THE IRIDIUM CATALYZED ORTHO BORYLATION OF AROMATICS
By
Donald Plattner

A THESIS
Submitted to
Michigan State University
in partial fulfillment of the requirements
for the degree of
Chemistry – Master of Science
2014

ABSTRACT
THE IRIDIUM CATALYZED ORTHO BORYLATION OF AROMATICS
By
Donald Plattner
The ability to functionalize arenes is one of the quintessential features of modern
chemistry. As such, being able to catalytically modify an arene substrate with perfect
regioselectivity is a worthwhile goal. To this end, two methods for functionalizing
substrates with precise ortho selectivity have been achieved, using the borylating reagent
pinacolborane (HBPin), and bis(pinacolato)borane (B2Pin2).
The first method involves the ortho borylation of aniline substrates using BPin as
an easily removable traceless directing group. By forming an N-BPin bond in situ, the
nitrogen’s remaining hydrogen is able to act as an outer sphere directing group,
coordinating to the oxygen bonds on a BPin group attached to the iridium catalyst. In
this way, the ortho borylation of aniline substrates was performed with great success and
with even higher yields than were obtained with the similar Boc protected method.
The second method involves the use of a new ligand, SiPBz, which enables the
ortho borylation of methyl benzoate substrates via a chelate driven mechanism. The full
substrate scope of the ligand shows high yields and very good selectivity. Subtle ligand
modifications were also tested in order to determine the optimum ligand for different
types of substrates.

iv	
  
	
  

Copyright by
DONALD PLATTNER
2014

v	
  	
  

	
  

ACKNOWLEDGEMENTS

First and foremost I would like to thank my advisor, Mitch Smith for his
enormous help and patience. Not only was his insight utterly invaluable, he also taught
me how to think like a chemist, a skill which will carry with me throughout my
professional life. I feel indebted to him for everything that I have learned, not just in
regards to chemistry.
I would also like to thank everyone involved in the Boron Group, especially Rob
Maleczka for his acute attention to detail. I could not have asked for better lab mates
than Kristin, Behnaz, Yu-Ling, Buddha, Dmitrijs, Tim, and Olivia. A special thanks also
goes to one-time graduate student and full time friend, Sean, who was always
encouraging and always helpful.
Dan Holmes and Kermit also deserve a great deal of thanks for their willingness
to help regardless of the time or their workload. Also I don’t know what I would have
done without Richard’s help in deciphering x-ray structures.
I would also like to thank my family, Shari, Virginia, and Don (Uno), for never
failing to give me encouragement throughout my graduate studies. They have supported
me through think and thin.

iv
	
  

	
  

TABLE OF CONTENTS

LIST OF TABLES ......................................................................................................... vii
LIST OF FIGURES ...................................................................................................... viii
KEY TO SYMBOLS ......................................................................................................xv
CHAPTER 1 .....................................................................................................................1
Introduction to Iridium Catalyzed C-H Borylation ...........................................................1
Arene Functionalization ....................................................................................................1
C-H Activation ..................................................................................................................3
Boronic Acids ...................................................................................................................5
Ir-Catalyzed C-H Borylation ............................................................................................7
Optimization of Ir-Catalyzed C-H Borylation .................................................................9
Mechanism ......................................................................................................................11
REFERENCES ...............................................................................................................18
CHAPTER 2 ...................................................................................................................20
Outer Sphere Directed Borylation ..................................................................................20
Introduction .....................................................................................................................20
Replication of Hydrogen Bonding Effect .......................................................................21
BPin as a Traceless Directing Group ..............................................................................23
Substrate Scope ...............................................................................................................25
Borylation of Aniline ......................................................................................................28
Application Towards the Borylation of Drugs................................................................30
REFERENCES ...............................................................................................................33
CHAPTER 3 ...................................................................................................................34
Chelate Directed C-H Borylation....................................................................................34
Silica-SMAP ...................................................................................................................34
F

PAr 3 Ligand and Derivatives ........................................................................................36
Silyl Directed Borylation ................................................................................................39
Development of SiPBz Ligand .......................................................................................40
Substrate Scope ...............................................................................................................41
Optimization of SiPBz Ligand ........................................................................................48
REFERENCES ...............................................................................................................54
CHAPTER 4 ...................................................................................................................56
Conclusion ......................................................................................................................56
CHAPTER 5 ...................................................................................................................57
Experimental Information ...............................................................................................57
v
	
  

	
  
Spectra.............................................................................................................................90
REFERENCES .............................................................................................................174

vi
	
  

	
  

LIST OF TABLES

Table 3.1. Variations of the SiPBz Ligand .....................................................................49
Table 3.2 Optimization of the SiPBz Ligand Comparing Results of 33 and 34 .............50
Table 3.3 Optimization of the SiPBz Ligand Comparing Results of 35 and 36 .............51
Table 3.4 Optimization of the SiPBz Ligand Comparing Results of 37 and 38 .............52

vii
	
  

	
  

LIST OF FIGURES

Figure 1.1. Outcomes of Electrophilic Aromatic Substitution .........................................2
Figure 1.2. Method for Ortho Functionalization ...............................................................3
Figure 1.3. First Example of C-H Activation ..................................................................4
Figure 1.4. First Sterically Driven C-H Activation..........................................................4
Figure 1.5. First Catalytically Driven Intermolecular Functionalization .........................5
Figure 1.6. BPin Conversion............................................................................................6
Figure 1.7. Traditional Methods for Borylation of Arenes ..............................................7
Figure 1.8. Thermodynamics for the Borylation of Hydrocarbons .................................7
Figure 1.9. First Trace Borylation....................................................................................8
Figure 1.10. Photochemical Borylation of Toluene .........................................................8
Figure 1.11. Rhenium Photocatalyzed Borylation of Alkanes ........................................9
Figure 1.12. First Thermodynamically Driven Iridium Catalyzed Aromatic C-H
Borylation .........................................................................................................................9
Figure 1.13. Contrast Between Iridum and Rhodium System in the Borylation of
Benzylic Bonds ...............................................................................................................10
Figure 1.14. Six Coordinate Complexes ........................................................................12
Figure 1.15. Isolated 5-Coordinate Complex .................................................................12
Figure 1.16. Proposed Catalytic Cycle ..........................................................................13
Figure 1.17. Effect of Charge on the Energies of intermediates ....................................15
Figure 2.1. Transition State For Iridium Catalyzed Borylation of Pyrrole ...................21
Figure 2.2. General Procedure for the Boc Protection of Anilines Followed by Ortho
Borylation .....................................................................................................................22
Figure 2.3. The Outer Sphere Transition State ...............................................................23
viii
	
  

	
  
Figure 2.4 Traceless Borylation of Aniline Substrates ..................................................25
Figure 2.5. The Failed Ortho Borylation of 2-Chloroaniline .........................................27
Figure 2.6. Transition State for the Ortho Borylated Products .......................................27
Figure 2.7. The Diborylation of Monoborylated Anilines .............................................29
Figure 2.8 Borylated Aniline Isomers ............................................................................30
Figure 2.9. The Borylation of 7-amino-4-methylcoumarin, and Bupropion HCl ..........31
Figure 3.1. Silica-SMAP Ligand ...................................................................................34
Figure 3.2. Reactions Involving Silica-SMAP ..............................................................35
F

Figure 3.3. Reactions using the PAr 3 ligand................................................................36
F

Figure 3.4. PAr 3 Transition State Leading to Ortho Borylation ..................................37
Figure 3.5. Functionalization Using AsPh3 Ligand .......................................................38
Figure 3.6. Mechanism for the Silyl Directed Borylation of Phenols ............................39
Figure 3.7. Synthesis of the SiPBz ligand .....................................................................40
Figure 3.8. SiPBz Substrate Scope ................................................................................42
Figure 3.9. SiPBz Substrate Scope Continued ...............................................................43
Figure 3.10. Borylation of Carbamates ...........................................................................45
Figure 3.11. Proposed Mechanism for the SiPBz Ligand ...............................................46
Figure 3.12. Carbamate Intermediate.............................................................................47
Figure 3.13 Failed Cyano Substrate Reactions ..............................................................48
Figure 4.1 methyl 2,3-dimethoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)benzoate
(21) ..................................................................................................................................72
Figure 4.2 methyl 2,3-dichloro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl(benzoate)
(32) ..................................................................................................................................80

ix
	
  

	
  
1

Figure 5.1. H NMR (500 MHz, CDCl3) (1) .................................................................90
13

Figure 5.2.

C NMR (125 MHz, CDCl3) (1) ..............................................................91

1

Figure 5.3. H NMR (500 MHz, CDCl3) (2) ................................................................92
13

Figure 5.4.

C NMR (125 MHz, CDCl3) (2) ...............................................................93

1

Figure 5.5. H NMR (500 MHz, C6D6) (3) ..................................................................94
13

Figure 5.6.

C NMR (125 MHz, C6D6) (3) ................................................................95

1

Figure 5.7. H NMR (500 MHz, CDCl3) (4) ................................................................96
13

Figure 5.8.

C NMR (125 MHz, CDCl3) (4) ..............................................................97

1

Figure 5.9. H NMR (500 MHz, CDCl3) (5) ................................................................98
Figure 5.10.

13

C NMR (125 MHz, CDCl3) (5) ............................................................99

1

Figure 5.11. H NMR (500 MHz, CDCl3) (6a) ..........................................................100
Figure 5.12.

13

C NMR (125 MHz, CDCl3) (6a) ........................................................101

1

Figure 5.13. H NMR (500 MHz, CD3CN) (6b) ........................................................102
Figure 5.14.

13

C NMR (125 MHz, CDCl3) (6b) ........................................................103

1

Figure 5.15. H NMR (500 MHz, CDCl3) (7) ............................................................104
Figure 5.16.

13

C NMR (125 MHz, CDCl3) (7) ..........................................................105

1

Figure 5.17. H NMR (500 MHz, CDCl3) (8) ............................................................106
Figure 5.18.

13

C NMR (125 MHz, CDCl3) (8) ..........................................................107

1

Figure 5.19. H NMR (500 MHz, CDCl3) (9) ............................................................108
Figure 5.20.

13

C NMR (125 MHz, CDCl3) (9) ..........................................................109

x
	
  

	
  
1

Figure 5.21. H NMR (500 MHz, DMSO-d6) (10) ....................................................110
Figure 5.22.

13

C NMR (125 MHz, DMSO-d6) (10)...................................................111

1

Figure 5.23. H NMR (500 MHz, CDCl3) (11) ..........................................................112
Figure 5.24.

13

C NMR (125 MHz, CDCl3) (11) ........................................................113

1

Figure 5.25. H NMR (500 MHz, DMSO-d6) (12) ....................................................114
Figure 5.26.

13

C NMR (125 MHz, CDCl3) (12) ........................................................115

1

Figure 5.27. H NMR (500 MHz, CDCl3) (13) ..........................................................116
Figure 5.28.

13

C NMR (125 MHz, CDCl3) (13) ........................................................117

1

Figure 5.29. H NMR (500 MHz, CDCl3) (14) ..........................................................118
Figure 5.30.

13

C NMR (125 MHz, CDCl3) (14) ........................................................119

1

Figure 5.31. H NMR (500 MHz, CDCl3) (15) ..........................................................120
Figure 5.32.

13

C NMR (125 MHz, CDCl3) (15) ........................................................121

1

Figure 5.33. H NMR (500 MHz, CDCl3) (16) ..........................................................122
Figure 5.34.

13

C NMR (125 MHz, CDCl3) (16) ........................................................123

1

Figure 5.34. H NMR (500 MHz, CDCl3) (17) ..........................................................124
Figure 5.35.

13

C NMR (125 MHz, CDCl3) (17) ........................................................125

1

Figure 5.36. H NMR (500 MHz, CDCl3) (18) ..........................................................126
Figure 5.37.

13

C NMR (125 MHz, CDCl3) (18) .........................................................127

1

Figure 5.38. H NMR (500 MHz, CDCl3) (19) ..........................................................128
Figure 5.39.

13

C NMR (125 MHz, CDCl3) (19) .........................................................129

xi
	
  

	
  
1

Figure 5.40. H NMR (500 MHz, CDCl3) (20a) .......................................................130
Figure 5.41.

13

C NMR (125 MHz, CDCl3) (20a) ......................................................131

1

Figure 5.42. H NMR (500 MHz, CDCl3) (20b) ........................................................132	
  
Figure 5.43.

13

C NMR (125 MHz, CDCl3) (20b) ......................................................133

1

Figure 5.44. H NMR (500 MHz, CDCl3) (21) ..........................................................134
Figure 5.45.

13

C NMR (125 MHz, CDCl3) (21) ........................................................135

1

Figure 5.46. H NMR (500 MHz, CDCl3) (22) ..........................................................136
Figure 5.47.

13

C NMR (125 MHz, CDCl3) (22) ........................................................137

1

Figure 5.48. H NMR (500 MHz, CDCl3) (23) ..................................................................... 138
Figure 5.49.

13

C NMR (125 MHz, CDCl3) (23)................................................................... 139

1

Figure 5.50. H NMR (500 MHz, CDCl3) (24a) ........................................................140
Figure 5.51.

13

C NMR (125 MHz, CDCl3) (24a) ......................................................141

1

Figure 5.52. H NMR (500 MHz, CDCl3) (24b) ........................................................142
Figure 5.53.

13

C NMR (125 MHz, CDCl3) (24b) ......................................................143

1

Figure 5.54. H NMR (500 MHz, CDCl3) (25) .........................................................144
Figure 5.55.

13

C NMR (125 MHz, CDCl3) (25) ........................................................145

1

Figure 5.56. H NMR (500 MHz, CDCl3) (26a) ........................................................146
Figure 5.57.

13

C NMR (125 MHz, CDCl3) (26a) ......................................................147

1

Figure 5.58. H NMR (500 MHz, CDCl3) (26b) .......................................................148
Figure 5.59.

13

C NMR (125 MHz, CDCl3) (26b) ......................................................149

xii
	
  

	
  
1

Figure 5.60. H NMR (500 MHz, CDCl3) (27) ..........................................................150
Figure 5.61.

13

C NMR (125 MHz, DMSO-d6) (27)...................................................151

1

Figure 5.62. H NMR (500 MHz, CDCl3) (28) ..........................................................152
Figure 5.63.

13

C NMR (125 MHz, CDCl3) (28) ........................................................153

1

Figure 5.64. H NMR (500 MHz, CDCl3) (29) ..........................................................154
Figure 5.65.

13

C NMR (125 MHz, CDCl3) (28) ........................................................155

1

Figure 5.66. H NMR (500 MHz, CDCl3) (30) ..........................................................156
Figure 5.67.

13

C NMR (125 MHz, CDCl3) (30) ........................................................157

1

Figure 5.68. H NMR (500 MHz, CDCl3) (31) ..........................................................158
Figure 5.69.

13

C NMR (125 MHz, CDCl3) (32) ........................................................159

1

Figure 5.70. H NMR (500 MHz, CDCl3) (32) ..........................................................160
1

Figure 5.71. H NMR (500 MHz, C6D6) (33) ............................................................161
Figure 5.72.

13

C NMR (125 MHz, CDCl3) (33) ........................................................162

1

Figure 5.73. H NMR (500 MHz, C6D6) (34) ............................................................163
Figure 5.74.

13

C NMR (125 MHz, CDCl3) (34) ........................................................164

1

Figure 5.75. H NMR (500 MHz, C6D6) (35) ............................................................165
Figure 5.76.

13

C NMR (125 MHz, CDCl3) (35) ........................................................166

1

Figure 5.77. H NMR (500 MHz, C6D6) (36) ............................................................167
Figure 5.78.

13

C NMR (125 MHz, CDCl3) (36) ........................................................168

1

Figure 5.79. H NMR (500 MHz, CD2Cl2) (37) ........................................................169

xiii
	
  

	
  
Figure 5.80.

13

C NMR (125 MHz, CDCl3) (37) ........................................................170

1

Figure 5.81. H NMR (500 MHz, CD3OD) (38) ........................................................171
Figure 5.82.

13

C NMR (125 MHz, CDCl3) (38) ........................................................172

xiv
	
  

	
  

KEY TO SYMBOLS

Ac

acyl

BCat

catecholborane

BDE

bond dissociation energy

Boc

tert-butoxycarbonyl

B2Pin2

bis(pinacolato)borane

COD

1,5-cyclooctadiene

COE

cis-cyclooctene

Cp

cyclopentadienyl

Cp*

pentamethylcyclopentadienyl

η

eta, hapicity

ΔE‡

activation energy

ΔE

energy difference between the ground states

DoM

directed ortho metallation

dmabpy

4,4'-Bis(N,N-diethylamino)-2,2'-bipyridine

dmpe

1,2-bis(dimethylphosphino)ethane

dppe

1,2-bis(diphenylphosphino)ethane

dtbpy

4,4’-di-tert-butyl-2,2’dipyridyl

HBPin

pinacolborane

m

meta

MTBE

methyl tert-butyl ether

n

normal (straight chain hydrocarbon)

xv
	
  

	
  
NPA

natural population analysis

o

ortho

p

para
F

PAr 3

P(3,5)-bis(CF3)2-C6H3)3

SiPBz

(2-(diisopropylsilyl)phenyl)di-p-tolylphosphane

TEA

triethylamine

tmphen

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

xvi
	
  

	
  

CHAPTER 1
Introduction to Iridium Catalyzed C-H Borylation
Arene Functionalization
Arenes are one of the most fundamental and important substances in all of
chemistry. They provide the backbone for millions of different types of chemicals, and
are the very foundation for many industrial syntheses and pharmaceuticals. Their utility
simply cannot be overstated.
Benzene itself was originally discovered in 1825 by Michael Faraday in what was
1

the first case of describing it as a unique chemical. A mere 24 years later, the first
2

industrial scale synthesis was described and implemented. Finally, benzene was
accurately described in the same way it is in modern textbooks; as a six member carbon
ring with six hydrogen’s and three alternating double bonds.

3

Of course, being able to further functionalize benzene substrate is essential, and
especially difficult due to general low reactivity. To these ends, numerous methods have
been developed. The most common method, and the one that most chemists remember
learning first, is the electrophilic aromatic substitution reactions, as shown in Figure 1.1.

1
	
  

	
  
Figure 1.1. Outcomes of Electrophilic Aromatic Substitution
CF3

CF3
Br 2

CF3
Br
H

AlBr3
OMe
Br 2
AlBr3

Br
2
AlB
r3
Br

Br

OMe
H
Br

OMe
Br

OMe

OMe

H

Br

As shown above, the regioselectivity of the reactions are governed almost entirely
by electronic factors, with electron donating groups causing substitution at the para and
ortho positions, and electron withdrawing groups causing substitution at the meta
positions. Unfortunately, this regioselectivity can cause a number of problems in the
design of variously substituted aromatic rings. For instance, creating an all metasubstituted arene with only ortho/para directing groups is incredibly difficult,

4,5

as is

functionalizing an aromatic ring with more than one deactivating group, and obtaining
only ortho functionalized products with no para isomers.
The latter of these problems is solved, at least in part, by directed ortho
metallation, DoM. In such reactions, exclusive ortho functionalization is achieved using a
directing metallation group, which can act as a Lewis base in order to coordinate with the
alkyl lithium metal and guide it towards deprotonating the ortho position and replacing it
with a lithium metal, as seen in Figure 1.2.

6,7

2
	
  

	
  
Figure 1.2 Method for Ortho Functionalization

O
N

Li
H O

n-BuLi

Li
N

THF, -78 °C

O
N

From there, the lithium metal can be replaced with a wide range of functional
groups. However, this method has multiple drawbacks inherit to the process, the most
obvious being the requirement of energy intensive low temperatures, and the necessity of
stoichiometric quantities of n-BuLi which is not present in the final product.

C-H Activation
Despite the utility of the above-mentioned functionalization methods, they and
others have their stated drawbacks. In order to find a way around many of the problems,
catalytic systems were designed in which the transition metal could be regenerated in
order to improve atom economy and in such a way that the reaction could be performed
with a different type of selectivity.
The first example of C-H activation was discovered in a reaction of between
8

azobenzene and a nickel catalyst. Figure 1.3.

3
	
  

	
  
Figure 1.3. First Example of C-H Activation

Ni

5 equiv azobenzene
135 °C, 4 hours

Ni

N
27%

+

C5H 6

N

Further progress was made in the category of transition metal catalyzed arene
functionalization when a ruthenium compound Ru(dmpe)2Cl2 (dmpe = 1,2bis(dimethylphosphino)ethane), was shown to undergo oxidative addition with the
9

napthalene solvent, as shown in Figure 1.4. Interestingly, this reaction was shown to
selectively activate only the least hindered C-H bonds of the naphthalene substrate.

Figure 1.4. First Sterically Driven C-H Activation

P

P

P

Ru
P

Cl

Cl

2 Na
- 2 NaCl

P

P

+

P

Ru

P

P

Ru
P

P

P

H

Although this was a large step in the right direction, in order for a catalytic cycle
to work, it of course has to have some component with which to undergo reductive
elimination and yield a functionalized product. To this end, the first transition metal
catalyzed intermolecular functionalization of an arene ring was designed, as depicted in
Figure 1.5.

10

4
	
  

	
  
Figure 1.5. First Catalytically Driven Intermolecular Functionalization
X
+

Et 3SiH +

1-8% [Cp*RhCl 2]2
100-150 °C

X
+
SiEt3

X = Me, CF3, F, Cl, Br

Boronic Acids
Being able to functionalize an aromatic ring with a functional group that can be
further modified is also a very useful tool. To this end, boronic acids are a particularly
useful functional group, as they have been shown not to be air sensitive, and can be
further converted to a number of functional groups
halogens,

14,15

and are used in coupling reactions.

5
	
  

11

16

including phenols,
(Figure 1.6)

12

anilines,

13

	
  
Figure 1.6. BPin Conversion
Cl

BPin

aqueous oxone, acetone Cl

OH

25 °C, 7 minutes
Br

Br

BPin

BPin

2 equiv H 2N-cylcohexane
1 equiv KF
10 mol % (Cu(OAc) 2 •H 2O
Molecular sieves
CH3CN, O2, 80 °C, 24 hours

3-3.5 equiv CuX2

87%

H
N
67%
X

MeOH/H 2O (1:1)
80-90 °C, 4-6 hours.

61%, X = Cl, Br

CN
CN

Br
BPin

1 mol % Pd(OAc) 2
PPh 3, KOH,
THF, MeOH (4:1)
60 °C, 72 hours

78%

The useful orgnaoboranes tend to come in the form of boronic acids and boronic
esters. However, putting a boron reagent on an aromatic ring is less trivial than it might
seem. Traditional methods for preparing boronic esters are shown below in Figure 1.7.

6
	
  

	
  
Figure 1.7. Traditional Methods for Borylation of Arenes

H

X

[X]

H

Mg

X

[X]

In both the Grignard

17

RO

MgX
B(OR) 3

Pd (0)
KOAc
B 2Pin 2

B

OR

BPin

18

and the palladium catalyzed method , a halogen, [X], is

required to be present in order for it to be further modified in the borylation process. This
is wasteful in terms of both atom economy and it can be nontrivial to install halogens on
various substrates. It can also be difficult to achieved selectivity when multiple halogens
are present.

Ir-Catalyzed C-H Borylation
The most efficient route to borylation would be performed directly and without
the necessary assistance of other functional groups. The thermodynamics of such a
conversion for methane are shown below in Figure 1.8 and are very encouraging.

19,20

Figure 1.8. Thermodynamics for the Borylation of Hydrocarbons
H 3C
BDE =

H

105.0

+

O
B
O

O
B
O

H

110.8

111.6

CH3

+

H H
104.2

ΔH = 0 kcal/mol

7
	
  

	
  
Because such a reaction is effectively thermoneutral, it supports the concept that
an unsubstituted hydrocarbon could be borylated directly.
The first ever direct aromatic borylation using an iridium catalyst resulted as a
6

byproduct of a reaction involving Ir(η -C6H5Me)(BCat)3 (BCat = catecholboryl) and a
toluene solvent.

21

However, the borylated product only occurred in trace amounts as

detected by GCMS. Figure 1.9.

Figure 1.9. First Trace Borylation
Ir(h 5-indenyl)(COD)

5 equiv HBCat,
toluene, 3 hours

BCat

+ Ir(h 6-C6H 5Me)(BCat) 3

trace yields

82 %

A much more successful aromatic borylation was obtained using
CpFe(CO)2BCat, to photochemically borylate toluene.

22

Curiously, borylation of the

substrate occurred only at the least sterically hindered locations (meta : para = 1.1 : 1).
Unfortunately, these reactions did not occur catalytically. Figure 1.10.

Figure 1.10. Photochemical Borylation of Toluene
CpFe(CO)2BCat

+

hv, 1 hour

BCat
m : p = 1.1 : 1, 70%

8
	
  

H 2 + Fp 2

	
  
Four years later, a method for photocatalytically borylating alkanes at the least
sterically hindered terminal methyl group was determined, using a rhenium catalyst.
(Figure 1.11)

23

Figure 1.11. Rhenium Photocatalyzed Borylation of Alkanes
+ B 2Pin 2

Cp*Re(CO)3
hv, CO, 25 °C, 56 hours

BPin

+ HBPin

95% yield by B 2Pin 2

That same year, the first thermodynamically driven iridium catalyzed aromatic CH borylation was observed, as shown in Figure 1.12.

24

Figure 1.12. First Thermodynamically Driven Iridium Catalyzed Aromatic C-H
Borylation

17 mol %
Me 3P
+

Ir

H
BPin

BPin
+ H2

HBPin
150 °C, 120 hours

53 %

Optimizing of Ir-Catalyzed C-H Borylation
Since that primitive era referred to as the “late 90’s,” many improvements have
been made to the overall catalytic system and much insight has been gained into how the

9
	
  

	
  
reaction proceeds. To begin with, following the development of the catalyst, the scope of
the catalytic reactions was found to be quite extensive. By generating the
Cp*Ir(PMe3)(H)(BPin) catalyst in situ from Cp*Ir(PMe3)(H)2 and then reacting it with
multiple substrates, it was observed that the catalytic system was almost totally sterically
driven, giving borylated products in the least hindered locations of the a variety of arene
25

rings.

The selectivity of the reactions was also much better than the reported
4

Cp*Rh(η -C6Me6) catalyst which had been shown to also be capable of sterically
directed C-H activation of alkanes.

26

In the case of the rhodium catalyst, not only did the

system cause defluorination of fluorinated aromatics, but it also caused borylation of
benzylic bonds as shown in Figure 1.13.

Figure 1.13. Contrast Between Iridum and Rhodium System in the Borylation of
Benzylic Bonds
BPin
HBPin
+

20 % [M]

PinB

[M] = Cp*Ir(PMe3)(H)(BPin)
[M] = Cp*Rh(η4-C6Me 6)

97

:

3

88

:

12

However, even though the selectivity of the iridium system was superior to the
rhodium system, the reaction yields were still hampered by low turnover numbers. In an
effort to improve the yield, a catalytically active Ir (III) species, Ir(dppe)(BPin)3 (dppe =
10
	
  

	
  
6

1,2-bis(diphenylphosphino)ethane) was proposed to be generated from (η mesitylene)Ir(BPin)3 and dppe.

27

This chelating ligand, dppe, was found to greatly

improve the turnover numbers of the catalyst. Furthermore, this species was able to
successfully borylate substrates containing iodine substituents, which contrasted with
tested Iridium (I) species, [Ir(BPin)(PMe3)4].
Around that time, a similar system was developed using the Iridium (I) source,
[Ir(COD)(OMe)]2 and a different electron donating ligand, 4,4’-di-tert-butyl2,2’dipyridyl (dtbpy). This ligand catalyst setup would form the basic framework for
many future iridium catalyzed borylations.

28

Mechanism
In order to determine how the actual catalytic cycle worked, as well as the type of
intermediates formed during the cycle, a variety of calculations and experiments were
performed. To begin with, it was widely believed that a five-coordinate complex was the
intermediate which performed the C-H functionalization of the arene substrates, but the
difficulty of isolating reactive intermediates is well known.

29

Because of this, pre-

catalyst complexes could only be isolated as six-coordinate complexes shown in Figure
1.14.

11
	
  

	
  
Figure 1.14. Six Coordinate Complexes

Me 3P
Me 3P

PMe 3
Ir
BPin

BPin

N

BPin

N

Ir

BPin
BPin

BPin

In these cases, it was believed to be necessary for the phosphorus ligand and COE
ligand, respectively, to dissociate in order to obtain the active catalyst that would then
undergo C-H activation of the substrate.
In order to obtain an actual five-coordinate iridium trisboryl complex that reacts
in the same way that other as the ligands, the mesitylene trisboryl complex was reacted
with a 1,2-bis(di-i-propyl-phosphino)ethane to yield the complex in Figure 1.15.

30

Figure 1.15. Isolated 5-Coordinate Complex

P

BPin
Ir

BPin
BPin

P

Reactions using this complex not only occurred with the same selectivity as other
Ir (III) complexes, but also occurred faster than them because ligand predissociation isn’t
necessary. The presence of such a complex lended credence to previous kinetic
experiments which had determined the complex in Figure 1.9 underwent dissociation of

12
	
  

	
  
the COE to obtain an active Ir-dtbpy complex.

31

The proposed mechanism for the

overall catalytic cycle is shown below in Figure 1.16.

Figure 1.16. Proposed Catalytic Cycle

Ar H

N
N

- COE

BPin

Ir

BPin

+ COE

BPin

N

Ar BPin

BPin

N

BPin
BPin

N

Ir

N

Ar

H
Ir BPin
BPin
N
BPin

N

H

BPin
BPin

R1

H
Ir BPin
BPin
N
BPin

N
R1 H

Ir

R1 BPin

R1 = H or BPin

To begin with, the reaction occurs after an iridium (I) source, such as
[Ir(COD)(OMe)]2, undergoes reaction with a ligand, such as dtbpy, and a boron source,
such as B2Pin2 or HBPin. The resulting product can then undergo reversible dissociation
of COE to yield a five-coordinate complex that undergoes oxidative addition with the
-

substrate to form an 18 e Ir (V) complex. Once reductive elimination occurs to yield a
borylated substrate (Ar-BPin), the catalyst is regenerated by undergoing oxidative
1

1

addition with a boron source, R -BPin (R = BPin or H), followed by reductive
1

elimination of R -H.

13
	
  

	
  
Although the iridium catalyzed borylations are sterically driven, certain pieces of
information suggest that electronics do play a factor. Even early publications showed
that aromatics containing electron withdrawing substituents tended to give higher yields
than their electron donating counterparts. One particularly interesting example was the
borylation of methoxy benzene, which yielded borylation, m : p = 4 : 1, and even
contained some ortho borylation, which contrasts with the expected ratio of m : p =
2 : 1.

25

Furthermore, the borylation of aromatic heterocycles has been shown to be

determined primarily by the position of the heteroatom.

32

In order to determine what role electronic factors were playing, the energies of
various transition states and intermediates were calculated for a group of reactions which
involved iridium complex.

33

Because there was a high correlation between the activation

energy for the transition state of the various substrates, ΔE‡, and the reliably calculated
energy difference between the ground states, ΔE, it was concluded that the products will
result from the ΔE‡ transition state.
With this in mind, Vanchura et al compared the ΔE of various substrates to the
natural population analysis, NPA, charge on the aromatic ring during the transition state
and obtained a linear fit, as shown in Figure 1.17.

14
	
  

	
  
Figure 1.17. Effect of Charge on the Energies of intermediates

Their interpretation of the data was that the best-fit line correlated to the effect
that charge had on the energies of the intermediates, and as a result the transition state,
and that based on what they knew from how various substrates like veratrole, anisole, and
benzodioxole reacted, that any intermediate below the line reacts favorably due to factors
that are irrespective of the electronic effects.
They also concluded that anything which promotes the transfer of negative charge
from the iridium catalyst to the arene substrate encourages product formation, as does any
substrate functional group which promotes proton transfer to the iridium catalyst.
The optimal boron source was also determined experimentally to be a pinacolate
derivative as opposed the catecholate.

34

The reason for this being that the electron

density of the pinacolate derivatives are much greater than that of the catecholate types,

15
	
  

	
  
which improves the ability of the catalytic system to undergo oxidative addition with a
substrate.
With these conditions, the optimal setup and mechanism behind iridium catalyzed
sterically driven C-H borylation had been determined.

16
	
  

	
  

REFERENCES

17
	
  

	
  
REFERENCES

1) Kaiser, R. Angew. Chem. Int. Ed. 1968, 7, 345.
2) Mansfield, C. For Fractal Distillation of Coal Tar. Patent no 11,960. 1848.
3) Kekulé, A. Liebigs Ann. Chem. 1872, 162, 77.
4) Hodgson, H. H.; Wignall, J. S. J. Chem. Soc. 1926, 2077-2079. (b) Kohn, M.;
Zandman, A. Monatsh. Chem. 1926, 47, 357-377.
5) Maleczka, R. E.; Shi, F.; Holmes, D.; Smith, M. R. J. Am. Chem. Soc. 2003, 125,
7792.
6) Snieckus, V. Chem. Rev. 1990, 90, 879.
7) Whisler, M. C.; MacNeil, S.; Snieckus, V.; Beak, P. Angew. Chem. Int. Ed. 2004,
43, 2206.
8) Kleiman, J. P.; Dubeck, M. J. Am. Chem. Soc. 1963, 85, 1544.
9) Chatt, J.; Davidson, J. M. J. Chem Soc. 1965, 843.
10) Ezbiansky, K.; Djurovich, P. I.; LaForest, M.; Sinning, D. J.; Zayes, Roberto,
Berry, D. H. Organometallics. 1998, 17, 1455.
11) Mkhalid, I. A. I.; Barnard, J. H.; Barder, T. B.; Murphy, M. J.; Hartwig, J. F.
Chem. Rev. 2010, 110, 890.
12) (a) Webb, K. S.; Levy, D. Tetrahedron Lett. 1995, 36, 5117. (b) Maleczka, R. E.;
Shi, F.; Holmes, D.; Smith, M. R. J. Am. Chem. Soc. 2003, 125, 7792.
13) Tzschucke, C. C.; Murphy, J. M.; Hartwig, J. F. Org. Lett. 2007, 9, 761.
14) Murphy, M. M.; Liao, X.; Hartwig, J. F. J. Am. Chem. Soc. 2007, 129, 15434.
15) Fier, P. S.; Luo, J.; Hartwig, J. F. J. Am. Chem. Soc. 2013, 135, 2552.
16) Myslinska, M.; Heise, G. L.; Walsh, D. J. Tetrahedron Lett. 2012, 53, 2937.
17) Clary, J. W.; Rettenmaier, T. J.; Snelling, R.; Bryks, W.; Banwell, J.; Wipke, T.
W. J. Org. Chem. 2011, 76, 9602.
18) Ishiyama, T.; Murata, M.; Miyaura, N. J. Org. Chem. 1995, 60, 7508

18
	
  

	
  

19) Rablen, P. R.; Hartwig, J. F. J. Am. Chem. Soc. 1994, 116, 4121.
20) Blanksby, S. J.; Ellison, G. B. Acc. Chem. Res. 2003, 36, 255
21) Henk, P. N.; Blom, H. P.; Westcott, S. A.; Taylor, N. T.; Marder, T. B. J. Am.
Chem. Soc. 1993, 115, 9329.
22) Waltz, K. M.; He, X.; Muhoro, C.; Hartwig, J. F. J. Am. Chem. Soc. 1995, 117,
11357.
23) Chen, H.; Hartwig, J. F. Angew. Chem. Int. Ed. 1999, 38, 3391.
24) Iverson, C. N.; Smith, M. R. J. Am. Chem. Soc. 1999, 121, 7696.
25) Cho, J.; Iverson, C. N.; Smith, M. R. J. Am. Chem Soc. 2000, 122, 12868.
26) Chen, H.; Schlecht, S.; Semple, T. C.; Hartwig, J. F. Science, 2000, 287, 1995.
27) Cho, J.; Tse, M. K.; Holmes, D.; Maleczka, R. E.; Smith, M. R. Science, 2002,
295, 305.
28) Ishiyama, T.; Takagi, J.; Hartwig, J. F.; Miyaura, N. Angew. Chem. Int. Ed. 2002,
41, 3056.
29) Halpern, J. Science, 1982, 217, 401.
30) Chotana, G. A.; Vanchura, B. A.; Tse, M. K.; Staples, R. J.; Maleczka, R. E.;
Smith, M. R. Chem. Commun. 2009, 5731.
31) Boller, T. M.; Murphy, J. M.; Hapke, M.; Ishiyama, T.; Miyuarua, N.; Hartwig, J.
F. J. Am. Chem Soc. 2005, 127, 14263.
32) (a) Cho, J.; Tse, M. K.; Holmes, D.; Maleczka, R. E.; Smith, M. R. Science, 2002,
295, 305. (b) Sulagna, P.; Chotana, G. A.; Holmes, D.; Reichle, R. C.; Maleczka,
R. E.; Smith, M. R. J. Am. Chem. Soc. 2006, 128, 15552. (c) Kallepalli, V. A.;
Shi, F.; Sulagna, P.; Onyeozili, E. N.; Maleczka, R. E.; Smith, M. R. J. Org
Chem. 2009, 74, 9119.
33) Mkhalid, I. A. I.; Barnard, J. H.; Marder, T. B.; Murphy, J. M.; Hartwig, J. F.
Chem. Rev. 2010, 110, 890.
34) Liskey, C. W.; Wei, C. S.; Pahls, D. R.; Hartwig, J. F. Chem. Commun. 2009,
5603.

19
	
  

	
  

CHAPTER 2
Outer Sphere Directed Borylation

Introduction
Although sterics tend to be the dominant controlling factor when it comes to the
1

C-H borylation of arene rings, recent findings have shown a situation where it is
2

possible to control regioselectivity through an outer sphere mechanism as well as a
chelate directed mechanism

3,4

5

and a relay directed mechanism . In the case of the outer

sphere mechanism, the regioselectivity of the reaction is caused by interactions between
the ligand on the catalyst and a functional group on a substrate.

6
7

While this type of mechanism has been seen before in previous work, its novelty
with regards to C-H borylation provides a unique alternative to the sterically driven
standard methods.
The clue that lead to the development of an iridium catalyzed outer sphere
borylation was found during the quest to elucidate how electronic effects play a role in
the iridium catalyzed borlyation of aromatic substrates.

8

The key and clear outlier in the comparison of natural population analysis, NPA,
to the energy difference between the ground states was the borylation of pyrrole at the 2
position, which was calculated to be 2.3 kcal/mol more favorable than would have
9

otherwise been expected. Even though the regioselectivity of the reaction isn’t altered
from the expected borylation at the 2 position, it was curious that the reaction was so

20
	
  

	
  
much more favorable than borylation at the 3 position despite sterics not being a factor.
Subsequent analysis of the bond angles and bond distances in the transition state
suggested that hydrogen bonding interactions were taking place between the boryl
oxygen and the hydrogen on the nitrogen, which resulted in the stabilized the transition
state for borylation at the 2 position. Figure 2.1.

Figure 2.1. Transition State For Iridium Catalyzed Borylation of Pyrrole

O

B

N
OB
Ir
O H

O

N
O
B
O
N H

With this in mind, a way to replicate the hydrogen bonding effect was sought in
order to alter the selectivity of a reaction to favor ortho borylation where it usually would
not be favored.

Replication of Hydrogen Bonding Effect
Further analysis determined that the tert-butoxycarbonyl (Boc) group, when
bonded to the nitrogen of an aniline substrate as a protecting group, was capable of
causing the hydrogen attached to the nitrogen to mimic the hydrogen bonding effect seen
in the pyrrole. In doing so, Boc protection of aniline substrates is able to alter the

21
	
  

	
  
regioselectivity of iridium catalyzed borylation to favor ortho substitution. The general
procedure is shown in Figure 2.2.

Figure 2.2. General Procedure for the Boc Protection of Anilines Followed by
Ortho Borylation
O
NH 2

O

O
NH

1.2 equiv Boc 2O
R1

R2

H 2O (RT, 24 h, open) R1

R2

O
2% [Ir(COD)(OMe)] 2
4% dtbpy
0.2 equiv HBPin, 1 equiv B 2Pin 2 R1
MTBE, 50 °C, 12-36 hours

NH
BPin
R2

The most supportive piece of evidence that the route by which this was
accomplished was indeed an outer sphere mechanism came from experiments involving
various dipyridyl ligands. By altering the functional groups on a multitude of dipyridyl
ligands, they were able to observe the ligand’s electronic effect on the regioselectivity of
the Boc protected anilines. What they observed was that functional groups that increased
the basicity of the dipyridyl ligands enhanced ortho selectivity of the reaction. It was
proposed that in a catalyst/ligand complex where the functional groups on the dipyridyl
ligand were electron donating, the basicity of the pinacolate oxygen’s was also increased.
This hypothesis is supported by the results, where reactions using ligands with electron
donating groups favored the ortho borylated product. Thus, outer sphere borylation was
the route by which ortho borylation occurred. (Figure 2.3.)

22
	
  

	
  
Figure 2.3. The Outer Sphere Transition State.

O

B

O

N

N

O
B
H O
N O t-butyl

Ir
O
B
O H
R2

O
R1

Even though many of the Boc protected aniline substrates showed high
selectivity, the overall process had its drawbacks. The most obvious issue was that
separate steps were required to add and remove the Boc protecting group before and after
borylation. This introduces extra steps and purifications that potentially decreased the
overall yield of the reaction.

BPin as a Traceless Directing Group
In order to provide a methodology wherein anilines could be protected in-situ, a
9

strategy involving pinacolborane (HBPin) was devised. N-BPin proved to be quite
advantageous as an outer sphere directing group. The fact that the N-BPin bonds could
be easily hydrolyzed with the addition of methanol at the end of the reaction allowed us
to overcome the drawbacks seen in the borylation of Boc protected anilines. In this way,
the HBPin could be used as a traceless directing group, which is highly advantageous
when compared to Boc protection.
It should be noted that in order for the HBPin to be effective in the outer sphere
23
	
  

	
  
borylation of anilines, an incubation period was required wherein the aniline substrate
and 1.5 equivalents of HBPin and were stirred together for an hour.
After full N-BPin conversion was achieved, an iridium catalyst was added, a
3,4,7,8-tetramethyl-1,10-phenanthroline (tmphen) ligand, as opposed to the 4,4′-di-tertbutyl-2,2′bipyridyl (dtbpy) ligand used for Boc protection, was added in order to mimic
the increased ortho selectivity seen with more electron donating ligands in Boc protected
ortho borylation, and extra HBPin was added so that it could be used as the borylating
reagent. In this way, outer sphere ortho borylation of aniline substrates was achieved.
Figure 2.4. shows the substrate scope for this reaction.

24
	
  

	
  
Substrate Scope
Figure 2.4. Traceless Borylation of Aniline Substrates
NH 2
R1

R2

NH 2

1) 1.5 equiv HBPin
THF, 1 hour
2) 0.25% [Ir(COD)(OMe)] 2
1% tmphen
1.5 equiv HBPin
80 °C, 16 hours
3) Methanol

BPin

Br

R1

BPin

BPin

OMe

2 87%

BPin

BPin

R2

NH 2

CF3

1 88%

NH 2

NH 2

NH 2

3 63%

NH 2

NH 2

BPin

BPin
PinB

MeO
CN
4 89%

CN
5 60%a

6a,b 72%b
ortho : meta
1.0 : 1.4

a Conditions: 1.5 mol% [Ir(OMe)COD] , 3.0 mol% dmabpy with
2
2.0 equivalents HBPin in n-hexane as reaction solvent.
b Conditions: 2.5 mol% [Ir(OMe)COD] , 5.0 mol% tmphen.
2

Immediately, we find that the 4-bromoaniline substrate 1 gives almost exactly the
same yield as it did in the Boc protected borylation, even before taking into account the
extra steps necessary to add and remove the Boc group. The reaction works well on both

25
	
  

	
  
electron withdrawing groups and electron donating groups, although the electron
donating methoxy group doesn’t seem to be quite as effective. This result can be
explained through virtue of the fact that for general iridium catalyzed borylation, proton
transfer character is the key electronic contributor to the transition state.

8

The diborylation of the 4-aminobenzonitrile 4 occurred under standard borylation
conditions, probably because the nitrile group does not provide much steric hindrance. In
order to obtain pure monoborylated product 5, a more highly electron donating ligand,
4,4'-Bis(N,N-diethylamino)-2,2'-bipyridine (dmabpy), was used, as was fewer
equivalents of HBPin.
When it came to the borylation of 3-methoxyaniline, the meta product 6b was
surprisingly the major isomer. This differs from what was seen in the borylation of other
9

meta anilines. as well as in the borylation of meta substituted Boc protected anilines. In
both of those cases, the meta borylated product was still observed, but only as the minor
product. The reason for the large amount of meta product, 6b, could be that the proton
transfer character of the meta transition state is simply much greater than in the ortho, due
to the presence of the electron donating methoxy group.
One of the drawbacks with this traceless directing method, as well as the Boc
protection method, is that 2-substituted anilines fail to give ortho regioselectivity, as seen
in Figure 2.5.

26
	
  

	
  
Figure 2.5. The Failed Ortho Borylation of 2-Chloroaniline

NH 2

1) 1.5 equiv HBPin
THF, 1 hour
2) 0.25% [Ir(COD)(OMe)] 2
1% tmphen
1.5 equiv HBPin
80 °C, 16 hours
3) Methanol

Cl

NH 2

Cl

BPin
7 68%

The reason for this failure becomes apparent when the transition state for the Boc
protected aniline is taken into account, as seen in Figure 2.6.

Figure 2.6. Transition State for the Ortho Borylated Products

O

B

N

O

O

N

Ir
O
B
H
O

N

O

O

N

Ir
O
B
H
O

B
H O
N O t-butyl
Cl

B

O

O
B
H O
N O
B
O
Cl

B

A

Based on the structure of the Boc protected aniline transition state A, there is a
large steric clash that occurs between the functional group ortho to the aniline nitrogen,
and the Boc group attached to the aniline nitrogen. If this is applied to the analogous NBPin transition state B, the same steric clash is observed.
It is worth noting that while ortho borylation didn’t occur, the reaction borylated
only the meta position, which is interesting considering that N,N-dimethyl aniline
27
	
  

	
  
borylation favors the meta position, while still resulting in some para borylation (meta :
para = 79:21).

10

Although the source of this meta selectivity is almost certainly

electronic, the exact reason behind it is unknown.

Borylation of Aniline
The borylation of aniline proved much more complex and interesting than
originally expected. While the borylation of Boc protected aniline yielded the ortho
product almost entirely (o : m : p = 90 : 5 : 5), the NMR of the crude reaction mixture of
BPin protected aniline was too complex to have only three products in it. A mass spec of
the mixture showed that not only was unborylated starting aniline present, but
diborylation had also occurred. Initial efforts to separate all seven compounds via TLC
were unsuccessful. Therefore, in order to determine the ratio of products, monoborylated
anilines were borylated under standard conditions to yield their diborylated counterparts,
as seen in Figure 2.7.

28
	
  

	
  
Figure 2.7. The Diborylation of Monoborylated Anilines
NH 2

BPin

1) 1.5 equiv HBPin
THF, 1 hour
2) 0.25% [Ir(COD)(OMe)] 2
1% tmphen
1.5 equiv HBPin
80 °C, 16 hours
3) Methanol

1) 1.5 equiv HBPin
THF, 1 hour
NH 2
2) 0.25% [Ir(COD)(OMe)] 2
1% tmphen
BPin 1.5 equiv HBPin
PinB
80 °C, 16 hours
3) Methanol
1) 1.5 equiv HBPin
THF, 1 hour
NH 2
BPin 2) 0.25% [Ir(COD)(OMe)] 2
1% tmphen
1.5 equiv HBPin
80 °C, 16 hours
3) Methanol

NH 2

BPin

BPin
8

70%

NH 2

PinB

NH 2

+
BPin

10
1
NH 2

9

66%

BPin

PinB

4

NH 2

+
BPin
1

80%

BPin

BPin
2.5

Using the data collected above, the precise quantities of borylated products were
determined. It should be noted that there was no 2,6-diborylated aniline, probably due to
steric hindrance. While the most common product was the ortho borylated product, there
were a large quantity of other isomers, as seen in Figure 2.8.

29
	
  

	
  
Figure 2.8. Borylated Aniline Isomers.
1) 1.5 equiv HBPin
1 ml THF, 1 hour
2) 0.25% [Ir(COD)(OMe)] 2
1% tmphen
1.5 equiv HBPin
80 °C, 16 hours
3) Methanol

NH 2

NH 2

NH 2
BPin

BPin
35

15

11

BPin
8

NH 2

NH 2
27

PinB

BPin

5
9

12
NH 2

BPin

NH 2
2

16
PinB
BPin
13

BPin
10

75% Overall Yield

However when the total quantity of HBPin used was decreased to 1.5 equivalents,
a majority of the diborylated products were eliminated, yielding isomers 11 : 12 : 13 : 8
in a ratio of 10 : 6.5 : 4.1 : 1, but with lower overall conversion.

Application Towards the Borylation of Drugs
Of course, being able to show the practical, real world applications of the
traceless protection technique is a worthwhile endeavor. To this ends, 7-amino-4methylcoumarin, a substrate chromophore, and bupropion HCl, also known as
30
	
  

	
  
Wellbutrin®, an antidepressant used as a smoking cessation aid,

11

were borylated, as

seen in Figure 2.9.

Figure 2.9. The Borylation of 7-amino-4-methylcoumarin, and Bupropion HCl
H 2N

O

O

HN
Cl

(±)

+ HCl

O 1)

O
1.5 % [Ir(COD)(OMe)] 2 H 2N
2.2 equiv HBPin
PinB
3 % tmphen
THF, 80 °C, 16 hours
14 80%
2) Methanol

O

O
1) 3 equiv TEA, 1 ml THF,
PinB
1 hour, filter
2)1.5 % [Ir(COD)(OMe)] 2
HN
2.2 equiv HBPin
Cl (±)
3 % tmphen
THF, 80° C, 16 hours
15 65%
3) Methanol

Although in both cases the least sterically hindered location is likely the one
borylated, the drugs do provide examples of the traceless protection effect.

31
	
  

	
  

REFERENCES

32
	
  

	
  
REFERENCES

1) Mkhalid, I. A. I.; Barnard, J. H.; Marder, T. B.; Murphy, J. M.; Hartwig, J. F.
Chem. Rev. 2010, 110, 890.
2) Roosen, P. C.; Kallepalli, V. A.; Chattopadhyay, B.; Singleton, D. A.; Maleczka,
R. E., Jr.; Smith, M. R. J. Am. Chem. Soc. 2012, 134, 11350.
3) Kawamorita, S.; Ohmiya, H.; Hara, K.; Fukuoka, A.; Sawamura, M. J. Am. Chem.
Soc. 2009, 131, 5058
4) Ishiyama, T.; Isou, H.; Kikuchi, T.; Miyaura, N. Chem. Commun. 2010, 46, 159.
5) Boebel, A. T.; Hartwig, J. F. J. Am. Chem. Soc. 2008, 130, 7534
6) Samec, J. S. M.; Backvall, J. E.; Andersson, P. G.; Brandt, P. Chem. Soc. Rev.
2006, 35, 237.
7) Das, S.; Incarvito, C. D.; Crabtree, R. H.; Brudvig, G. W. Science, 2006, 212,
1941.
8) Vanchura, B. A., II; Preshlock, S. M.; Roosen, P. C.; Kallepalli, V. A.; Staples, R.
J.; Maleczka, R. E., Jr; Smith, M. R. Chem. Commun. 2010, 46, 7724.
9) Paper Pending: Preshlock, S. M.; Plattner, D. L.; Maligres, P. E.; Krska, S. W.;
Maleczka, R. E.; Smith, M. R. Agnew. Chem. Int. Ed. 2013.
10) Tajuddin, H.; Harrison, P.; Bitterlich, B.; Collings, J. C.; Sim, N.; Batsanov, A.
S.; Cheung, S. M.; Kawamorita, S.; Maxwell, A. C.; Shukla, L.; Morris, J.; Lin,
Z.; Marder, T. B.; Steel, P. G. Chem. Sci., 2012, 3, 3505
11) Jorenby, D. E.; Hays, J. T.; Rigotti, N. A.; Azoulay, S.; Watsky, E. J.; Williams,
K. E.; Billing, C. B.; Gong, J.; Reebes, K. R. J. Am. Med. Assoc., 2006, 296, 53.

33
	
  

	
  

CHAPTER 3
Chelate Directed C-H Borylation

In recent years there has been a growing interest in iridium catalyzed ortho
borylation of methyl benzoates and other aryl ketones,

1,2

with reactions involving silica3

constrained monodentate trialkyl phosphine, silica-SMAP and the P(3,5-bis(CF3)2F

4

C6H3)3, PAr 3 ligand , being particularly noteworthy.

Silica-SMAP
At the surface, borylations of methyl benzoate using the heterogeneous ligand
silica-SMAP (Figure 3.1.) were shown to give high yields with high selectivity and few
drawbacks.

Figure 3.1. Silica-SMAP Ligand

P
SiMe3

Si
O
O
Si
O
O
O Si O
O
O
[SiO 2]

5

Other silica-SMAP reactions using functional groups such carbamates ,

34
	
  

	
  
heteroatoms bearing methylbenzoate functional groups, and even phenylmethyl
6

sulfonate , to a lesser degree, were also shown to have high selectivity and yields under
relatively mild conditions, as seen in Figure 3.2.

Figure 3.2. Reactions Involving Silica-SMAP
0.5 equiv B 2Pin 2

O
OMe

hexane

NEt 2
O

OMe
O

O

0.5% SMAP-Ir(OMe)COD
0.5 equiv HBPin
hexane
70 °C, 12 hours

BPin
O
64%a,b

BPin
OMe
O

p-xylene

NEt 2
O

1 equiv B 2Pin 2
0.5% SMAP-Ir(OMe)COD

O

92%

50 °C, 1 hours

O Me
S
O O

OMe
BPin
a,b
89%

25 °C, 2 hours

O

O

0.5% SMAP-Ir(OMe)COD

0.25% SMAP-Ir(OMe)COD
0.5 equiv HBPin
octane
100 °C, 24 hours

BPin
O Me
S
O O
33%b

a plus additional minor diborylated products
b yields based on B Pin /HBPin
2 2

35
	
  

	
  
Unfortunately, the largest weakness of silica-SMAP comes in the ligand’s
preparation which can only be obtained through an arduous process with a 24 percent
yield.

7,8

This means that silica-SMAP’s viability for large scale reactions, is minimal.

F

PAr 3 Ligand and Derivatives
F

The PAr 3 ligand, on the other hand, can be purchased from chemical retailers.
F

But while reactions with the PAr 3 ligand yielded borylated products in with high
selectivity’s and yields, (Figure 3.3), there were some drawbacks.

F

Figure 3.3. Reactions using the PAr 3 ligand.

Y

O

O
OMe

Y

O
OMe

BPin

BPin

OMe
Y

BPin

Y = Me 2N 97%

Y = Me 2N 99%

Y = Me 2N 93%

Y= Me

92%

Y= Me

98%

Y= Me

Y= Br

60%

Y= Br

64%

Y= Br

99%
57%a

Y = CF3

98%

Y = CF3

94%

Y = CF3

98%

Reactions were carried out at 80 °C for 16 hours using 5.0 mmol nonborylated
substrate, 1.0 mmol B 2Pin 2, 0.015 mmol [Ir(OMe)(COD)] 2, 0.06 mmol PArF 3,
6 ml octane. Yields were obtained through GC and based on B 2Pin 2.
a reaction carried out in a mixture of octane and mesitylene (1:1)
F

The main issue with the PAr 3 ligand is the requirement of a large excess of
substrate. This is most likely because the HBPin formed in during reactions acts as an

36
	
  

	
  
inhibitor to the catalyst.

9

F

The actual mechanism behind the PAr 3 ligand provides insight into how better,
more efficient ligands could be made. Based on the proposed mechanism shown in Figure
3.4, the catalyst thus required either coordination by the ester of the methyl benzoate
F

F

followed by dissociation of one of the PAr 3 ligands, or dissociation of the PAr 3 ligand
followed by coordination of the ester of the methyl benzoate, in order to form the active
F

catalyst. Regardless of which route it takes, one PAr 3 ligand must dissociate in order
for the reaction to occur.
F

Figure 3.4. PAr 3 Transition State Leading to Ortho Borylation.
MeO

Ar3FP

O

PinB

Ar3FP
PinB

O

BPin

BPin

PAr 3F

MeO

Ir

PAr 3F

HBpin
B 2Pin 2

Ar3FP

Ir

PinB

BPin
BPin

Ir

+ PAr 3F
BPin

BPin
Ar-BPin
PAr3F
MeO
O

MeO
Ar3FP
PinB

O
Ir
BPin

H
BPin

37
	
  

	
  
In this same vein of chelate directed mechanisms, the ligand AsPh3 was shown to
borylate a number of different substrate types, and was not limited to methyl benzoates.
F

Whereas the PAr 3 ligand was only able to borylate ketones with a 56% yield, the new
AsPh3 ligand obtained yields of over 100% for a number of ketone substrates, based on
10

B2Pin2.

Furthermore, the ligand was shown to effectively borylate α,β–unsaturated

esters, although it should be noted that the substrates were limited to ones where the
double bond was part of a ring.

11

F

(Figure 3.5) Unlike the PAr 3 ligand, HBPin was

shown to not to have as adverse an effect on reaction yields.

Figure 3.5. Functionalization Using AsPh3 Ligand
O

FG

0.2 equiv B 2Pin 2
3% [Ir(COD)(OMe)] 2
12% AsPh3
octane, 120 °C, 16 hours

O

FG

BPin

154-48% GC yield
based on B 2Pin 2
O

n

1.2 equiv B 2Pin 2
1.5% [Ir(COD)(OMe)] 2
OR
6% AsPh3
octane, 80 °C, 16 hours

O
OR
n BPin
96-20 %

where FG = OMe, Me, Cl, CF3
And R = alkyl groups

38
	
  

	
  
Silyl Directed Borylation
Indirectly related to ortho borylation of methyl benzoates, was the development of
a technique which allowed for the ortho borylation of silated phenols, benzylic
hydrosilanes,

12

13

secondary benzylic C-H bonds,

and nitrogen containing heterocycles.

14

The quintessential aspect of this reaction was that it occurred through a relay directed
mechanism, wherein the silyl group binds to the iridium catalyst in order to direct C-H
borylation, as seen in Figure 3.6.

Figure 3.6. Mechanism for the Silyl Directed Borylation of Phenols

O
HBPin

Me 2HSiO

N
N

SiMe2

Ir

BPin

BPin

N
N

Ir
BPin

BPin
BPin

- COE

N
N

+ COE

BPin

N

BPin
BPin

N

Ir

O
H
SiMe2
Ir
BPin
BPin

BPin
Me 2HSi

O

O
PinB

B 2Pin 2

N
N

Ir

SiMe2
H

BPin

Following the borylation of the substrate, reductive elimination of the ArMe2Si-H
bond from the iridium occurred, releasing the substrate and allowing the catalyst cycle to
continue.
39
	
  

	
  
Development of the SiPBz Ligand
F

Using the knowledge gained from work done on the PAr 3 ligand mechanism and
the insight gained from relay directed borylation of silylated substrates, a new ligand
capable of ortho borylation of methyl benzoates was designed. The ligand’s synthesis is
shown in Figure 3.7.

Figure 3.7. Synthesis of the SiPBz ligand.
0.5% Pd(PPh 3) 4

I
Br

P

1.3 equiv NEt 3

+

HP

1.1 equiv

80 °C, 14 hours

1 equiv

P
Br

Br

toluene,
90%

1) 1.2 equiv n-BuLi
ether, -30 °C, 1 hour
2) filter, evap volatiles
3) 1.25 equiv diisopropylchlorosilane
toluene, -30 °C, 3 hours
4) concentrate, filter, remove volatiles

P
SiH

33 99%

The SiPBz ligand was developed with three key features in mind. The first
feature was that the presence of steric bulk around the silicon part of the ligand, and the
second was the presence of a strong backbone, in this case a benzene ring. The reason
for these two features was that the work on a previous ligand prototype, as well as work
done to isolate the active 5 coordinate Ir

III

catalyst used for C-H borylation,

15

proved that

without the necessary steric bulk, you can get multiple ligands binding to the catalyst, or
40
	
  

	
  
you can get ligands which bind to two metal centers. The third part of the ligand, the
phosphorus part, was designed to be electron donating enough that C-H activation could
occur. Furthermore, the phosphorus tethers the ligand to the iridium metal, which is
useful because ability of the Aripr2Si-H to reductively eliminate from the iridium.
Because of the presence of a silicon group which binds to the iridium metal, a stable
Ir(III) transition state can be obtained when only two other boryl ligands are bound to it.
This leaves two coordination sites vacant on the 14 electron catalyst, which allows for a
chelate directed mechanism.

Substrate Scope
This ligand, SiPBz, is easy to synthesize, which was the major problem with the
silica-SMAP ligands, and is able to react in the presence of HBPin, and therefore
reactions do not require an excess of substrate, which was one of the major issues with
F

the PAr 3 ligand. The full substrate scope is shown below in Figure 3.8. and Figure 3.9.

41
	
  

	
  
Figure 3.8. SiPBz Substrate Scope

R2

1.25 mol% [Ir(OMe)COD] 2

R1 O

2.5 mol% SiPbz
O

R3
O

1.0 equiv B 2Pin 2
hexane
80 °C, 16h
PinB

BPin
17 63%c

19 82%e

BPin

CF3 O

MeO

BPin
18 60% (95%)d
OMeO
MeO

O

BPin
b
20 66%
F 3C

BPin
22 82%

O

O
BPin

21 70%

O
O

BPin
O

O
O

O

Br

O

OMeO

R1 O

R3

O

O
BPin
16 41% (81%)a,b

R2

O
O

BPin
23 83%

O
F 3C

BPin
24 49%b

a used 0.5 equiv B Pin . b resulted in di borylated byproducts. c used 2.0 equiv B Pin .
2
2
2
2
d used half the amount of substrate, but kept other reagent quantities the same. e used
1.25 equiv B 2Pin 2.

Initial tests on methyl benzoate using one equivalent of B2Pin2, yielded a mixture
of mono and diborylated product with yields high enough to imply that both HBPin and
B2Pin2 can be used as reagents for the reaction. Indeed, when one equivalent of HBPin
was used, monoborylation does occur, albeit with meta and para borylated products as
well (o : m : p = 40 : 14 : 13). However, when 0.5 equivalents of B2Pin2 were used,
products were mostly monoborylated, and the yield was high relative to B2Pin2.

42
	
  

	
  
F

In the case of the PAr 3 ligand, one of the drawbacks was the low yields obtained
when using brominated methyl benzoate substrates. Even with the SiPBz ligand, the
conversion to 18 using standard conditions was only 33%. However, by halving the
amount of substrate and then doubling the quantity of B2Pin2 while keeping all other
factors the same, 18 was obtained with 95% assay yield using DHT standard, and 60%
overall yield, with the low yields relative to conversion being attributed to difficulty
recrystallizing due to the excess B2Pin2.
Substrates containing an electron donating methoxy group, 19, 20, 21, gave
borylation with high selectivity as did the borylation substrates with the electron
withdrawing trifluoromethyl groups, 22, 23, 24.
Figure 3.9. SiPBz Substrate Scope Continued

R2

1.25 mol% [Ir(OMe)COD] 2

R1 O

2.5 mol% SiPbz
O

R3

BPin
25 82%

28 70%

F

BPin
26 49%a
F

O
BPin

BPin
O
O

O

BPin
27 84%

O

Cl
O

O
Br

O

R3

O
O

F

R2

1.0 equiv B 2Pin 2
hexane
80 °C, 16h

O

R1 O

Cl

O
O

Br

BPin

BPin
29 80%b

30 72%

a resulted in di borylated byproducts b used 2.5% dtbpy as a ligand instead of SiPbz

43
	
  

	
  
It is worth pointing out that the para substituted methyl benzoates, 24 and 26, both gave
diborylation, which was to be expected considering the results of 16. Attempts to curb
diborylation of the substrates by using 0.5 equivalents B2Pin2 merely lowered the overall
borylation.
The borylation of 28 occurred with a much higher yield than was expected when
compared to 18. The presence of the fluorine substituent obviously improved yield of 28
compared to 18, while the presence of the bromine decreased the yield when compared to
27. The source of the different yields most likely has electronic origins, though nonobvious ones.
Similarly, it is curious that borylation of 30 performed under standard conditions
resulted in a modest yield, showing that other halogens like chlorine didn’t decrease the
reactivity.
Following the borylation of methyl benzoates, it was decided to expand the scope
of the reactions to include carbamates, a substrate which had been effectively borylated
using silica-SMAP (Figure 3.10).

44
	
  

	
  
Figure 3.10. Borylation of Carbamates
OH
R1

O

N
O

0.5 mmol

O

N
O

Cl
0.5 mmol

1.5 equiv Me 2NCOCl
1.5 equiv K 2CO3
acetonitrile
80 °C, 6 hours
2.5 mol% [Ir(OMe)COD] 2
5 mol% SiPbz
1 equiv B 2Pin 2
THF
80 °C, 16h

2.5 mol% [Ir(OMe)COD] 2
5 mol% SiPbz
1 equiv B 2Pin 2
THF
80 °C, 16h

O

N
O

R1 52%-69%16
BPin
O

N
O

31 21.5%

BPin
O

N
O

Cl
32 12%

Low yields for these reactions could be traced to two factors. The first came from
the theorized transition state. The SiPBz mechanism was designed to perform via a
F

chelate directed mechanism, much like the PAr 3 ligand, as seen in Figure 3.11.

45
	
  

	
  
Figure 3.11. Proposed Mechanism for the SiPBz Ligand
BPin

Si

O

Ir

BPin

P

MeO

O
MeO

Si

BPin

Si

Ir

BPin

BPin
Ir

P

BPin
H

O

P

MeO

HBPin

BPin

Si

Ir

P

H

O
OMe

B 2Pin 2

BPin
Where P

Si is SiPBz

The key transition state in the mechanism comes in the form of a five-membered
intermediate. The borylation of carbamates, however, would require a six-membered
ring intermediate, and the resulting ring strain, could cause both to lower yields. (Figure
3.12)

46
	
  

	
  
Figure 3.12. Carbamate Intermediate

Si
P

BPin
BPin
H

Ir
O

Me 2N

O

The second factor that caused low yields resulted from difficulty purifying the
product and separating it from starting material, due to a lack of carbamate fluorescence.
Previous work on the borylation of carbamates using silica-SMAP must have had similar
problems, and were therefore forced to use gel permeation chromatography, GPC, to
isolate the products. Fortunately, a TLC indicator Alizarin was found to be adequate,
although streaking of the products was observed, which resulted in low isolated yields.
Worth noting is the fact that no diborylation of 31 was observed. However, this could
simply be attributed to the low overall conversion.
Some of the reactions that failed were just as curious as those that worked, and are
shown in Fig 3.14. Initial tests on a cyano carbamate revealed no conversion. However,
seeing as how low the conversion of other carbamate substrates was, the cause of the
failed reaction might of have been simply due to the transition state. Yet when a cyano
methyl benzoate substrate was used, no reaction occurred. From here there were two
possibilities. The first was that the substrates with a cyano functional group were simply
incompatible with the reaction, and the second was that the cyano group was somehow
interfering with the catalytic process. The latter looks to be the answer, seeing as how a
mixture of cyano methyl benzoate and pure methyl benzoate yield no conversion at all.
47
	
  

	
  
Figure 3.13 Failed Cyano Substrate Reactions.

O
NC

N
O

80 °C, 16h

O

2.5 mol% SiPbz

No Reaction

80 °C, 16h

O

0.5 mmol

1.25 mol% [Ir(OMe)COD] 2
1 equiv B 2Pin 2
THF

CN
1 mmol

+

No Reaction

THF

O

O

3 mol% SiPbz
1 equiv B 2Pin 2

0.5 mmol

O

1.5 mol% [Ir(OMe)COD] 2

O
CN
0.5 mmol

1.25 mol% [Ir(OMe)COD] 2
2.5 mol% SiPbz
1 equiv B 2Pin 2
THF

No Reaction

80 °C, 16h

Optimization of the SiPBz Ligand
One of the greatest attributes of the SiPBz ligand is the ease with which it can be
modified in order to optimize selectivity. Phosphorus groups, silicon groups, and even
the benzene backbone can easily be changed in order to tweak the reaction selectivity. In
order to determine how such alterations might affect the selectivity and conversion of the
catalyst, six variations of the catalyst were synthesized and tested on four different
substrates, as shown below in Table 3.1, 3.2, 3.3, and 3.4.

48
	
  

	
  
Table 3.1. Variations of the SiPBz Ligand

R1

R2

R1

R1

=
P

P

2

P
R2 =

R1

=

P

2

P

2

P

SiH

HSi

=

SiH

SiH

2
33 99%

35 50%

P
R2 = HSi

Me

P
SiHMe2

37 73%

P
SiHMe2

SiHMe2

2
34 85%

36 65%

38 92%

The two minor variations on the phosphorus part of the standard SiPBz ligand, 33,
were chosen in order to determine how a less electron donating ligand, 35, and how a
more constrained ligand, 37, would affect the conversion.

17

Less sterically hindered methyl groups on the silicon groups had been shown
increase the NMR yield for the borylation of plain carbamate by 5%, and were therefore
also tested, 34, 36, 38.
In general, the original SiPBz ligand, 33, was shown to be the most efficient
catalyst of the bunch as seen in the table below.

49
	
  

	
  
Table 3.2 Optimization of the SiPBz Ligand Comparing Results of 33 and 34.

PinB

O
OMe

BPin
O

PinB

OMe

PinB

O

NMe 2

N

O
Br

Cl

Ligands

33

37 %

45 %

8.5 %

43 %

34

17 %

43 %

0.6 %

45 %

Reaction were conducted on a 0.1 mmol scale. Conditions are as follows: 1.25 mol% [Ir(OMe)COD] 2,
1.0 equiv B2Pin2, 2.5 mol% ligand, 0.1 mmol unborylated substrate, THF, 80 °C, 16 hours.
Yields are NMR yields based on a DHT standard.

The less electron donating ligands, 35 and 36, didn’t seem to have much affect on
the conversion of starting material when compared to 33 and 34, as shown in table 3.3.

50
	
  

	
  

	
  
Table 3.3 Optimization of the SiPBz Ligand Comparing Results of 35 and 36.

PinB

O
OMe

BPin
O

PinB

OMe

PinB

O

NMe 2

N

O
Br

Cl

Ligands

35

47 %

37 %

7.0 %

43 %

36

14 %

33 %

0.6 %

44 %

Reaction were conducted on a 0.1 mmol scale. Conditions are as follows: 1.25 mol% [Ir(OMe)COD] 2,
1.0 equiv B2Pin2, 2.5 mol% ligand, 0.1 mmol unborylated substrate, THF, 80 °C, 16 hours.
Yields are NMR yields based on a DHT standard.

The exception to this being with the conversion of the brominated methyl
benzoate, where 35 gave a 10 % higher conversion than 33, and with chlorinated
carbamate, where 35 gave a 7 % lower conversion than 33.
The sterically altered ligands, 37 and 38, almost always gave much lower yields
than the rest of the ligands as shown in Table 3.4. This is most likely because the steric
bulk prevents coordination to the iridium metal.

51
	
  

	
  
Table 3.4 Optimization of the SiPBz Ligand Comparing Results of 37 and 38.

PinB

O
OMe

BPin
O

PinB

OMe

PinB

O

NMe 2

N

O
Br

Cl

Ligands

37

0.0 %

4.0 %

0.0 %

19 %

38

3.0 %

0.0 %

7.0 %

36 %

Reaction were conducted on a 0.1 mmol scale. Conditions are as follows: 1.25 mol% [Ir(OMe)COD] 2,
1.0 equiv B2Pin2, 2.5 mol% ligand, 0.1 mmol unborylated substrate, THF, 80 °C, 16 hours.
Yields are NMR yields based on a DHT standard.

Those ligands where the silica groups had been made less hindered, 34, 36, 38.
tended to show a mild decrease in conversion compared to their isopropyl counterparts,
which was contrary to what was seen with the borylation of pure carbamate by 34, but
followed the line of thinking that a decrease in steric bulk around the silica groups could
cause a decrease in conversion.

52
	
  

	
  

REFERENCES

53
	
  

	
  
REFERENCES

1) Miyaura, N. Bull. Chem. Soc. Jpn. 2008, 81, 1535
2) Itoh, H.; Kikuchi, T.; Ishiyama, T.; Miyaura, N. Chem Lett. 2011, 40, 1007
3) Kawamorita, S.; Ohmiya, H.; Hara, K.; Fukuoka, A.; Sawamura, M. J. Am.
Chem. Soc. 2009, 131, 5058
4) Ishiyama, T.; Isou, H.; Kikuchi, T.; Miyaura, N. Chem. Commun. 2010, 46,
159.
5) Yamazaki, K.; Kawamorita, S.; Ohmiya, H.; Sawamura, M. Org. Lett. 2010,
12, 3978
6) Kawamorita, S.; Ohmiya, H.; Sawamura, M. J. Org. Chem. 2010, 75, 3855
7) Hamasaka, G.; Kawamorita, S.; Ochida, A.; Akiyama, R.; Hara, K.; Fukuoka,
A.; Asakura, K.; Chun, W. J.; Ohmiya, H.; Sawamura, M. Organometallics.
2008, 27, 6495.
8) Ochida, A.; Hamasaka, G.; Yamauchi, Y.; Kawamorita, S.; Oshima, N.; Hara,
K.; Ohmiya, H.; Sawamura, M. Organometallics. 2008, 27, 5494.
9) Preshlock, S. M. Ph. D. Thesis. Mich. State. University. 2013
10) Itoh, H.; Kikuchi, T.; Ishiyama, T.; Miyaura, N. Chem Lett. 2011. 40, 1007.
11) Sasaki, I.; Doi, H.; Hashimoto, T.; Kikuchi, T.; Ito, H.; Ishiyama, T. Chem
Commun. 2013, 49, 7546.
12) Boebel, A. T.; Hartwig, J. F. J. Am. Chem. Soc. 2008, 130, 7534
13) Cho, S. H.; Hartwig, J. F. J. Am. Chem. Soc. 2013, 135, 8157.
14) Robbins, D. W.; Boebel, T. A.; Hartwig, J. F. J. Am. Chem. Soc. 2010, 132,
4068
15) 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.
16) John, A.; Nicholas, K. M. J. Org. Chem. 2012, 77, 5600

54
	
  

	
  
17) (a)Broggi, J.; Urbina-Blanco, C.; Clavier, H.; Leitgeb, A.; Slugovc, C.;
Slawin, A. M. Z.; Nolan, S. P. Chem. Eur. J. 2010, 16, 9125. (b) Oyetnuji, O.
A.; Ramokongwa, G.; Ogunlusi, G. O.; Becker, C. A.L. Transition. Met.
Chem. 2013, 38, 235. (c) Sun, X.; Kryatov, S. V.; Rybak-Akimova, E. V.
Dalton Trans. 2013, 42, 4427.

55
	
  

	
  

CHAPTER 4
Conclusion
In summary, ortho directed borylation was achieved using HBPin as a traceless
directing group for aniline substrates via an outer sphere mechanism. Although the
regioselectivity was best for para-substituted anilines, the reactions still displayed
relatively good regioselectivity for meta substituted anilines as well. However, the
borylation of ortho substituted anilines gave no ortho borylation, although the reaction
did yield a single borylated product. The borylation of aniline occurred with a
surprisingly diverse quantity of isomers, and the borylation of monoborylated anilines
was required in order to determine their ratios. In the end it was concluded that the
monoborylated ortho product was the most common product. Furthermore, the
borylation of both bupropion HCl and 7-amino-4-methylcoumarin was performed using
HBPin as a traceless protecting group.
A new SiPBz ligand was also developed and used for the ortho borylation of
methyl benzoate substrates and methyl benzoate derivatives. Such reactions occurred
through an inner sphere mechanism and generally gave high yields. Exceptions include
substrates which had a bromine group, which gave much lower yields, and those with a
nitrile group which gave no yield at all, probably due to interaction of the cyano group
with the open coordination sight in the iridium catalyst complex. Slight alterations were
also made to the SiPBz ligand in order to determine how minor variations in steric bulk
and electronics affected the borylation of difficult substrates, like carbamates. In the end
it was determined that the original SiPBz ligand was the best of the variations tested.

56
	
  

CHAPTER 5
Experimental Information

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
TM

Sigma-Aldrich (Sure/Seal

) and were stored in the glove-box. All other commercially
1

available materials were used as received. H 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.
Melting points were measured on a MEL-TEMP® capillary melting apparatus and are
uncorrected.

General Procedure for ortho-directed Borylation of Anilines. In a nitrogen filled glovebox, 1
mmol aniline substrate 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. and
recrystallization from MeOH/H2O.

57
	
  

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

NH 2 O
BO
Br
1

White solid (246 mg, 88% isolated yield); mp: 101-102 °C; H NMR (500 MHz, CDCl3, 7.27) δ
7.70 (d, J = 2.4 Hz, 1H), 7.30 (dd, J = 8.8, 2.9 Hz, 1H), 6.54 (d, J = 8.8 Hz, 1H), 5.05 (br s, 2H),
1.34 (s, 12H);
11

13

C NMR (125 MHz, CDCl3) δ 151.7, 138.7, 135.2, 116.9, 109.2, 83.9, 24.9;

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

H] 298.0614, found 298.0609.

2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)-4-(trifluoromethyl)-benzenamine (2)
NH 2 O
BO
CF3

White solid (250 mg, 87% isolated yield); mp: 110-113 °C; 1H NMR (500 MHz, CDCl3, 7.27) δ
7.86 (s, 1H), 7.42 (dd, J = 8.3, 2.0, 1H), 6.61 (d, J = 8.4 Hz, 1H), 5.05 (br s, 2H), 1.35 (s, 12H);
13

C NMR (125 MHz, DMSO-d6) δ 151.2, 129.5, 124,7, 120.2 (q, 270.8), 113.9 (q, 32,5), 109.4,

79.2, 20.1;

19

F NMR (470 MHz, CDCl3 ) δ -65.9;

11
+

B NMR (160 MHz, CDCl3) δ 30 (br s);

HRMS (ESI) m/z calcd for C13H17BF3NO2 [M + H] 288.1385, found 288.1389.

58
	
  

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

NH 2 O
BO
OMe
1

Pale red solid (157 mg, 63% isolated yield); mp: 73-74 °C; H NMR (500 MHz, C6D6, 7.16) 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);
83.8, 56.0, 24.9;

11

13

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

B NMR (160 MHz, C6D6) δ 31 (br s); HRMS (ESI) m/z calcd for
+

C13H20BNO3 [M + H] 250.1617, found 250.1616.

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

NH 2 O
BO
OB
O

CN
1

White solid (329 mg, 89% isolated yield); mp: 175-180 °C; H NMR (500 MHz, CDCl3, 7.26) δ
7.93 (s, 1H), 6.97 (s, 1H), 5.15 (br, s, 2H), 1.36 (s, 12H) 1.33 (s, 12H);

13

C NMR (125 MHz,

CDCl3) δ155.3, 143.0, 121.3, 120.2, 103.5, 84.6, 84.1, 24.8; 11B NMR (160 MHz, CDCl3) δ 29.7
+

(br s), 22.3 (s); HRMS (ESI) m/z calcd for C19H28B2N2O4 [M + H] 371.2313, found 371.2314.

59
	
  

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

NH 2 O
BO
CN
The reaction solvent was hexanes. The reaction was performed using 2.0 equiv HBpin (290 µL).
The reaction was performed using 1.5 µmol [Ir(OMe)COD]2 (1.5 mol%)
4

4

4’

and

3.0 µmol

4’

N ,N ,N ,N -tetramethyl-[2,2'-bipyridine]-4,4'-diamine (3.0 mol%). White solid (146 mg,
1

1

60% isolated yield, (83% assay yield by H NMR); mp: 96-97 °C; H NMR (500 MHz, CDCl3,
7.27) 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);
84.2, 24.9;

11

13

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

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

+

[M + H] 245.1464, found 245.1467.

5-methoxy-2-(4,4,5-trimethyl-1,3,2-dioxaborolan-2-yl)aniline (6a)

NH 2 O
BO
MeO
The reaction was performed using 2.5 µmol [Ir(OMe)COD]2 (2.5 mol%) and 5.0 µmol 3,4,7,8tetramethyl-1,10-phenanthroline (5.0 mol%). Purified by column chromatography; hexanes:
1

EtOAc (70: 30). Red gel (91.0 mg, 26%); H NMR (500 MHz, CDCl3, 7.26) δ 7.54 (d, J = 8.3
Hz, 1H), 6.27 (dd, J = 8.3, 2.4 Hz, 1H), 6.11 (d, J = 2.4 Hz, 1H), 4.76 (br s, 2H), 3.76 (s, 3H),
1.32 (s, 12H);
11

13

C NMR (125 MHz, CDCl3) δ163.6, 155.4, 138.4, 103.7, 99.4, 83.2, 54.9, 24.8;
+

B NMR (160 MHz, CDCl3) δ 30 (br s); HRMS (ESI) m/z calcd for C13H20BNO3 [M + H]

250.1617, found 250.1626
60
	
  

3-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (6b)
NH 2
BO
O

MeO

The reaction was performed using 2.5 µmol [Ir(OMe)COD]2 (2.5 mol%) and 5.0 µmol 3,4,7,8tetramethyl-1,10-phenanthroline (5.0 mol%). Purified by column chromatography; hexanes:
EtOAc (70: 30). Red crystal solid (163.8 mg, 47%); mp: 90-93 °C;

1

H NMR (500 MHz,

CD3CN, 1.94) δ 6.61 (d, J = 1.4 Hz, 1H), 6.54 (d, J = 1.9 Hz, 1H), 6.39 (t, J = 2.6, 1.9 Hz, 1H),
4.15 (br s, 2H), 3.73 (s, 3H), 1.32 (s, 12H);
109.1, 104.9, 83.7, 55.2, 24.8;

11

13

C NMR (125 MHz, CDCl3) δ163.3, 146.7, 114.5,

B NMR (160 MHz, CD3CN) δ 31 (br s); HRMS (ESI) m/z

+

calcd for C13H20BNO3 [M + H] 250.1617, found 250.1620.

2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (7)
NH 2

O

B

Cl

O

Brown solid (170 mg, 68% isolated yield); mp: 78 °C;

1

H NMR (500 MHz, CDCl3, 7.26) δ

7.69 (s, 1H), 7.49 (d, J = 7.8 Hz, 1H), 6.74 (d, J = 7.9 Hz, 1H), 4.25 (br s, 2H), 1.31 (s, 12H);
13

C NMR (125 MHz, CDCl3) δ 145.4, 136.0, 134.3, 118.7, 114.9, 83.6, 24.8;

11

B NMR (160

MHz, CDCl3) δ 30 (br s); HRMS (ESI) m/z calcd for C12H17BClNO2 [M + H]+ 254.1121,
found 254.1126.
61
	
  

2,4-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (8)
NH 2 O
BO

O

B

O

Red solid (242 mg, 70% isolated yield); mp: 152-157 °C;

1

H NMR (500 MHz, CDCl3, 7.26) δ

8.11 (s, J = 1.4 Hz, 1H), 7.67 (dd, J = 15, 8.3Hz, 1H), 6.62 (d, J = 7.8 1H) 5.30 (br, s, 2H),
1.33 (s, 24H);
11

13

C NMR (125 MHz, CDCl3) δ 156.1, 144.4, 139.4, 113,8, 83.4, 83.1, 24.9, 24.8;
+

B NMR (160 MHz, CDCl3) δ 31 (br s); HRMS (ESI) m/z calcd for C18H29B2NO4 [M + H]

346.2368, found 346.2366.

2,5-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (9)

NH 2 O
BO
OB
O
White crystal powder (200 mg, 57% yield); mp: 270-272 °C;

1

H NMR (500 MHz, CDCl3,

7.26) δ 7.61 (d, J =7.3 Hz, 1H), 7.09 (d, J =7.4 Hz, 1H), 7.04 (s, 1H), 4.70 (br, s, 2H), 1.33 (s,
24H);

13

C NMR (125 MHz, CDCl3) δ 152.8, 135.9, 122.8 (d, J= 22.8), 121.0 (d, J=22.9), 83.7,

83.5, 24.9, 24.7;

11

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

C18H29B2NO4 [M + H] 346.2368 found 346.2367.

62
	
  

3,5-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (10)
NH 2
OB
O
Clear gel (37 mg, 18% yield);

1

H NMR (500 MHz, DMSO-d6, 2.48) δ 7.21 (s, 1H), 7.00 (s,

2H), 5.01 (br, s, 2H), 1.25 (s, 24H);
83.7, 25.1;

11

BO
O

13

C NMR (125 MHz, DMSO-d6) δ 147.9, 129.3, 123.2,

B NMR (160 MHz, DMSO-d6) δ 31 (br, s); HRMS (ESI) m/z calcd for
+

C18H29B2NO4 [M + H] 346. 2368 found 346.2365.

2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (11)

NH 2 O
BO
1

Brown solid (58 mg, 26% NMR yield); mp: 60-62 °C; H NMR (500 MHz, CDCl3, 7.27) δ
7.63 (dd, J = 7.3, 1.5 Hz, 1H), 7.24 (td, J = 8.3, 2.0 Hz, 1H), 6.68 (td, J = 8.3, 1.0 Hz, 1H), 6.61
(d, J = 8.3 Hz, 1H), 4.73 (br, s, 2H), 1.35 (s, 12H);
135.7, 132.7, 116.8, 114.7, 83.4, 24.9;

11

13

C NMR (125 MHz, CDCl3) δ 153.6,

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

+

m/z calcd for C12H18BNO2 [M + H] 220.1511, found 220.1511

63
	
  

3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (12)
NH 2
BO
O
Brown crystal powder (45 mg, 20% NMR yield); mp: 80-82 °C;

1

H NMR (500 MHz, DMSO-

d6, 2.49) δ 7.01 (t, J = 7.3 Hz, 1H), 6.98 (d, J =1.5 Hz, 1H), 6.81 (d, J = 7.3 Hz, 1H), 6.65 (dd, J
= 8.3, 1.5 Hz, 1H), 5.07 (br, s, 2H), 1.25 (s, 12H);
124.9, 121.1, 117.9, 83.6, 24.8;

11

13

C NMR (125 MHz, CDCl3) δ 145.7, 128.7,

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

+

calcd for C12H18BNO2 [M + H] 220.1511, found 220.1514.

4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (13)
NH 2

O

B

O

Brown crystal powder (26 mg, 12.6% NMR yield); mp: 140-148 °C;

1

H NMR (500 MHz,

CDCl3, 7.26) δ 7.62 (d, J = 8.4 Hz, 2H), 6.66 (d, J = 8.4 Hz, 2H), 3.83 (br, s, 2H), 1.32 (s, 12H);
13

C NMR (125 MHz, CDCl3) δ 149.2, 136.5, 114.0, 83.2, 24.8;
+

11

B NMR (160 MHz, CDCl3) δ

30 (br s); HRMS (ESI) m/z calcd for C12H18BNO2 [M + H] 220.1511, found 220.1513.

64
	
  

7-amino-4-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-chromen-2-one (14)

O
OB
H 2N

O

O

The reaction was performed by taking 50 mg of starting 7-amino-4- methylcoumarin (0.285
mmol). The rest of the reaction was performed using 2.85µmol [Ir(OMe)COD]2 (1.0 mol%),
8.55 µmol 4,4'-di-tert-butyl-2,2'-bipyridine (3.0 mol%), 2.2 equiv HBPin. Reddish Brown Solid
1

(68 mg, 80% isolated yield); mp: 200-202 °C; H NMR (500 MHz, CDCl3, 7.26) δ 7.83 (s, 1H),
6.43 (s, 1H), 5.96 (s, 1H), 5.3 (s, 2H), 2.38 (s, 3H), 1.35 (s, 12H);

13

C NMR (125 MHz, CDCl3)

δ161.6, 157.7, 156.7, 153.2, 134.6, 110.9, 109.6, 100.2, 84.0, 24.8, 18.6;
+

11

B NMR (160 MHz,

CDCl3) δ 30 (br s); HRMS (ESI) m/z calcd for C16H20BNO4 [M + H] 302.1566, found
302.1571.

65
	
  

2-(tert-butylamino)-1-(3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)phenyl)propan-1-one (15)

O

O
OB

HN
Cl
The reaction was performed by taking 100 mg of starting buproprion HCl (0.36 mmol), and
adding 3.0 equiv triethylamine, and stirring for two hours in 1 ml THF. The mixture was then
filtered and the volatiles removed under reduced pressure to yield the starting buproprion. The
rest of the reaction was performed using 3.60 µmol [Ir(OMe)COD]2 (1.0 mol%), 10.8 µmol
4,4'-di-tert-butyl-2,2'-bipyridine (3.0 mol%), 2.2 equiv HBPin, and 0.75 equiv B2Pin2. Orange
1

Yellow Gel (101 mg, 76% isolated yield); Spectra contains minor starting material H NMR
(500 MHz, CDCl3, 7.26) δ 8.19 (d, J = 1.0 Hz, 1H), 8.02 (td, J = 2.5, 3.9 Hz, 1H), 7.97 (dd, J =
1.0, 2.5 Hz, 1H), 4.35 (q, J = 7.3, 1H), 1.35 (s, 12H), 1.27 (d, J = 4.2 Hz, 3H), 1.05 (s, 9H);

13

C

NMR (125 MHz, CDCl3) δ 203.7, 139.2, 136.1, 134.9, 132.1, 130.8, 84.5, 75.0, 52.2, 50.9, 29.6,
24.8, 22.2;

11

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

C19H29BClNO3 [M + H]+ 366.2008, found 366.2008. Mixture was racemic.
General Procedure for ortho-directed Borylation of Methyl Benzoates. In a nitrogen filled
glovebox, 1.25 µmol [Ir(OMe)COD]2 (1.25 mol%) was dissolved in 1 mL THF in a 15 mL
pressure tube containing a magnetic stir bar. 1 equiv B2Pin2 (254 mg), 2.5 µmol (2(diisopropylsilyl)phenyl)di-p-tolylphosphane (2.5 mol%), and 1 mmol methyl benzoate substrate
were also 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.
The volatiles were then removed under reduced pressure and the product was purified by passing
it through a short plug of SiO2 in MTBE.

	
  

66

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

1

O
O
BO
O

The reaction was performed using 2.0 mmol substrate (272 mg), 1.25 µmol [Ir(OMe)COD]2
(1.25 mol%), 0.5 equiv B2Pin2 (254 mg), 2.5 µmol (2-(diisopropylsilyl)phenyl)di-ptolylphosphane (2.5 mol%). Obtained via column chromatography; hexanes: EtOAc (9: 1) was a
1

Yellow-Brown Oil (110 mg, 41% yield based on B2Pin2 (81% assay yield by H NMR) and 5%
diborylated product);

1

H NMR (500 MHz, CDCl3, 7.26) δ 7.94 (d, J = 7.8 Hz, 1H), 7.53-7.48

(m, 2H), 7.42 (dt, J = 2.5, 8.4 Hz, 1H), 3.91 (s, 3H), 1.42 (s, 12H).

67
	
  

methyl 2,6-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (17)
O

B

O

O
O
BO
O

The reaction was performed using 1.0 mmol substrate (126 µl), 2.5 µmol [Ir(OMe)COD]2 (2.5
mol%), 2.0 equiv B2Pin2 (508 mg), 5.0 µmol (2-(diisopropylsilyl)phenyl)di-p-tolylphosphane
(5.0 mol%). Obtained by recrystallization from MeOH/ H2O a White solid (244 mg, 63%
1

isolated yield); H NMR (500 MHz, CDCl3, 7.27) 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);
84.0, 52.0, 24.8;

11

13

C NMR (125 MHz, CDCl3) δ 170.6, 141.7, 135.4, 128.9,

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

C20H31B2O6 [M + H] 389.2307, found 389.2307.

68
	
  

methyl 5-bromo-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (18)
O
Br

O
BO
O

The reaction was performed using 0.5 mmol substrate (107.5 mg), 2.5 µmol [Ir(OMe)COD]2 (2.5
mol%), 2.0 equiv B2Pin2 (254 mg), 5.0 µmol (2-(diisopropylsilyl)phenyl)di-p-tolylphosphane
(5.0 mol%). Purified by column chromatography; hexanes: EtOAc (9: 1). Obtained Yellow Oil
1

(139 mg, 60% yield (95% assay yield by 1H NMR)); H NMR (500 MHz, CDCl3, 7.26) δ 8.07
(s, J = 1.5 Hz, 1H), 7.64 (dd, J = 2.0, 7.8 Hz, 1H), 7.37 (d, J = 7.8 Hz, 1H), 3.91 (s, 3H), 1.40
(s, 12H);
24.8;

11

13

C NMR (125 MHz, CDCl3) δ 167.1, 135.3, 134.7, 133.7, 131.7, 123.3, 84.2, 52.5,

B NMR (160 MHz, CDCl3) δ 31 (br, s); HRMS (ESI) m/z calcd for C14H18BBrO4 [M +

+

H] 341.0562, found 341.0575.

69
	
  

methyl 2-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (19)

O

O
O
BO
O

The reaction was performed using 1.0 mmol substrate (166 mg), 1.25 µmol [Ir(OMe)COD]2
(1.25 mol%), 1.25 equiv B2Pin2 (317 mg), 2.5 µmol (2-(diisopropylsilyl)phenyl)di-ptolylphosphane (2.5 mol%). Obtained from recrystallization from MeOH/H2O Brown Crystals
1

(240 mg, 82% yield); mp: 84 °C; H NMR (500 MHz, CDCl3, 7.26) δ 7.38 (t, J = 7.3 Hz, 1H),
7.32 (d, J =6.4 Hz, 1H), 7.02 (d, J = 8.3 Hz, 1H), 3.88 (s, 3H), 3.83 (s, 3H), 1.32 (s, 12H);
NMR (125 MHz, CDCl3) δ 169.1, 156.0, 130.5, 128.1, 126.5, 113.7, 84.0, 55.9, 52.3, 24.8;

13
11

C
B
+

NMR (160 MHz, CDCl3) δ 30 (br, s); HRMS (ESI) m/z calcd for C15H21BO5 [M + H]
293.1563, found 293.1574.

methyl 5-methoxy-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (20a)

2

O
O

O
BO
O

Purified by column chromatography; hexanes: EtOAc (9: 1). Yellow Oil (193 mg, 66% yield)
Spectra contains minor amounts of methyl 3-methoxy-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan2-yl)benzoate 1H NMR (500 MHz, CDCl3, 7.26) δ 7.45-7.42 (m, 2H), 7.05 (dd, J =2.4, 8.3 Hz,
1H), 3.89 (s, 3H), 3.83 (s, 3H), 1.39 (s, 12H).

	
  

70

methyl 3-methoxy-2,6-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (20b)
O

B

O

O

O
O
BO
O

Purified by column chromatography; hexanes: EtOAc (9: 1). Yellow Powder (20 mg, 5% yield);
mp: 98 °C;

1

H NMR (500 MHz, CDCl3, 7.26) δ 7.50 (d, J = 7.9, Hz, 1H), 6.93 (d, J = 8.3 Hz,

1H), 3.87 (s, 3H), 3.79 (s, 3H), 1.39 (s, 12H), 1.34 (s, 12H);

13

C NMR (125 MHz, CDCl3) δ

169.3, 163.6, 139.0, 135.4, 112.3, 83.8, 83.6, 55.6, 52.1, 24.86, 24.81;

11

B NMR (160 MHz,
+

CDCl3) δ 31 (br, s); HRMS (ESI) m/z calcd for C21H32B2O7 [M + H] 419.2420, found
419.2434.

methyl 2,3-dimethoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (21)

O
O

O
O
BO
O

Obtained via recrystallization with MeOH/H2O White crystals (227 mg, 70% yield); mp: 85 °C;
1

H NMR (500 MHz, CDCl3, 7.26) δ 7.51 (d, J = 7.8 Hz, 1H), 6.94 (d, J =8.3 Hz, 1H), 3.89 (s,
13

3H), 3.88 (s, 3H), 3.85 (s, 3H), 1.30 (s, 12H);

C NMR (125 MHz, CDCl3) δ 168.7, 155.0,

145.4, 134.6, 131.8, 112.6, 83.8, 61.6, 55.8, 52.2, 24.8;
+

s); HRMS (ESI) m/z calcd for C16H23BO6 [M

B NMR (160 MHz, CDCl3) δ 30 (br,

+ H] 323.1669, found 323.1677.
71

	
  

11

Figure 4.1 methyl 2,3-dimethoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate
(21)
The following are 50% thermal ellipsoidal drawings of the molecule in the asymmetric cell with
various amount of labeling.

Crystal structure determination of methyl 2,3-dimethoxy-6-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)benzoate (21) Crystal Data. C16H23O6B, M =322.15, monoclinic, a =
23.4123(4) Å, b = 9.0701(2) Å, c = 18.5703(3) Å, β = 118.6010(10)°, V = 3462.24(12) Å3, T =
172.99, space group C2/c (no. 15), Z = 8, µ(CuKα) = 0.767, 15915 reflections measured, 3362
unique (Rint = 0.0246) which were used in all calculations. The final wR2 was 0.1943 (all data)
72
	
  

and R1 was 0.0663 (I > 2\s(I)).
methyl 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-(trifluoromethyl)benzoate (22)

2

CF3 O
O
BO
O

Obtained via recrystallization with MeOH/H2O; Black Crystals (270 mg, 82% yield); mp: 60
1

°C; H NMR (500 MHz, CDCl3, 7.27) δ 7.99 (d, J = 7.9, Hz, 1H), 7.76 (d, J =8.3 Hz, 1H), 7.55
(t, J = 7.8 Hz, 1H), 3.92 (s, 3H), 1.34 (s, 12H).

methyl 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)benzoate (23)

2

O
F 3C

O
BO
O

Obtained via recrystallization with MeOH/H2O; Brown Powder (266 mg, 81% yield); mp: 55
1

°C; H NMR (500 MHz, CDCl3, 7.27) δ 8.19 (s, 1H), 7.76 (dd, J = 1.0, 7.8 Hz, 1H), 7.62 (d, J =
7.8 Hz, 1H), 3.95 (s, 3H), 1.42 (s, 12H).

73
	
  

methyl 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)benzoate (24a)
O
O
BO
O

F 3C

Purified by column chromatography; hexanes: EtOAc (9: 1). Yellow Oil (163 mg, 49% yield);
1

H NMR (500 MHz, CDCl3, 7.27) δ 8.04 (d, J = 8.3 Hz, 1H), 7.74 (s, 1H), 7.69 (dd, J = 7.8, 0.9
13

Hz, 1H), 3.95 (s, 3H), 1.43 (s, 12H);

C NMR (125 MHz, CDCl3) δ 167.4, 136.7, 133.7 (J =

32.4 Hz), 129.1 (J = 3.8), 129.0, 126.0 (J = 3.8 Hz), 124.8 (J = 272.8 Hz), 84.5, 52.7, 24.8;
NMR (470 MHz, CDCl3) δ -63.0 (s);

11

19

F

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

+

m/z calcd for C15H18BF3O4 [M + H] 331.1331, found 331.1334.

methyl 2,6-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)benzoate
(24b)

O

B

O

O
O
BO
O

F 3C

Purified by column chromatography; hexanes: EtOAc (9: 1).Brown Crystals (77 mg, 17% yield);
mp: 70-80 °C;
13

1

H NMR (500 MHz, CDCl3, 7.26) δ 7.93 (s, 2H), 3.89 (s, 3H), 1.34 (s, 12H);

C NMR (125 MHz, CDCl3) δ 169.8, 145.9, 132.6 (J = 3.8 Hz), 130.7 (J = 32.4 Hz), 124.9 (J =

272.7 Hz), 84.5, 52.3, 24.7;

19

F NMR (470 MHz, CDCl3) δ -62.8 (s);

11

B NMR (160 MHz,
+

CDCl3) δ 31 (br, s); HRMS (ESI) m/z calcd for C21H29B2F3O6 [M + H] 457.2188, found
457.2198.
74
	
  

methyl 5-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (25)

3

O
O
BO
O

Purified by column chromatography; hexanes: EtOAc (9: 1). Yellow Oil (227 mg, 82% yield);
1

H NMR (500 MHz, CDCl3, 7.27) δ 7.76 (s, 1H), 7.41 (d, J =7.3 Hz, 1H), 7.34 (d, J = 7.4 Hz,

1H), 3.91 (d, J = 1 Hz, 3H), 2.38 (s, 3H), 1.42 (s, 12H).

methyl 4-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (26a)

3

O
O
BO
O

Product by column chromatography; hexanes: EtOAc (9: 1).White Powder (135 mg, 49% yield);
1

mp: 54 °C; H NMR (500 MHz, CDCl3, 7.27) δ 7.85 (d, J = 7.8 Hz, 1H), 7.29 (s, 1H), 7.22 (dd,
J = 1.0, 7.9 Hz, 1H), 3.90 (s, 3H), 2.38 (s, 3H), 1.43 (s, 12H).

75
	
  

methyl 4-methyl-2,6-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (26b)
O

B

O

O
O
BO
O

Purified by column chromatography; hexanes: EtOAc (9: 1) Brown Crystals (54 mg, 13% yield);
mp: 158-168 °C;
1.36 (s, 12H);

13

1

H NMR (500 MHz, CDCl3, 7.27) δ 7.45 (s, 1H), 3.87 (s, 3H), 2.35 (s, 3H),

C NMR (125 MHz, CDCl3) δ 170.3, 139.3, 137.7, 135.4, 83.9, 51.9, 116.9;

11

B
+

NMR (160 MHz, CDCl3) δ 30 (br, s); HRMS (ESI) m/z calcd for C21H32B2O6 [M + H]
403.2471, found 403.2462.

methyl 2-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (27)
F

O
O
BO
O

Purified by column chromatography; hexanes: EtOAc (9: 1). Yellow Oil (281 mg, 84% yield);
1

H NMR (500 MHz, CDCl3, 7.26) δ 7.46 (m, 2H), 7.16 (m, 1H), 3.92 (s, 1H), 1.36 (s, 12H);

13

C NMR (125 MHz, DMSO-d6) δ 166.1, 160.3 (J = 251.8 Hz), 133.2 (J = 8.6 Hz), 130.1 (J =

3.8 Hz), 124.9 (J = 13.3 Hz), 118.8 (J = 21.0 Hz), 84.6, 53.0, 24.9;
δ –115.0 (s);

11

F NMR 470 MHz, CDCl3)

B NMR (160 MHz, CDCl3) δ 31 (br, s); HRMS (ESI) m/z calcd for C14H18BFO4

+

[M + H] 281.1363, found 281.1371.
76
	
  

19

methyl 4-bromo-2-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (28)
F

O
O
BO
O

Br

Purified by column chromatography; hexanes: EtOAc (8.5: 1). Yellow Oil (255 mg, 70% yield);
1

H NMR (500 MHz, CDCl3, 7.28) δ 7.53 (s, 1H), 7.35 (d, J= 9.3 Hz, 1H), 3.93 (s, J = 1.5 Hz,

3H), 1.38 (s, J=0.9 Hz, 12H);

13

C NMR (125 MHz, CDCl3) δ 166.2, 160.9 (J = 261.3), 132.0 (J

= 3.8), 126.1 (J = 8.6), 122.7 (J = 12.4), 121.4 (J = 24.8), 84.6, 52.8, 24.7;
CDCl3) δ -109.7 (s);

11

F NMR (470 MHz,

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

C14H17BBrFO4 [M + H] 343.0155, found 343.0150.

77
	
  

19

methyl 4-bromo-2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (29)
F

O
O

Br
O

B

O

The reaction was performed using 1.0 mmol substrate (233 mg), 1.25 µmol [Ir(OMe)COD]2
(1.25 mol%), 1 equiv B2Pin2 (254 mg), 2.5 µmol 4,4-di-tert-butyl bipyridine (2.5 mol%), 1 ml
hexanes. Obtained via recrystallization with MeOH/H2O a Pale White Powder (370 mg, 80%
yield) Spectra contains minor amounts of 4-bromo-2-fluoro-3-(4,4,5,5-tetramethyl-1,3,21

dioxaborolan-2-yl)benzoate; mp: 133 °C; H NMR (500 MHz, CDCl3, 7.27) δ 8.23 (d, J = 8.3
Hz, 1H), 7.40 (d, J = 10.3 Hz, 1H), 3.97 (s, 3H), 1.38 (s, 12H) Aromatic couplings are due to HF couplings;

13

C NMR (125 MHz, CDCl3) δ 164.2, 163.6 (J = 268), 140.2 (J = 1.9 Hz), 133.7

(J = 9.5 Hz), 121.8 (J = 24.8 Hz), 117.1 (J = 8.6 Hz), 84.6, 52.4, 24.8 (J = 10.5 Hz);
470 MHz, CDCl3) δ –104.6 (s);

11

F NMR

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

calcd for C14H17BBrFO4 [M + H]+ 343.0155, found 343.0160.

78
	
  

19

methyl 2,3-dichloro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (30)
Cl
Cl

O
O
BO
O

Recrystalized from Pentane Green Crystals (240 mg, 72%
amounts of unreacted B2Pin2; mp: 49 °C;

1

yield) Spectra contains minor

H NMR (500 MHz, CDCl3, 7.27) δ 7.64 (d, J = 7.8

Hz, 1H), 7.51 (d, J =8.3 Hz, 1H), 3.93 (s, 3H), 1.32 (s, 12H);
167.5, 140.8, 136.0, 134.0, 130.6, 129.0, 84.6, 52.6, 24.7;

11

13

C NMR (125 MHz, CDCl3) δ

B NMR (160 MHz, CDCl3) δ 30 (br,

s); HRMS (ESI) m/z calcd for C14H17BCl2O4 [M + H]+ 333.0651, found 333.0662.

79
	
  

Figure 4.2

methyl 2,3-dichloro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate

(30)
The following are 50% thermal ellipsoidal drawings of the molecule in the asymmetric cell with
various amount of labeling.

Crystal Structure Determination of methyl 2,3-dichloro-6-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)benzoate (30).

Crystal	
   Data.	
   C14H17BCl2O4,	
   M	
  =330.99,	
   triclinic,	
   a	
  =	
  

8.3136(8)	
  Å,	
   b	
  =	
   10.1181(9)	
  Å,	
   c	
  =	
   11.2272(11)	
  Å,	
   α	
  =	
   112.5120(10)°,	
   β	
  =	
   92.2620(10)°,	
   γ	
  =	
  
110.8860(10)°,	
   V	
  =	
   798.00(13)	
  Å3,	
   T	
  =	
   173.15,	
   space	
   group	
   P-­‐1	
   (no.	
   2),	
   Z	
  =	
   2,	
   μ(MoKα)	
  =	
   0.417,	
  
13234	
  reflections	
  measured,	
  2930	
  unique	
  (Rint	
  =	
  0.0266)	
  which	
  were	
  used	
  in	
  all	
  calculations.	
  The	
  
final	
   wR2	
   was	
   0.0905	
   (all	
   data)	
   and	
   R1	
   was	
   0.0337	
  (>2sigma(I)).	
  

80
	
  

2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl dimethylcarbamate (31)

O

B

O
O

N
O

The reaction was performed using 0.5 mmol substrate (82.5 mg), 2.5 µmol [Ir(OMe)COD]2 (2.5
mol%), 1 equiv B2Pin2 (127 mg), 2.5 µmol 4,4-di-tert-butyl bipyridine (5.0 mol%), 1.5 ml THF.
Purified by column chromatography; hexanes: EtOAc (8.5: 1) using Alizarin as an indicator.
Clear Gel (30 mg, 21.5% yield);

1

H NMR (500 MHz, CDCl3, 7.26) δ 7.75 (dd, J = 1.5, 7.3 Hz,

1H), 7.45 (dt, J =1.9, 7.8 Hz, 1H), 7.20 (t, J = 7.4 Hz, 1H), 7.07 (d, J = 7.8 Hz, 1H), 3.13 (s,
3H), 3.00 (s, 3H) 1.30 (s, 12H);

13

C NMR (125 MHz, CDCl3) δ 156.3, 155.6, 136.1, 132.2,

124.8, 122.1, 83.4, 36.6, 36.4, 24.9; 11B NMR (160 MHz, CDCl3) δ 30 (br, s); HRMS (ESI) m/z
+

calcd for C15H22BNO4 [M + H] 292.1723 found 292.1714.

81
	
  

5-chloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl dimethylcarbamate (32)
O

B

O
O

N
O

Cl
The reaction was performed using 0.5 mmol substrate (99.5 mg), 2.5 µmol [Ir(OMe)COD]2 (2.5
mol%), 1 equiv B2Pin2 (127 mg), 2.5 µmol 4,4-di-tert-butyl bipyridine (5.0 mol%), 1.5 ml THF.
Purified by column chromatography; hexanes: EtOAc (8.5:1) using Alizarin as an indicator.
1

Clear Gel (26 mg, 12% yield); H NMR (500 MHz, CDCl3, 7.26) δ 7.69 (d, J = 8.3 Hz, 1H),
7.18 (dd, J =1.9, 7.8 Hz, 1H), 7.11 (d, J = 1.9 Hz, 1H), 3.12 (s, 3H), 2.99 (s, 3H), 1.30 (s, 12H);
13
11

C NMR (125 MHz, CDCl3) δ 156.8, 155.1, 137.6, 136.9, 125.2, 122.8, 83.6, 36.7, 36.4, 24.9;
+

B NMR (160 MHz, CDCl3) δ 30 (br, s); HRMS (ESI) m/z calcd for C15H21BClNO4 [M + H]

326.1333 found 326.1324.

82
	
  

(2-(diisopropylsilyl)phenyl)di-p-tolylphosphane (SIPBz) (33)

P
SiH

In a nitrogen filled glove box, 1.0 g (2-bromophenyl)di-p-tolylphosphine (2.7 mmol) was
dissolved in 2 mL ether and cooled to -30 °C. 2.03 mL of a 1.6 M n-BuLi solution was then
added drop wise, and the reaction stirred for 30 minutes. Volatiles were removed under reduced
pressure, and the leftover material was then dissolved in 2 mL toluene. To the mixture, 0.512 g
chlorodiisopropylsilane (3.35 mmol) was then added drop-wise, and the mixture was stirred for 3
hours. The mixture was then filtered, and the precipitate was washed with toluene. Volatiles
were removed under reduced pressure to yield a colorless solid white crystals (650 mg, 60%
yield); mp: 75 °C;

1

H NMR (500 MHz, C6D6, 7.14) δ 7.62-7.58 (m, 1H), 7.36-7.33 (m, 1H),

7.31 (d, J = 7.8 Hz, 4H), 7.08-7.02 (m, 2H), 6.90 (d, J = 7.8 Hz, 4H), 4.57 (m, 1H), 1.98 (s, 6H),
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, CDCl3) δ

144.3 (d, J = 10.4 Hz), 143.2, 142.9, 138.1, 136.7 (d, J = 15.3 Hz), 134.5 (d, J = 10.5 Hz), 134.0,
133.6 (d, J = 19.1 Hz), 129.1 (d, J = 6.7 Hz), 127.7, 21.2, 19.3 (d, J = 10.5 Hz), 12.1 (d, J = 6.7
Hz);

31

P NMR (202 MHz, C6D6) δ -9.82. (s). HRMS (ESI) m/z calcd for C26H24PSi [M + H]+

405.2167, found 405.2159.

83
	
  

(2-(dimethylsilyl)phenyl)di-p-tolylphosphane (34)

P
Si

H

In a nitrogen filled glove box, 500 mg (2-bromophenyl)di-p-tolylphosphine (1.35 mmol) was
dissolved in 2 mL ether and cooled to -30 °C. 1.01 mL of a 1.6 M n-BuLi solution was then
added drop wise, and the reaction stirred for 30 minutes. Volatiles were removed under reduced
pressure, and the leftover material was then dissolved in 2 mL toluene. To the mixture, 0.16 g
chlorodimethylsilane (1.69 mmol) was then added drop-wise, and the mixture was stirred for 3
hours. The mixture was then filtered, and the precipitate was washed with toluene. Volatiles
were removed under reduced pressure to yield a colorless solid (400 mg, 85% yield); mp: 68 °C;
1

H NMR (500 MHz, C6D6, 7.14) δ 7.61 (d, J = 6.8 Hz, 1H), 7.37-7.29 (m, 5H), 7.09 (quintet, J

= 7.4, 15.2 Hz, 2H), 6.90 (d, J = 7.8 Hz, 4H), 5.10-5.06 (m, 1H), 1.99 (s, 6H), 0.42 (d, J = 3.4
Hz, 6H);

13

C NMR (125 MHz, CDCl3) δ 145.1, 144.8, 144.0 (d, J = 10.5 Hz), 138.2, 135.1 (d, J

= 9.3 Hz), 134.3 (d, J = 9.5 Hz), 133.8, 133.6 (d, J = 19.1 Hz), 129.4, 129.2 (d, J = 6.6 Hz),
128.1, 21.3, -2.2 (d, J = 7.6 Hz);

31

P NMR (202 MHz, CDCl3) δ -12.28 (s). HRMS (ESI) m/z

calcd for C22H26PSi [M + H]+ 349.1541, found 349.1529.

84
	
  

(2-(diisopropylsilyl)phenyl)diphenylphosphane (35)

P
Si

H

In a nitrogen filled glove box, 500 mg (2-bromophenyl)diphenylphosphane (1.47 mmol) was
dissolved in 3.5 mL toluene and cooled to -30 °C. 1.1 mL of a 1.6 M n-BuLi solution was then
added drop wise, and the reaction stirred for 40 minutes. Volatiles were removed under reduced
pressure, and the leftover material was then dissolved in 3.5 mL toluene. To the mixture, 0.277 g
chlorodiisopropylsilane (1.83 mmol) was then added drop-wise, and the mixture was stirred for 3
hours. The mixture was then filtered, and the precipitate was washed with toluene. Volatiles
were removed under reduced pressure to yield a yellow solid (189 mg, 50% yield); mp: 69 °C;
1

H NMR (500 MHz, C6D6, 7.15) δ 7.60-7.58 (m, 1H), 7.35 (dt, J =1.9, 7.3 Hz, 4H), 7.26 (q, J =

2.9 Hz, 1H), 7.07-6.97 (m, 8H), 4.57-4.54 (m, 1H), 1.47-1.41 (m, 2H), 1.17 (d, J = 3.9 Hz, 6H),
0.99 (d, J = 7.3 Hz, 6H);

13

C NMR (125 MHz, CDCl3) δ 143.7 (d, J = 11.5 Hz), 143.4, 143.0,

137.8 (d, J = 11.5 Hz), 136.8 (d, J = 15.3 Hz), 134.1, 133.6 (d, J = 18.1 Hz) 129.2, 128.3 (d, J =
9.5 Hz), 127.9, 19.3 (d, J = 5.8 Hz), 12.1 (d, J = 6.6 Hz);

31

P NMR (202 MHz, CDCl3) δ -8.52

(s); HRMS (ESI) m/z calcd for C24H30PSi [M + H]+ 377.1854, found 377.1840.

85
	
  

(2-(dimethylsilyl)phenyl)diphenylphosphane (36)

P
Si

H

In a nitrogen filled glove box, 500 mg (2-bromophenyl)diphenylphosphane (1.47 mmol) was
dissolved in 2 mL toluene and cooled to -30 °C. 1.1 mL of a 1.6 M n-BuLi solution was then
added drop wise, and the reaction stirred for 40 minutes. Volatiles were removed under reduced
pressure, and the leftover material was then dissolved in 2 mL toluene. To the mixture, 0.174 g
chlorodimethylsilane (1.85 mmol) was then added drop-wise, and the mixture was stirred for 3
hours. The mixture was then filtered, and the precipitate was washed with toluene. Volatiles
1

were removed under reduced pressure to yield a yellow oil (300 mg, 64% yield); H NMR (500
MHz, C6D6, 7.14) δ 7.58 (d, J = 6.9 Hz, 1H), 7.33 (dt, J = 1.9, 7.8 Hz, 4H), 7.25 (q, J = 3.9 Hz,
1H), 7.08 (t, J = 7.4 Hz, 1H), 7.02-6.98 (m, 7H), 5.07 (m, 1H), 0.39 (dd, J = 1.0, 3.9 Hz);

13

C

NMR (125 MHz, CDCl3) δ 145.3, 145.0, 143.4 (d, J = 10.4 Hz), 137.6 (d, J = 10.5 Hz), 135.2
(d, J = 14.3 Hz), 134.0, 133.8, 133.6 (d, J = 19.6 Hz), 129.5, 128.4 (m), -2.26 (d, J = 7.6 Hz);
31

P NMR (202 MHz, CDCl3) δ -10.34 (s). HRMS (ESI) m/z calcd for C20H22PSi [M + H]+

321.1228, found 321.1208.

86
	
  

(2-(diisopropylsilyl)phenyl)di-o-tolylphosphane (37)

P
Si

H

In a nitrogen filled glove box, 250 mg (2-bromophenyl)di-o-tolylphosphane (0.679 mmol) was
dissolved in 2 mL ether and cooled to -30 °C. 0.505 mL of a 1.6 M n-BuLi solution was then
added drop wise, and the reaction stirred for 3 hours. Volatiles were removed under reduced
pressure, and the leftover material was then dissolved in 3.5 mL toluene. To the mixture, 0.138 g
chlorodiisopropylsilane (0.92 mmol) was then added drop-wise, and the mixture was stirred for 3
hours. The mixture was then filtered, and the precipitate was washed with toluene. Volatiles
were removed under reduced pressure to yield a yellow solid (200 mg, 73% yield) Spectra
1

contains minor amounts of water; mp: 86 °C; H NMR (500 MHz, CD2Cl2, 5.32) δ 7.60 (d, J =
5.9 Hz, 1H), 7.37 (t, J = 7.4 Hz, 1H), 7.29-7.23 (m, 5H), 7.09 (t, J = 5.9 Hz, 2H), 6.93 (q, J = 3.9
Hz, 1H), 6.71-6.69 (m, 2H), 4.24 (m, 1H), 2.37 (s, 6H), 1.32-1.25 (m, 2H), 1.07 (d, J = 7.3 Hz,
6H), 0.86 (d, J = 7.4 Hz, 6H);

13

C NMR (125 MHz, CDCl3) δ 142.6, 142.37 (d, J = 7.6 Hz),

142.31, 136.3 (d, J = 3.4 Hz), 133.6 (J = 4.7 Hz), 129.9 (d, J = 4.8 Hz), 129.2, 128.4, 127.5,
125.9, 21.2 (d, J = 10.1 Hz), 19.0, 18.9;

31

P NMR (202 MHz, CDCl3) δ -24.85 (s). HRMS (ESI)

m/z calcd for C26H34PSi [M + H]+ 405.2167, found 405.2156.

87
	
  

(2-(dimethylsilyl)phenyl)di-o-tolylphosphane (38)

P
H
Si
In a nitrogen filled glove box, 125 mg (2-bromophenyl)di-o-tolylphosphane (1.47 mmol) was
dissolved in 2 mL ether and cooled to -30 °C. 0.26 mL of a 1.6 M n-BuLi solution was then
added drop wise, and the reaction stirred for 40 minutes. Volatiles were removed under reduced
pressure, and the leftover material was then dissolved in 4 mL toluene. To the mixture, 0.04 g
chlorodimethylsilane (0.42 mmol) was then added drop-wise, and the mixture was stirred for 3
hours. The mixture was then filtered, and the precipitate was washed with toluene. Volatiles
were removed under reduced pressure to yield a whitish yellow solid (110 mg, 92% yield)
Spectra contains minor amounts of starting material; mp: 97 °C;

1

H NMR (500 MHz, CD3OD,

3.31) δ 7.69 (d, J = 5.9 Hz, 1H), 7.39 (t, J = 7.3 Hz, 1H) 7.31-7.21 (m, 5H), 7.08 (t, J = 6.4 Hz,
2H), 6.91 (q, J = 6.4 Hz, 1H), 6.65 (m, 2H), 4.62 (m, 1H), 2.33 (s, 6H), 0.29 (d, J = 1 Hz, 6H);
13

C NMR (125 MHz, CDCl3) δ 135.5 (d, J = 10.5 Hz), 135.4, 135.3, 134.1, 133.1, 130.0 (d, J =

4.8 Hz), 129.5, 128.4, 128.22, 125.9, 21.3 (d, J = 20.0 Hz), -2.52 (d, J = 8.6 Hz);

31

P NMR (202

MHz, C6D6) δ -24.871 (s). HRMS (ESI) m/z calcd for C22H26PSi [M + H]+ 349.1541, found
349.1532.

88
	
  

2-(2-methoxy-4-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (39)

4

OMe
BO
O
1

Colorless Solid. mp: 59.5-60 °C; H NMR (500 MHz, CDCl3) δ 7.55 (d, 1H, J = 7.5 Hz), 6.74
(d, 1H, J = 7.3 Hz), 6.65 (s, 1H), 3.80 (s, 3H), 2.33 (s, 3H), 1.32 (s, 12H);

13

C NMR (125 MHz,

CDCl3) δ 164.3, 142.9, 136.8, 120.9, 111.4, 83.2, 55.7, 24.9, 24.7, 21.9.

N-dimethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (40)

5

O
NMe 2
BO
O
1

White Solid. H NMR (500 MHz, CDCl3) δ 7.80 (dd, J = 7.5, 0.6 Hz, 1H), 7.45 (dt, J = 7.5, 1.5
Hz, 1H), 7.37 (dt, J = 7.5, 1.5 Hz, 1H), 7.30 (dd, J = 7.5, 0.6 Hz, 1H), 2.97 (br, 6H), 1.31 (s,
12H);

13

C NMR (125 MHz, CDCl3) δ 172.6, 142.6, 135.0, 131.0, 128.2, 125.5, 83.5, 24.8.

89
	
  

	
  

1

Figure 5.1. H NMR (500 MHz, CDCl3) (1)
NH 2

BPin

Br

90
	
  

	
  

Figure 5.2.
NH 2

13

C NMR (125 MHz, CDCl3) (1)

BPin

Br

	
  
91
	
  

	
  

1

Figure 5.3. H NMR (500 MHz, CDCl3) (2)
NH 2

BPin

CF3

92
	
  

	
  

Figure 5.4.
NH 2

13

C NMR (125 MHz, CDCl3) (2)

BPin

CF3

93
	
  

	
  

1

Figure 5.5. H NMR (500 MHz, C6D6) (3)
NH 2

BPin

OMe

94
	
  

	
  

Figure 5.6.
NH 2

13

C NMR (125 MHz, C6D6) (3)

BPin

OMe

95
	
  

	
  

1

Figure 5.7. H NMR (500 MHz, CDCl3) (4)
NH 2
BPin
PinB
CN

96
	
  

	
  

Figure 5.8.

13

NH 2

C NMR (125 MHz, CDCl3) (4)

BPin

PinB
CN

97
	
  

	
  

1

Figure 5.9. H NMR (500 MHz, CDCl3) (5)
NH 2

BPin

CN

	
  
98
	
  

	
  

Figure 5.10.
NH 2

13

C NMR (125 MHz, CDCl3) (5)

BPin

CN

	
  
99
	
  

	
  

1

Figure 5.11. H NMR (500 MHz, CDCl3) (6a)
NH 2

BPin

MeO

100
	
  

	
  

Figure 5.12.

13

NH 2

C NMR (125 MHz, CDCl3) (6a)

BPin

MeO

	
  
101
	
  

	
  

1

Figure 5.13. H NMR (500 MHz, CD3CN) (6b)
NH 2
MeO

BPin

	
  
102
	
  

	
  

Figure 5.14.

13

C NMR (125 MHz, CDCl3) (6b)

NH 2
MeO

BPin

	
  
103
	
  

	
  

1

Figure 5.15. H NMR (500 MHz, CDCl3) (7)
NH 2

Cl

BPin

	
  
104
	
  

	
  

Figure 5.16.
NH 2

13

C NMR (125 MHz, CDCl3) (7)

Cl

BPin

	
  
105
	
  

	
  

1

Figure 5.17. H NMR (500 MHz, CDCl3) (8)
NH 2

BPin

BPin

	
  
106
	
  

	
  

Figure 5.18.
NH 2

13

C NMR (125 MHz, CDCl3) (8)

BPin

BPin

	
  
107
	
  

	
  

1

Figure 5.19. H NMR (500 MHz, CDCl3) (9)
PinB

NH 2
BPin

	
  
108
	
  

	
  

Figure 5.20.
PinB

13

C NMR (125 MHz, CDCl3) (9)

NH 2
BPin

	
  
109
	
  

	
  

1

Figure 5.21. H NMR (500 MHz, DMSO-d6) (10)
NH 2
PinB

BPin

	
  
110
	
  

	
  

Figure 5.22.

13

C NMR (125 MHz, DMSO-d6) (10)

NH 2
PinB

BPin

	
  
111
	
  

	
  

1

Figure 5.23. H NMR (500 MHz, CDCl3) (11)
NH 2

BPin

112
	
  

	
  

Figure 5.24.
NH 2

13

C NMR (125 MHz, CDCl3) (11)

BPin

113
	
  

	
  

1

Figure 5.25. H NMR (500 MHz, DMSO-d6) (12)
NH 2
BPin

114
	
  

	
  

Figure 5.26.

13

C NMR (125 MHz, CDCl3) (12)

NH 2
BPin

115
	
  

	
  

1

Figure 5.27. H NMR (500 MHz, CDCl3) (13)
NH 2

BPin

	
  
116
	
  

	
  

Figure 5.28.

13

C NMR (125 MHz, CDCl3) (13)

NH 2

BPin

	
  
117
	
  

	
  

1

Figure 5.29. H NMR (500 MHz, CDCl3) (14)
H 2N

O

O

PinB

	
  
118
	
  

	
  

Figure 5.30.
H 2N

13

C NMR (125 MHz, CDCl3) (14)

O

O

PinB

119
	
  

	
  

1

Figure 5.31. H NMR (500 MHz, CDCl3) (15)
O
PinB
HN
Cl

	
  
120
	
  

	
  

Figure 5.32.

13

C NMR (125 MHz, CDCl3) (15)
O

PinB
HN
Cl

	
  
121
	
  

	
  

1

Figure 5.33. H NMR (500 MHz, CDCl3) (16)
O
O
BPin

	
  
122
	
  

	
  

Figure 5.34.

13

C NMR (125 MHz, CDCl3) (16)

O
O
BPin

	
  
123
	
  

	
  

1

Figure 5.34. H NMR (500 MHz, CDCl3) (17)
PinB

O
O
BPin

	
  
124
	
  

	
  

Figure 5.35.
PinB

13

C NMR (125 MHz, CDCl3) (17)

O
O
BPin

	
  
125
	
  

	
  

1

Figure 5.36. H NMR (500 MHz, CDCl3) (18)
O
Br

O
BPin

	
  
126
	
  

	
  

Figure 5.37.

13

C NMR (125 MHz, CDCl3) (18)

O
Br

O
BPin

	
  
127
	
  

	
  

1

Figure 5.38. H NMR (500 MHz, CDCl3) (19)
OMeO
O
BPin

	
  
128
	
  

	
  

Figure 5.39.

13

C NMR (125 MHz, CDCl3) (19)

OMeO
O
BPin

	
  
129
	
  

	
  

1

Figure 5.40. H NMR (500 MHz, CDCl3) (20a)
O
MeO
O
BPin

7.4

10

7.3

9

7.2

8

7

7.1 ppm

6

5

4

3

2

1 ppm
	
  

130
	
  

	
  

Figure 5.41.

13

C NMR (125 MHz, CDCl3) (20a)

O
MeO

O
BPin

131
	
  

	
  

1

Figure 5.42. H NMR (500 MHz, CDCl3) (20b)	
  
BPinO
MeO

O
BPin

7.5

10

7.4

9

7.3

8

7.2

7

7.0 ppm

7.1

6

5

4

3

2

1 ppm
	
  

132
	
  

	
  

Figure 5.43.

13

C NMR (125 MHz, CDCl3) (20b)

BPinO
MeO

O
BPin

	
  
133
	
  

	
  

1

Figure 5.44. H NMR (500 MHz, CDCl3) (21)
OMeO
MeO

O
BPin

	
  
134
	
  

	
  

Figure 5.45.

13

C NMR (125 MHz, CDCl3) (21)

OMeO
MeO

O
BPin

	
  
135
	
  

	
  

1

Figure 5.46. H NMR (500 MHz, CDCl3) (22)
CF3 O
O
BPin

	
  
136
	
  

	
  

Figure 5.47.

13

C NMR (125 MHz, CDCl3) (22)

CF3 O
O
BPin

	
  
137
	
  

	
  

1

Figure 5.48. H NMR (500 MHz, CDCl3) (23)
O
F 3C
O
BO
O

	
  

138
	
  

	
  

Figure 5.49.

13

C NMR (125 MHz, CDCl3) (23)

O
F 3C

O
BO
O

	
  

139
	
  

	
  

1

Figure 5.50. H NMR (500 MHz, CDCl3) (24a)
O
O
F 3C

BPin

	
  
140
	
  

	
  

Figure 5.51.

13

C NMR (125 MHz, CDCl3) (24a)

O
O
F 3C

BPin

	
  
141
	
  

	
  

1

Figure 5.52. H NMR (500 MHz, CDCl3) (24b)
BPinO
O
F 3C

BPin

	
  
142
	
  

	
  

13

Figure 5.53. C NMR (125 MHz, CDCl3) (24b)
	
  
BPinO
O
F 3C

BPin

133.5

132.5

160

131.5

140

130.5

120

ppm

100

80

60

143
	
  

40

20

ppm

	
  

1

Figure 5.54. H NMR (500 MHz, CDCl3) (25)
O
O
BPin

	
  
144
	
  

	
  

13

Figure 5.55. C NMR (125 MHz, CDCl3) (25)
	
  
O
O
BPin

160

140

120

100

80

60

40

20

ppm
	
  

145
	
  

	
  

1

Figure 5.56. H NMR (500 MHz, CDCl3) (26a)
	
  
O
	
  
O
BPin

8.1

10

7.9

9

7.7

8

7.5

7

7.3

6

ppm

5

4

3

2

ppm
	
  

146
	
  

	
  

Figure 5.57.

13

C NMR (125 MHz, CDCl3) (26a)

O
O
BPin

	
  
147
	
  

	
  

1

Figure 5.58. H NMR (500 MHz, CDCl3) (26b)
BPinO
O
BPin

	
  
148
	
  

	
  

Figure 5.59.

13

C NMR (125 MHz, CDCl3) (26b)

BPinO
O
BPin

	
  
149
	
  

	
  

1

Figure 5.60. H NMR (500 MHz, CDCl3) (27)
F

O
O
BPin

	
  
150
	
  

	
  

Figure 5.61.
F

13

C NMR (125 MHz, DMSO-d6) (27)

O
O
BPin

	
  
151
	
  

	
  

1

Figure 5.62. H NMR (500 MHz, CDCl3) (28)
F

O
O

Br

BPin

	
  
152
	
  

	
  

Figure 5.63.
F

13

C NMR (125 MHz, CDCl3) (28)

O
O

Br

BPin

	
  
153
	
  

	
  

1

Figure 5.64. H NMR (500 MHz, CDCl3) (29)
F O
O
Br
BPin

	
  
154
	
  

	
  

13

Figure 5.65. C NMR (125 MHz, CDCl3) (28)
	
  
F O
O
Br

BPin

132

160

140

128

120

124

100

120

80

ppm

60

40

20

ppm
	
  

155
	
  

	
  

1

Figure 5.66. H NMR (500 MHz, CDCl3) (30)
Cl O
Cl
O
BPin

	
  
156
	
  

	
  

13

Figure 5.67. C NMR (125 MHz, CDCl3) (30)
Cl O
Cl
O
BPin

	
  
157
	
  

	
  

1

Figure 5.68. H NMR (500 MHz, CDCl3) (31)
BPin
O

N
O

	
  
158
	
  

	
  

Figure 5.69.
BPin
O

13

C NMR (125 MHz, CDCl3) (32)

N
O

	
  
159
	
  

	
  

1

Figure 5.70. H NMR (500 MHz, CDCl3) (32)
BPin
O

N
O

Cl

	
  
160
	
  

	
  

1

Figure 5.71. H NMR (500 MHz, C6D6) (33)

P
SiH

	
  
161
	
  

	
  

Figure 5.72.

13

C NMR (125 MHz, CDCl3) (33)

P
SiH

162
	
  

	
  

1

Figure 5.73. H NMR (500 MHz, C6D6) (34)
P
SiHMe2

	
  
163
	
  

	
  

Figure 5.74.

13

C NMR (125 MHz, CDCl3) (34)

P
SiHMe2

	
  
164
	
  

	
  

1

Figure 5.75. H NMR (500 MHz, C6D6) (35)
P
SiH

10

9

8

7

6

5

4

3

2

1 ppm
	
  

165
	
  

	
  

Figure 5.76.

13

C NMR (125 MHz, CDCl3) (35)

P
SiH

	
  
166
	
  

	
  

1

Figure 5.77. H NMR (500 MHz, C6D6) (36)
P
SiHMe2

	
  
167
	
  

	
  

Figure 5.78.

13

C NMR (125 MHz, CDCl3) (36)

P
SiHMe2

	
  
168
	
  

	
  

1

Figure 5.79. H NMR (500 MHz, CD2Cl2) (37)

P
SiH

	
  
169
	
  

	
  

Figure 5.80.

13

C NMR (125 MHz, CDCl3) (37)

P
SiH

	
  
170
	
  

	
  

1

Figure 5.81. H NMR (500 MHz, CD3OD) (38)
P
SiHMe2

	
  
171
	
  

	
  

Figure 5.82.

13

C NMR (125 MHz, CDCl3) (38)

P
SiHMe2

	
  
172
	
  

REFERENCES

173
	
  

REFERENCES

1) Wolan, A.; Zaidlewicz, M. Org. Biomol. Chem. 2003, 1, 3274
2) Kawamorita, S.; Ohmiya, H.; Hara, K.; Fukuoka, A.; Sawamura, M. J. Am.
Chem. Soc. 2009, 131, 5058
3) Ishiyama, T.; Isou, H.; Kikuchi, T.; Miyaura, N. Chem. Commun. 2010, 46,
159.
4) Iwashita, M.; Fuji, S.; Hirano, T.; Kagechika, H. Tetrahedron. 2011, 67, 6073
5) Kawamorita, S.; Ohimya, H.; Hara, K.; Fukuoka, A.; Sawamura, M. J. Am.
Chem. Soc. 2009, 131, 5058.

	
  

174