was sealed and stirred at room temperature for 1h. 0.25 μmol
[Ir(OMe)COD]2

(0.25 mol%)

and

1.0 μmol 3,4,7,8-tetramethyl-1,10-phenanthroline (1.0

mol%) were added and the reaction vessel was sealed and heated at 80 °C for 16h. The reaction
mixture was allowed to return to room temperature and the reaction mixture was exposed to air
and diluted with 5 mL MeOH. The volatiles were then removed under reduced pressure and the
product was purified by passing it through a short plug of SiO2 in DCM. Compound was purified
1

by recrystallized from DCM: hexanes. White solid (165 mg, 70% isolated yield); H NMR (500
MHz, CDCl3) δ 7.06 (d, J = 2.9 Hz, 1H), 6.78 (dd, J = 8.3, 3.0 Hz, 1H), 6.53 (d, J = 8.3 Hz, 1H),
4.44 (br s, 3H), 1.33 (s, 12H);
83.7, 24.9;

13

C NMR (125 MHz, CDCl3) δ 147.6, 147.0, 121.9, 120.6, 116.5,

11

B NMR (160 MHz, CDCl3) δ 30 (br s); HRMS (ESI) m/z calcd for C12H18BNO3

+

[M + H] 236.1414, found 236.1413.

169

4-amino-2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)-phenol (33)

In a nitrogen filled glovebox, 143 mg 4-amino-2-chlorophenol (1.0 mmol, 1.0 equiv) was
dissolved in 1 mL THF in a 15 mL pressure tube containing a magnetic stir bar. 4.0 equiv HBPin
(580 μL) was added and the reaction vessel was sealed and stirred at room temperature for 1h.
0.25 μmol [Ir(OMe)COD]2 (0.25 mol%) and 1.0 μmol 3,4,7,8-tetramethyl-1,10-phenanthroline
(1.0 mol%) were added and the reaction vessel was sealed and heated at 80 °C for 16h. The
reaction mixture was allowed to return to room temperature and the reaction mixture was
exposed to air and diluted with 5 mL MeOH. The volatiles were then removed under reduced
pressure and the product was purified by passing it through a short plug of SiO2 in DCM.
Compound was purified by recrystallization from DCM / hexanes. White solid (170 mg, 63%
1

isolated yield); H NMR (500 MHz, CDCl3) δ 7.36 (s, H), 6.61 (s, 1H), 4.84 (br s, 1H), 4.40 (br
s, 2H), 1.33 (s, 12H);
24.9;

13

C NMR (125 MHz, CDCl3) δ 147.8, 142.8, 124.5, 123.1, 115.0, 83.8,

11

B NMR (160 MHz, CDCl3) δ 30 (br s); HRMS (ESI) m/z calcd for C12H17BClNO3 [M

+

+ H] 270.1068, found 270.1066.

170

4-amino-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (34)

In a nitrogen filled glovebox, 118 mg 4-aminobenzonitrile (1.0 mmol, 1.0 equiv) was dissolved
in 1 mL n-hexane in a 15 mL pressure tube containing a magnetic stir bar. 2.0 equiv HBPin (290
μL) was added and the reaction vessel was sealed and stirred at room temperature for 1h. 1.5
4

4

4’

4’

μmol [Ir(OMe)COD]2 (1.5 mol%) and 3.0 μmol N ,N ,N ,N -tetramethyl-[2,2'-bipyridine]4,4'-diamine (3.0 mol%) were added and the reaction vessel was sealed and heated at 80 °C for
16h. The reaction mixture was allowed to return to room temperature and the reaction mixture
was exposed to air and diluted with 5 mL MeOH. The volatiles were then removed under
reduced pressure and the product was purified by passing it through a short plug of SiO2 in
MTBE. Product isolated by recrystallization from MeOH/H2O. White solid (146 mg, 60%
1

1

isolated yield, (83% assay yield by H NMR); mp: 96-97 °C; H NMR (500 MHz, CDCl3) δ
7.92 (d, J = 2.0 Hz, 1H), 7.43 (dd, J = 8.8, 2.0 Hz, 1H), 6.57 (d, J = 8.8 Hz, 1H), 5.27 (br s, 2H),
1.37 (s, 12H);
24.9;

13

C NMR (125 MHz, CDCl3) δ 156.5, 141.9, 135.9, 120.2, 114.5, 99.0, 84.2,

11

B NMR (160 MHz, CDCl3) δ 30 (br s); HRMS (ESI) m/z calcd for C13H17BN2O2 [M +

+

H] 245.1464, found 245.1594.

171

4-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)-benzamine (35)

In a nitrogen filled glovebox, 95 µL 4-fluoroaniline (1.0 mmol, 1.0 equiv) was dissolved in 1 mL
n-hexane in a 15 mL pressure tube containing a magnetic stir bar. 2.0 equiv HBPin (290 μL) was
added and the reaction vessel was sealed and stirred at room temperature for 1h. 1.5 μmol
4

4

4’

4’

[Ir(OMe)COD]2 (1.5 mol%) and 3.0 μmol N ,N ,N ,N -tetramethyl-[2,2'-bipyridine]-4,4'diamine (3.0 mol%) were added and the reaction vessel was sealed and heated at 80 °C for 16h.
The reaction mixture was allowed to return to room temperature and the reaction mixture was
exposed to air and diluted with 5 mL MeOH. The volatiles were then removed under reduced
pressure and the product was purified by passing it through a short plug of SiO2 in MTBE.
Compound was purified by recrystallization from DCM / hexanes. Yellow oil (102 mg, 43%
1

1

isolated yield (74% assay yield by H NMR)); H NMR (500 MHz, CD2Cl2) δ 7.20 (dd, J = 9.3,
3.0 Hz, 1H), 6.91 (td, J = 17.1, 8.8, 3.5 Hz, 1H), 6.54 (q, J = 4.4 Hz, 1H), 4.46 (br s, 2 H), 1.33
(s, 12H);

13

C NMR (125 MHz, CD2Cl2) δ 155.9 (d J = 276.2 Hz), 150.1, 121.2 (d, J = 20 Hz),

119.4 (d, J = 23 Hz), 115.7 (d, J = 6.7 Hz), 84.0, 24.6;
(td, J = 21.6, 13.2, 5.0 Hz);

11

19

F NMR (470 MHz, CD2Cl2) δ 130.2

B NMR (160 MHz, CD2Cl2) δ 30 (br s); HRMS (ESI) m/z calcd

+

for C12H17BFNO2 [M + H] 238.1417, found 238.1540.

172

2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)-benzenamine (37)

In a nitrogen filled glovebox, 113 µL o-anisidine (1.0 mmol, 1.0 equiv) was dissolved in 1 mL
THF in a 15 mL pressure tube containing a magnetic stir bar. 1.5 equiv HBPin (218 μL) was
added and the reaction vessel was sealed and stirred at room temperature for 1h. 0.25 μmol
[Ir(OMe)COD]2

(0.25 mol%)

and

1.0 μmol 3,4,7,8-tetramethyl-1,10-phenanthroline (1.0

mol%) were added followed by an additional 1.5 equiv HBPin (218 μL) and the reaction vessel
was sealed and heated at 80 °C for 16h. The reaction mixture was allowed to return to room
temperature and the reaction mixture was exposed to air and diluted with 5 mL MeOH. The
volatiles were then removed under reduced pressure and the product was purified by passing it
through a short plug of SiO2 in MTBE. Product isolated by recrystallization from MeOH/H2O.
1

White solid (152 mg, 61% isolated yield); mp: 68-70 °C; H NMR (500 MHz, CDCl3) δ 7.30
(dd, J = 7.8, 1.5 Hz, 1H), 7.20 (d, J = 1.5 Hz, 1H), 6.71 (d, J = 7.5 Hz, 1H), 4.08 (br s, 2H), 3.89
(s, 3H), 1.33 (s, 12H);
55.5, 24.8;

13

C NMR (125 MHz, CDCl3) δ 146.5, 139.3, 128.8, 115.9, 114.1, 83.3,

11

B NMR (160 MHz, CDCl3) δ 31 (br s); HRMS (ESI) m/z calcd for C13H20BNO3

+

[M + H] 250.1614, found 250.1612.

173

Figure 5.1. 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)-benzenamine (37).
The following are 50% thermal ellipsoidal drawings of the molecule in the asymmetric cell with
various amount of labeling.

Crystal structure determination of 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan2yl)-benzenamine. Crystal Data. C13H20BNO3, M = 249.11, orthorhombic, a = 7.76150(10)
3

Å, b = 9.78630(10) Å, c = 17.9222(2) Å, V = 1371.31(3) Å , T = 173(2) K, space group P212121
-1

(# 19), Z = 4, µ(Cu Kα) = 0.678 mm , 9806 reflections measured, 2457 unique (Rint = 0.0258)
which were used in all calculations. The final wR2 was 0.0842 (all data) an R1 was 0.0319
(>2σ(I)).

174

5-amino-2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)-pyridine (38)

In a nitrogen filled glovebox, 128 mg 6-chloropyridin-3-amine (1.0 mmol, 1.0 equiv) was
dissolved in 1 mL THF in a 15 mL pressure tube containing a magnetic stir bar. 1.2 equiv HBPin
(173 μL) was added and the reaction vessel was sealed and stirred at room temperature for 1h.
1.5 μmol [Ir(OMe)COD]2 (1.5 mol%), 3.0 μmol 3,4,7,8-tetramethyl-1,10-phenanthroline (3.0
mol%) and 0.5 equiv B2Pin2 (127 mg) were added and the reaction vessel was sealed and heated
at 80 °C for 8h. The reaction mixture was allowed to return to room temperature and the reaction
mixture was exposed to air and diluted with 5 mL MeOH. The volatiles were then removed
under reduced pressure and the product was purified by passing it through a short plug of SiO2 in
DCM. Compound was purified by recrystallization from DCM / hexanes. White solid (224 mg,
1

88% isolated yield); mp: 116-117 °C; H NMR (500 MHz, CDCl3) δ 7.81 (s, 1H), 7.41 (s, 1H),
4.68 (br s, 2H), 1.34 (s, 12H);
24.9;

13

C NMR (125 MHz, CDCl3) δ 147.3, 138.7, 136.8, 129.4, 84.6,

11

B NMR (160 MHz, CDCl3) δ 30 (br s); HRMS (ESI) m/z calcd for C11H16BClN2O2 [M

+

+ H] 255.1016, found 255.0990.

175

5-amino-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)-2-methyl pyridine (39)

In a nitrogen filled glovebox, 108 mg 6-methylpyridin-3-amine (1.0 mmol, 1.0 equiv) was
dissolved in 1 mL THF in a 15 mL pressure tube containing a magnetic stir bar. 1.2 equiv HBPin
(173 μL) was added and the reaction vessel was sealed and stirred at room temperature for 1h.
1.5 μmol [Ir(OMe)COD]2 (1.5 mol%), 3.0 μmol 3,4,7,8-tetramethyl-1,10-phenanthroline (3.0
mol%) and 0.5 equiv B2Pin2 (127 mg) were added and the reaction vessel was sealed and heated
at 80 °C for 8h. The reaction mixture was allowed to return to room temperature and the reaction
mixture was exposed to air and diluted with 5 mL MeOH. The volatiles were then removed
under reduced pressure and the product was purified by passing it through a short plug of SiO2 in
MTBE. Compound was purified by recrystallization from hexanes / EtOAc. White solid (152
1

mg, 63% isolated yield); mp: 68-70 °C; H NMR (500 MHz, CD2Cl2) δ 7.95 (s, H), 7.23 (s, 1H),
4.55 (br s, 2H), 2.37 (s, 3H), 1.36 (s, 12H);
136.7, 128.2, 84.2, 24.7, 22.5;

13

C NMR (125 MHz, CD2Cl2) δ 146.2, 145.6,

11

B NMR (160 MHz, CD2Cl2) δ 30 (br s); HRMS (ESI) m/z

+

calcd for C12H19BN2O2 [M + H] 235.1620, found 235.1387.

176

2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-4-amine (40)

In a nitrogen filled glovebox, 128 mg 2-chloropyridin-4-amine (1.0 mmol, 1.0 equiv) was
dissolved in 1 mL THF in a 15 mL pressure tube containing a magnetic stir bar. 1.2 equiv HBPin
(173 μL) was added and the reaction vessel was sealed and stirred at room temperature for 1h.
1.5 μmol [Ir(OMe)COD]2 (1.5 mol%), 3.0 μmol 3,4,7,8-tetramethyl-1,10-phenanthroline (3.0
mol%) and 0.5 equiv B2Pin2 (127 mg) were added and the reaction vessel was sealed and heated
at 80 °C for 8h. The reaction mixture was allowed to return to room temperature and the reaction
mixture was exposed to air and diluted with 5 mL MeOH. The volatiles were then removed
under reduced pressure and the product was purified by passing it through a short plug of SiO2 in
DCM. Product isolated by recrystallized from MeOH/ H2O. White solid (249 mg, 98% isolated
1

yield); mp: 170-171 °C; H NMR (500 MHz, CDCl3) δ 8.34 (s, 1H), 6.46 (s, 1H), 5.29 (br s, 2H),
1.34 (s, 12H);

13

C NMR (125 MHz, CDCl3) δ 160.3, 157.5, 154.8, 107.7, 84.1, 24.9;

11

B NMR
+

(160 MHz, CDCl3) δ 30 (br s); HRMS (ESI) m/z calcd for C11H16BClN2O2 [M + H]
255.1074, found 255.1206.

177

2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-4-amine (41)

In a nitrogen filled glovebox, 124 mg 2-methoxypyridin-4-amine (1.0 mmol, 1.0 equiv) was
dissolved in 1 mL THF in a 15 mL pressure tube containing a magnetic stir bar. 1.2 equiv HBPin
(173 μL) was added and the reaction vessel was sealed and stirred at room temperature for 1h.
1.5 μmol [Ir(OMe)COD]2 (1.5 mol%), 3.0 μmol 3,4,7,8-tetramethyl-1,10-phenanthroline (3.0
mol%) and 0.5 equiv B2Pin2 (127 mg) were added and the reaction vessel was sealed and heated
at 80 °C for 8h. The reaction mixture was allowed to return to room temperature and the reaction
mixture was exposed to air and diluted with 5 mL MeOH. The volatiles were then removed
under reduced pressure and the product was purified by passing it through a short plug of SiO2 in
DCM. Product isolated by recrystallized from MeOH/ H2O. White solid (150 mg, 60% isolated
yield); mp: 91-94 °C; ; 1H NMR (500 MHz, CDCl3) δ 8.27 (s, 1H), 5.83 (s, 1H), 5.10 (br s, 2H), 3.89 (s,
3H), 1.34 (s, 12H); 13C NMR (125 MHz, CDCl3) δ 160.7, 156.3, 148.5, 92.0, 83.5, 53.3, 24.9; 11B NMR
(160 MHz, CDCl3) δ 30 (br s); HRMS (ESI) m/z calcd for C12H19BN2O3 [M + H]+ 251.1569, found
251.1700.

4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-(trifluoromethyl)pyridin-2-amine (42)
178

In a nitrogen filled glovebox, 162 mg 6-(trifluoromethyl)pyridin-2-amine (1.0 mmol, 1.0 equiv)
was dissolved in 1 mL THF in a 15 mL pressure tube containing a magnetic stir bar. 1.2 equiv
HBPin (173 μL) was added and the reaction vessel was sealed and stirred at room temperature
for 1h. 1.5 μmol [Ir(OMe)COD]2 (1.5 mol%), 3.0 μmol 3,4,7,8-tetramethyl-1,10-phenanthroline
(3.0 mol%) and 0.5 equiv B2Pin2 (127 mg) were added and the reaction vessel was sealed and
heated at 80 °C for 8h. The reaction mixture was allowed to return to room temperature and the
reaction mixture was exposed to air and diluted with 5 mL MeOH. The volatiles were then
removed under reduced pressure and the product was purified by passing it through a short plug
of SiO2 in DCM. Product isolated by recrystallized from MeOH/ H2O. White solid (282 mg,
1

98% isolated yield); mp: 97-98 °C; H NMR (500 MHz, CDCl3) δ 7.32 (s, 1H), 7.03 (s, 1H),
4.74 (br s, 2H), 1.34 (s, 12H);

13

C NMR (125 MHz, CDCl3) δ 158.0, 145.9 (q, J = 33 Hz),

122.8 (q, J = 273 Hz), 117.8, 114.5 (q, J = 3 Hz), 84.7, 24.8;
68.5;

19

F NMR (470 MHz, CDCl3) δ

11

B NMR (160 MHz, CDCl3) δ 30 (br s); HRMS (ESI) m/z calcd for C12H16BF3N2O2 [M

+

+ H] 289.1337, found 289.1680.

6-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (43)
179

In a nitrogen filled glovebox, 128 mg 6-chloropyridin-2-amine (1.0 mmol, 1.0 equiv) was
dissolved in 1 mL THF in a 15 mL pressure tube containing a magnetic stir bar. 1.2 equiv HBPin
(173 μL) was added and the reaction vessel was sealed and stirred at room temperature for 1h.
1.5 μmol [Ir(OMe)COD]2 (1.5 mol%), 3.0 μmol 3,4,7,8-tetramethyl-1,10-phenanthroline (3.0
mol%) and 0.5 equiv B2Pin2 (127 mg) were added and the reaction vessel was sealed and heated
at 80 °C for 8h. The reaction mixture was allowed to return to room temperature and the reaction
mixture was exposed to air and diluted with 5 mL MeOH. The volatiles were then removed
under reduced pressure and the product was purified by passing it through a short plug of SiO2 in
DCM. Product isolated by recrystallized from MeOH/ H2O. White solid (170 mg, 67% isolated
1

yield); mp: 160-163 °C; H NMR (500 MHz, CDCl3) δ 6.99 (s, 1H), 6.75 (s, 1H), 4.54 (br s, 2H),
1.34 (s, 12H);

13

C NMR (125 MHz, CDCl3) δ 158.1, 149.4, 117.8, 112.0, 84.6, 24.8;

11

B NMR
+

(160 MHz, CDCl3) δ 30 (br s); HRMS (ESI) m/z calcd for C11H16BClN2O2 [M + H]
255.1074, found 255.1205.

180

In Situ generation of 6-chloro-N-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2amine

In a nitrogen filled glovebox 128 mg 6-chloropyridin-2-amine (1 mmol) was dissolved in 1 mL
CDCl3 in a screw cap NMR tube. 1.5 equiv HBpin (218 μL) was added and the tube was sealed
1

and kept at room temperature for 1h. Quantitative conversion was observed by NMR. H NMR
(500 MHz, CDCl3) δ 7.40 (t, J = 7.8, 7.3 Hz, 1H), 7.24 (d, J = 8.3 Hz, 1H), 6.72 (d, J = 7.3 Hz,
1H), 5.55 (s, 1H), 1.26 (s, 12H) );

11

B NMR (160 MHz, CDCl3) δ 24 (br s).

181

Table 5.3. Crystal data and structure refinement for 37.
Identification code
37
Empirical formula
C13 H20 B N O3
Formula weight
249.11
Temperature
173(2) K
Wavelength
1.54178 Å
Crystal system
Orthorhombic
Space group
P 21 21 21
Unit cell dimensions
a = 7.76150(10) Å
b = 9.78630(10) Å
Volume
Z
Density (calculated)
Absorption coefficient
F(000)
Crystal size
Theta range for data collection
Index ranges
Reflections collected
Independent reflections
Completeness to theta = 67.99°
Absorption correction
Max. and min. transmission
Refinement method
Data / restraints / parameters
Goodness-of-fit on F2

c = 17.9222(2) Å
1361.31(3) Å3
4
1.215 Mg/m3
0.678 mm-1

α= 90°.
β= 90°.
γ= 90°.

536
0.44 x 0.35 x 0.35 mm3
4.94 to 67.99°.
-9<=h<=9, -11<=k<=11, -19<=l<=21
9806
2457 [R(int) = 0.0258]
99.4 %
Semi-empirical from equivalents
0.7967 and 0.7555
Full-matrix least-squares on F2

Final R indices [I>2sigma(I)]
R indices (all data)

2457 / 0 / 168
1.123
R1 = 0.0317, wR2 = 0.0839
R1 = 0.0319, wR2 = 0.0842

Absolute structure parameter
Largest diff. peak and hole

0.03(17)
0.156 and -0.214 e.Å-3

182

F

Table 5.4. Crystal data and structure refinement for Trans-(Ar 3P)2Ir(BPin)3 (12).
Identification code
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°
Absorption correction
Max. and min. transmission
Refinement method
Data / restraints / parameters
Goodness-of-fit on F2
Final R indices [I>2sigma(I)]
R indices (all data)
Largest diff. peak and hole

F

Trans-(Ar 3P)2Ir(BPin)3 (12).
C66 H54 B3 F36 Ir O6 P2
1913.66
173(2) K
0.71073 Å
Monoclinic
C 2/c
a = 24.853(2) Å
α= 90°.
b = 13.8099(10) Å
β= 105.221(2)°.
c = 22.283(2) Å
7379.7(11) Å3

γ= 90°.

4
1.722 Mg/m3
1.994 mm-1
3776
0.21 x 0.11 x 0.07 mm3
1.70 to 25.36°.
-29<=h<=29, -16<=k<=16, -26<=l<=26
53170
6768 [R(int) = 0.0526]
100.0 %
Semi-empirical from equivalents
0.8665 and 0.6773
Full-matrix least-squares on F2
6768 / 177 / 620
1.043
R1 = 0.0279, wR2 = 0.0665
R1 = 0.0320, wR2 = 0.0687
0.903 and -0.638 e.Å-3

183

F

Table 5.5. Crystal data and structure refinement for Trans-(Ar 3P)2Ir(H)(BPin)2 (13).
Identification code
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 = 68.53°
Absorption correction
Max. and min. transmission
Refinement method
Data / restraints / parameters
Goodness-of-fit on F2
Final R indices [I>2sigma(I)]
R indices (all data)
Largest diff. peak and hole

F

Trans-(Ar 3P)2Ir(H)(BPin)2 (13).
C60 H42 B2 F36 Ir O4 P2
1786.70
120(2) K
1.54178 Å
Triclinic
P -1
a = 10.6867(4) Å
α= 79.792(4)°.
b = 14.1473(6) Å
β= 88.238(3)°.
c = 24.3165(10) Å
3485.9(2) Å3

γ= 74.490(3)°.

2
1.702 Mg/m3
5.440 mm-1
1750
0.295 x 0.215 x 0.074 mm3
3.29 to 68.53°.
-12<=h<=12, -16<=k<=17, 0<=l<=29
24742
24742 [R(int) = 0.0000]
98.3 %
Semi-empirical from equivalents
0.753056 and 0.529282
Full-matrix least-squares on F2
24742 / 147 / 1036
1.100
R1 = 0.0903, wR2 = 0.2198
R1 = 0.1106, wR2 = 0.2377
1.632 and -2.387 e.Å-3

184

1

H NMR (500 MHz, CDCl3) N,N-Dimethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborlan-2-yl)-5-methyl benzamine (5b)

185

13

C NMR (125 MHz, CDCl3) N,N-Dimethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborlan-2-yl)-5-methyl benzamine (5b)

186

1

H NMR (500 MHz, CD2Cl2) (tmphen)Ir(COD(Cl)

187

13

C NMR (125 MHz, CD2Cl2) (tmphen)Ir(COD(Cl)

188

1

H NMR (500 MHz, THFd8, -35 °C) (tmphen)Ir(BPin)3(COE)

189

13

C NMR (125 MHz, THFd8, -35 °C) (tmphen)Ir(BPin)3(COE)

190

1

H NMR (500 MHz, CDCl3) methyl 2,6-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (10c)

191

13

C NMR (125 MHz, CDCl3) methyl 2,6-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (10c)

192

1

H NMR (500 MHz, C6D6) (2-(diisopropylsilyl)phenyl)di-p-tolylphosphane (SiPbz)

193

13

C NMR (125 MHz, C6D6) (2-(diisopropylsilyl)phenyl)di-p-tolylphosphane (SiPbz)

194

1

H NMR (500 MHz, C6D6) N-(dimethylsilyl)-N-(pyridin-2-yl)pyridin-2-amine (14b)

195

13

C NMR (125 MHz, C6D6) N-(dimethylsilyl)-N-(pyridin-2-yl)pyridin-2-amine (14b)

196

1

H NMR (500 MHz, CDCl3) 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)-7-azaindole (18a)

197

13

C NMR (125 MHz, CDCl3) 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)-7-azaindole (18a)

198

1

H NMR (500 MHz, CDCl3) 3,5-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)-7-azaindole (18b)

199

13

C NMR (125 MHz, CDCl3) 3,5-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)-7-azaindole (18b)

1

H NMR (500 MHz, DMSO-d6) 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)-4-azaindole (19)
200

13

C NMR (125 MHz, DMSO-d6) 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)-4-azaindole (19)

201

1

H NMR (500 MHz, CDCl3) 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)-5-(trifluoromethyl)-benzenamine (20f)
202

13

C NMR (125 MHz, CDCl3) 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)-5-(trifluoromethyl)-benzenamine (20f)

203

1

H NMR (500 MHz, CDCl3) 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)-5-(trifluoromethyl)-benzenamine (20e)

204

13

C NMR (125 MHz, CDCl3) 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)-5-(trifluoromethyl)-benzenamine (20e)

205

1

H NMR (500 MHz, CDCl3) N-methyl-3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)-benzenamine (21b)

206

207

13

C NMR (125 MHz, CDCl3) N-methyl-3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)-benzenamine (21b)

208

1

H NMR (500 MHz, CDCl3) 5-chloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)-benzenamine (22c)

209

13

C NMR (125 MHz, CDCl3) 5-chloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)-benzenamine (22c)

210

1

H NMR (500 MHz, CDCl3) 3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (22b)

211

13

C NMR (125 MHz, CDCl3) 3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (22b)

212

1

H NMR (500 MHz, CDCl3) 4-bromo-5-chloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)-benzamine (23)

213

13

C NMR (125 MHz, CDCl3) 4-bromo-5-chloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)-benzamine (23)

214

1

H NMR (500 MHz, C6D6) 4-methoxy-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)-benzenamine (24)

215

13

C NMR (125 MHz, CDCl3) 4-methoxy-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)-benzenamine (24)

216

1

H NMR (500 MHz, CDCl3) 4-chloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)-benzenamine (25)

217

13

C NMR (125 MHz, CDCl3) 4-chloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)-benzenamine (25)

218

1

H NMR (500 MHz, CDCl3) 5-chloro-4-methoxy-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)-benzamine (27)

219

13

C NMR (125 MHz, CDCl3) 5-chloro-4-methoxy-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)-benzamine (27)

220

1

H NMR (500 MHz, CD2Cl2) 4-bromo-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)-benzenamine (29)

221

13

C NMR (125 MHz, CD2Cl2) 4-bromo-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)-benzenamine (29)

222

1

H NMR (500 MHz, CDCl3) 4-amino-2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)-benzonitrile (30)

223

13

C NMR (125 MHz, CDCl3) 4-amino-2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)-benzonitrile (30)

224

1

H NMR (500 MHz, CDCl3) 4-chloro-5-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)-benzamine (31)

225

13

C NMR (125 MHz, CDCl3) 4-chloro-5-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)-benzamine (31)

226

1

H NMR (500 MHz, CDCl3) 4-amino-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)-phenol (32)

227

13

C NMR (125 MHz, CDCl3) 4-amino-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)-phenol (32)

228

1

H NMR (500 MHz, CDCl3) 4-amino-2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)-phenol (33)

229

13

C NMR (125 MHz, CDCl3) 4-amino-2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)-phenol (33)

230

1

H NMR (500 MHz, CDCl3) 4-amino-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (34)

231

13

C NMR (125 MHz, CDCl3) 4-amino-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (34)

232

1

H NMR (500 MHz, CD2Cl2) 4-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)-benzamine (35)

233

13

C NMR (125 MHz, CD2Cl2) 4-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)-benzamine (35)

234

1

H NMR (500 MHz, CDCl3) 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)-benzenamine (37)

235

13

C NMR (125 MHz, CDCl3) 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)-benzenamine (37)

236

1

H NMR (500 MHz, CDCl3) 5-amino-2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)-pyridine (38)

237

13

C NMR (125 MHz, CDCl3) 5-amino-2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)-pyridine (38)

238

1

H NMR (500 MHz, CD2Cl2) 5-amino-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)-2-methyl pyridine (39)

239

13

C NMR (125 MHz, CD2Cl2) 5-amino-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)-2-methyl pyridine (39)

240

1

H NMR (500 MHz, CDCl3) 2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-4-amine (40)

241

13

C NMR (125 MHz, CDCl3) 2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-4-amine (40)

242

1

H NMR (500 MHz, CDCl3) 2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-4-amine (41)

243

13

C NMR (125 MHz, CDCl3) 2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-4-amine (41)

244

1

H NMR (500 MHz, CDCl3) 6-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (42)

245

13

C NMR (125 MHz, CDCl3) 6-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (42)

246

1

H NMR (500 MHz, CDCl3) 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-(trifluoromethyl)pyridin-2-amine (43)

247

13

C NMR (125 MHz, CDCl3) 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-(trifluoromethyl)pyridin-2-amine (43)

248

REFERENCES

249

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