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Novel fluoroalkylation reactions and microwave-assisted methodologies

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Novel fluoroalkylation reactions and microwave-assisted methodologies

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Content NOVEL FLUOROALKYLATION REACTIONS AND MICROWAVE-
ASSISTED METHODOLOGIES

by

Hema Sivaram Krishnan

A Dissertation presented to the
FACULTY OF THE GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
DOCTOR OF PHILOSOPHY
(CHEMISTRY)

August 2015

Copyright 2015 Hema Sivaram Krishnan
ii

DEDICATION
To
My Family

iii

ACKNOWLEDGEMENTS
I would first like to thank my mentor, Prof. G. K. Surya Prakash for giving me the
opportunity to work for him in his research group here at USC. He has been a source of
constant support, encouragement and knowledge and I am very grateful for all of it.
Besides being a wonderful teacher, he is a wonderful person and has made my stay at
USC very memorable and I will treasure my time in his lab. I would also like to offer my
sincere gratitude to Prof. George A. Olah. His wisdom and vast knowledge of chemistry
have been very helpful, and his unending zeal for chemical research continues to
motivate me.
I would like to especially thank Dr. Thomas Mathew for always being there to
help, support and guide me throughout my graduate studies. I am also very grateful to Dr.
Parag Jog for teaching me techniques and being a great mentor and friend. I worked with
him on many projects and his knowledge and patience have taught me a lot. I am also
grateful to him and Sonali for treating me like a part of their family. I also want to
express my gratitude to Dr. Alain Goeppert, Dr. Miklos Czaun, Dr. Matthew Moran and
John-Paul Jones for their help in maintaining and teaching me the proper use of various
instruments, and for their friendship.
There are many other people at the Loker Hydrocarbon Institute and the Olah-
Prakash lab in particular, to whom I am greatly indebted to for their help and friendship
over the years. They include Dr. Beate Burkhart, Dr. Fabrizio Pertusati, Dr. Patrice
Batamack, Dr. Arjun Narayanan, Dr. Habiba Vaghoo, Dr. Fang Wang, Dr. Somesh
Ganesh, Jothi, Sankar, Hang, Huong, Laxman, Socrates, Gigi, Kavita, Marc, Dean, and
iv

Dr. Bo Yang. I would also like to thank Dr. Robert Aniszfeld, Prof. Golam Rasul, Dr.
Akihisa Saitoh and all other past and present members of the Olah-Prakash group for
their support and friendship. I would also like to thank the staff in the Chemistry
department and Loker Hydrocarbon Institute including Carole, David, Ralph, Gloria,
Magnolia, Susan, and Danielle. I am especially grateful to Jessy and Michele for always
helping me with administrative questions. I am also grateful to the high-school students I
have had a chance to work with, including Anjali, Keshav, Nimisha, Shikha, and Shreya
for their help in the laboratory and for giving me a unique opportunity to teach them and
learn from them
I would like to extend my gratitude to late Prof. A Srikrishna for giving me a
position in his lab and for introducing me to organic chemistry research. His discipline
and dedication to science are characteristics I hope to emulate in my career. I thank my
thesis committee members Dr. Katherine Shing, Prof. Thieo E. Hogen-Esch, and Prof.
Matthew Pratt for their helpful suggestions and discussions
I would also like to thank my closest friends Madhuri, Savita, Bhavna, Jenny,
Divya, and Leena for their constant support and encouragement. I am very grateful to my
Mom, brother and husband for being supportive and encouraging me to pursue my
dreams. I am especially grateful to my Dad for being my first and most favorite chemistry
teacher.

v

DEDICATION
ACKNOWLEDGEMENTS
LIST OF SCHEMES
LIST OF FIGURES
LIST OF TABLES
ABSTRACT
1 Chapter 1: An Introduction to Fluoroalkylation Methods
1.1 Chapter 1: Introduction to Fluorine Chemistry
1.2 Chapter 1: Role and Significance of Organofluorine Compounds
1.3 Chapter 1: Fluoroalkylation Methods
1.3.1: Trifluoromethylation Reactions
1.3.2: Difluoromethylation Reactions
1.3.3: Monofluorination Reactions
1.4 Chapter 1: Aim and Scope of Current Work
1.5 Chapter 1: References

2 Chapter 2: Synthesis of gem-Difluorinated Cyclopropanes:
(Trifluoromethyl)trimethylsilane as a Difluorocarbene Source
2.1 Chapter 2: Introduction
2.2 Chapter 2: Results and Discussion
2.3 Chapter 2: Conclusions
2.4 Chapter 2: Experimental
2.4.1: General
2.4.2: Experimental Procedures
2.4.3: Spectral Data and Representative Spectra
2.5 Chapter 2: References

3 Chapter 3: An Introduction to the Mizoroki-Heck Coupling Reaction
3.1 Chapter 3: Introduction
3.2 Chapter 3: Mizoroki-Heck Coupling Reaction s
3.2.1: History
ii
iii
viii
ix
xi
xii
1
1
2
6
6
11
14
15
17

22
22
28
38
38
38
39
41
52

55
55
56
56
vi

3.2.2: Mechanism
3.3.3: Regioselectivity in the Mizoroki-Heck Reaction
3.3 Chapter 3: Mizoroki-Heck Reaction with Modern Solvents and
Techniques
3.3.1: Modern Solvent Systems
3.3.2: Mizoroki-Heck Reactions in Water as the Solvent
3.3.3: Modern Techniques
3.4 Chapter 3: Mizoroki-Heck Reactions in Domino Processes
3.5 Chapter 3: Aim and Scope of Present Work
3.6 Chapter 3: References

4 Chapter 4: A Domino Approach (Hydrolysis/Elimination/Mizoroki-Heck
Coupling) Towards the Synthesis of Styrene Sulfonate Salts
4.1 Chapter 4: Introduction
4.2 Chapter 4: Results and Discussion
4.3 Chapter 4: Conclusions
4.4 Chapter 4: Experimental
4.4.1: General
4.4.2: General Experimental Procedure
4.4.3: Spectral Data and Representative Spectra
4.5 Chapter 4: References

5 Chapter 5: A Domino Approach (Elimination/Mizoroki-Heck Coupling)
Towards the Synthesis of β-Trifluoromethylstyrenes and
Related Compounds
5.1 Chapter 5: Introduction
5.2 Chapter 5: Results and Discussion
5.3 Chapter 5: Conclusions
5.4 Chapter 5: Experimental
5.4.1: General
5.4.2: General Experimental Procedure
5.4.3: Spectral Data and Representative Spectra
5.5 Chapter 5: References

6 Chapter 6: A Domino Approach (Elimination/Mizoroki-Heck Coupling)
Towards the Synthesis of α-Fluorostyrenes
6.1 Chapter 6: Introduction
6.2 Chapter 6: Results and Discussion
58
60

63
63
65
69
70
71
73

77
77
79
91
91
91
92
93
105

106
106
109
115
116
116
116
117
130

132
132
135
vii

6.3 Chapter 6: Conclusions
6.4 Chapter 6: References

BIBLIOGRAPHY
145
146

148

viii

LIST OF SCHEMES

Scheme 1.1 Nucleophilic Trifluoromethylation using TMS-CF
3

Scheme 2.1 Generation of :CF
2
Under Thermal and Low/Room Temperature
Conditions

Scheme 3.1 Intital Reactions Performed by Mizoroki and Heck

Scheme 3.2 Mizoroki-Heck Reactions in Water as the Only Solvent

Scheme 3.3 Mizoroki-Heck Reactions in Water Mediated by Surfactants

Scheme 3.4 Polymer Supported Catalysts in Mizoroki-Heck Coupling Reactions
in Water

Scheme 3.5 First Example of a Microwave Assisted Mizoroki-Heck Reaction

Scheme 4.1 Methods for the synthesis of styrenesulfonate salts

Scheme 4.2 (a) Synthesis of Sodium Styrenesulfonate; (b) Hydrolysis of
Sodium Vinylsulfonate 1

Scheme 4.3 Hydrolysis/Elimination/Heck Domino Sequence for the Synthesis
of Styrene Sulfonate Salts
Scheme 5.1 Elimination-Heck-Heck coupling domino reaction pathway
Scheme 6.1 Previous methods for the synthesis of α-fluorostyrenes
Scheme 6.2 Mechanism of the Heck reaction between Ar-I 2 and
1-iodo-2-fluoroethane 3
Scheme 6.3 Mechanism of Heck reaction between Ar-I 2 and
1-iodo-2,2-difluoroethane 5
Scheme 6.4 Formation of side-products during the Elimination/Heck Reaction
9

26

57

66

67

68

69

79

81

82

115

135

136

137

142
ix

LIST OF FIGURES

Figure 1.1 Popular Fluoropolymers

Figure 1.2 Popular Fluorinated Drugs

Figure 1.3 Fluorinated Agrochemicals

Figure 1.4 Examples of Trifluoromethylation Reagents

Figure 1.5 Examples of Difluoromethylation Reagents

Figure 1.6 Examples of Monofluoromethylation Reagents

Figure 2.1 Polarities of Bridging Units in Triphosphate Anion and CF
2

Substituted Analog

Figure 2.2 Stabilization of Singlet :CF
2
Species

Figure 3.1 Mechanism of the Mizoroki-Heck Reaction

Figure 3.2 The Cationic and Neutral Mizoroki-Heck Routes for
Electron Rich Alkenes

Figure 3.3 Total Synthesis of Estradiol via a Domino Heck/Heck Coupling
Reaction

Figure 4.1 Proposed Synthetic Route for Styrene Sulfonate Salts

Figure 4.2 Retrosynthetic Analysis of the Proposed Domino Sequence
for the Synthesis of Styrene Sulfonate Salt

Figure 5.1 Various Approaches Towards Synthesis of
β- Trifluoromethylstyrenes

Figure 5.2 Heterocyclic and bis( β-Trifluoromethyl)styrenes

Figure 6.1 Monofluoroalkenes as Bioisosteres of Peptide Bonds
3

5

6

7

11

15

23

24

60

62

71

80

81

108

114

132
x

Figure 6.2 Reaction of 2b with 5 at 200
o
C for 1h

Figure 6.3 Reaction of 2b with 5 at 130
o
C for 1h

Figure 6.4 Reaction of 5 in the presence of base and catalyst at 130
o
C for 1h

142

143

144

xi

LIST OF TABLES
Table 2.1 Optimization of reaction conditions for the reaction between
TMSCF
3
(1) and alkene 2d

Table 2.2 [2+1] cycloaddition reaction between alkenes 2 and difluorocarbene
(:CF
2
) generated from TMSCF
3
1

Table 2.3 Optimization of conditions for the [2+1] cycloaddition reaction
between vinylboronic acids/ vinylboronate esters with :CF
2

Table 2.4 Substrate scope for the reaction between vinylboronate esters 4
and :CF
2

Table 4.1 Optimization of Base for the Synthesis of Styrene Sulfonate Salts

Table 4.2 Substrate Scope of the Hydrolysis/Elimination/Heck Domino
Reaction to Synthesize Styrene Sulfonate Salts

Table 4.3 Comparison of Reactivities of Various Halobenzenes

Table 4.4 Synthesis of Heteroaryl Sulfonate Salts

Table 4.5 Synthesis of Aryl-bis-Sulfonate Salts

Table 5.1 Screening of solvents for the reaction between iodobenzene and
1-iodo-3,3,3- trifluoropropane

Table 5.2 Screening of palladium catalysts for the reaction between
3-iodotoluene and 1-iodo-3,3,3-trifluoropropane

Table 5.3 Synthesis of β-trifluoromethylstyrenes via elimination/
Mizoroki-Heck reaction

Table 6.1 Optimization of reaction conditions for the reaction between
2 and 5

Table 6.2 Control experiments between 2b and alkene

29

32

35

37

84

85

88

89

90

110

110

112

139

141
xii

ABSTRACT

This dissertation is divided into two parts. The first part describes the generation
of the reactive species difluoromethylene (:CF
2
) from (trifluoromethyl)trimethylsilane,
also called the Ruppert-Prakash reagent, and its subsequent application in synthesizing
gem-difluorocyclopropanes. The second part describes the synthesis of various
substituted styrenes via a domino process involving the Mizoroki-Heck coupling
reaction.
Chapter 1 describes the history and significance of fluorine in organic chemistry,
and its many applications in fields ranging from pharmaceuticals to materials sciences.
Methods to incorporate fluorine as a single atom and various fluoroalkyl groups are also
described.
In Chapter 2, the utility of the nucleophilic trifluoromethylating reagent,
(trifluoromethyl)trimethylsilane is expanded. The generation of difluoromethylene (:CF
2
)
from (trifluoromethyl)trimethylsilane under different reaction conditions is described.
Difluorocarbene has been generated from (trifluoromethyl) trimethylsilane under low
temperature conditions using a fluoride initiator and under high temperature conditions
using an iodide initiator. The [2+1] addition of the difluorocarbene to alkenes yielding
gem-difluorocyclopropanes is described. The procedure is extended to the synthesis of
gem-difluorocyclopropyl boronates as well.
xiii

Chapter 3 describes the history and many applications of the Mizoroki-Heck
coupling reaction. Different aspects of the reaction such as regioselectivity, catalyst, and
solvent scope are discussed. Also discussed are the applications of the Mizoroki-Heck
reaction in microwave systems and domino processes.
Chapter 4 describes the synthesis of potassium styrenesulfonate salts from aryl
iodides and 2-chloroethansulfonyl chloride under basic conditions in the presence of a
palladium catalyst. Three reactions are carried out in a one-pot fashion namely,
hydrolysis, dehydrohalogenation and Mizoroki-Heck coupling. Several potassium
styrenesulfonate salts with different steric and electronic properties have been isolated.
Hydrogenation of a few substrates to yield potassium ethylbenzenesulfonate salts is also
described.
Chapter 5 describes an extension of work detailed in the previous chapter. The
synthesis of β-trifluoromethylstyrenes via a domino process involving the Mizoroki-Heck
reaction is discussed. Iodoarenes are reacted with 1-chloro-3,3,3-trifluoropropane in the
presence of base and palladium catalyst in a microwave to yield the corresponding β-
trifluoromethylstyrenes in good yields.
Finally, in Chapter 6, the attempted synthesis of α-fluorostyrenes is discussed. A
domino process involving the Mizoroki-Heck coupling is utilized in the synthesis of α-
fluorostyrenes from iodoarenes and 1-iodo-2,2-difluoroethane. Initial results for the
reaction between iodoarenes and 1-iodo-2-fluoroethane, and the reaction mechanism to
xiv

yield the desired product are also described. An explanation for the poor yields of the
product is also attempted.

1

1. Chapter 1: An Introduction to Fluoroalkylation Methods

1.1 Chapter 1: Introduction to Fluorine Chemistry
Fluorine was first used in its naturally occurring mineral source fluorite, CaF
2
, in
1529. Fluorite was added to metals to lower their melting points during smelting. Early
chemists were aware of an element similar to chlorine that formed metal halides, and in
1810 fluorine was proposed as an element. Although the presence of fluorine as an
element and even hydrofluoric acid (HF) was known, several scientists tried to isolate
elemental fluorine and failed. In 1886, Henri Moissan became the first person to isolate
fluorine using low temperature electrolysis, and this method is still employed to
synthesize fluorine.
1
Moissan received the Nobel Prize in Chemistry in 1906 for his work
on synthesizing and isolating fluorine. A purely chemical approach to the synthesis of
fluorine was described by K. O. Christie in 1986,
2
100 years after Moissan’s first
synthesis.
Fluorine is the 13
th
most abundant element in the earth’s crust and is a pale yellow
gas at room temperature with a boiling point of -188.1
o
C, melting point of -219.6
o
C, and
density of 1.5 g/mL. It is extremely corrosive and the most reactive element in the
periodic table. It is also the most electronegative (3.98) and consequently the least
polarizable of all elements. The low energy of the F-F bond (36.0 kcal/mol) combined
with the very high energy of bonds between fluorine and other elements (bond energy of
a C-F bond is 105.4 kcal/mol) makes it react readily and in many cases violently with
other elements and with other organic compounds.
3,4
For example, steel wool bursts into
2

flame, when it comes in contact with fluorine. Unlike HF, fluorine does not etch glass
and as such can be stored in glass vessels. However, due to its extreme reactivity, it is
usually diluted with nitrogen and can be stored in this manner in pressurized tanks.
Despite the slow and difficult start in the development of fluorine chemistry and
the extreme caution required for its handling, fluorine and its chemistry has currently
found important applications spanning a variety of disciplines from pharmaceuticals and
agrochemicals to polymer science and materials chemistry.
5

1.2 Chapter 1: Role and Significance of Organofluorine Compounds
Even though fluorine was first synthesized only in 1886,
1
the first organofluorine
compound was synthesized earlier in 1863, when Alexander Borodin synthesized benzoyl
fluoride.
6
One of the major applications of fluorine chemistry was during the Second
World War in the Manhattan Project. Fluorine was used for uranium enrichment,
7
and
hydrofluoric acid (HF) was used as the starting compounds for lubricants, coolants, and
other inert materials. One of the other major industrial applications of fluorine containing
compounds is in refrigerants. Freons, also called chlorofluorocarbons (CFCs) were
invented by Thomas Midgley of DuPont in 1928
8
and were used as refrigerants until the
Montreal Protocol banned their use in 1987 due to studies demonstrating their detrimental
effect on the ozone layer. They have since been replaced with other fluorine containing
compounds such as hydrochlorofluorocarbons and hydrofluorocarbons. The study of
freons led to the discovery of Teflon (polytetrafluoroethylene),
9
one of the best known
fluoropolymers. About 60-80% of worldwide fluoropolymer production can be attributed
3

to Teflon
®
(Figure 1.1). Teflon
®
has applications in electric insulation, non-stick
cookware, rainwear, piping and tubing, etc. Another fluoropolymer that is used in a wide
range of applications is polyvinylene difluoride (PVDF) (Figure 1.1). This polymer is
often used as a low-weight and flexible replacement for glass. (Perfluoro)polyethers are
also gaining a lot of importance as polymer membranes for electrochemical cells.
Nafion
®
(Figure 1.1) is one of the most popular of these polyethers; it is considered to be
a polymer of trifluoromethanesulfonic acid. Therefore, in addition to applications as
polymer membranes, Nafion
®
is also a very widely used and an efficient solid superacid.
In fact, it is the first solid superacid to be used in chemical transformations and has been
studied by our group and others extensively.
10,11

Figure 1.1 Popular Fluoropolymers
More recently, organofluorine chemistry has been used for applications in
pharmaceutical and agrochemical industries and several drugs and pesticides contain
fluorine.
12–14
In 1954, Fried and Sabo showed that the introduction of a fluorine atom to
the 9α-carbon of cortisol improved its anti- inflammatory properties.
15
Fluorocortisol was
the first fluorinated pharmaceutical to be synthesized and used. Since then, about 20% of
all approved drugs have been designed as having at least one fluorine atom. In 2011, 7 of
the 35 approved drugs, and 3 of the 10 best-selling drugs had at least one fluorine atom.
16

4

Only 13 naturally occurring organofluorine compounds are known and no
biological processes depend on fluorine.
17
Thus, in most cases, the presence of fluorine is
a matter of design rather than chance. C-H and C-F bonds are relatively similar in terms
of steric parameters even though they are very different in terms of their electronic
nature. While elimination of F
-
is very easy, elimination of H
-
is extremely unfavorable in
biological systems. Similarly, elimination of H
+
is easy in enzymatic processes, while
that of F
+
is not. This orthogonal behavior of fluorine and hydrogen has been exploited in
drug design, for example in the discovery of 5-fluorouracil, a widely used anti-cancer
therapeutic agent.
18

Substitution of fluorine has become an important design strategy in drug
development. Fluorine increases the stability of the given molecule by decreasing the rate
of oxidative degradation.
5,19–21
In vivo, aromatic rings can undergo oxidation to form
epoxides that can further react with any number of other metabolites leading to early
degradation of a drug molecule, leading to overall lower efficacy. The presence of
fluorine can eliminate the formation of epoxides and inhibit oxidation thus increasing
stability. Fluorine and fluoroalkyl groups are also more lipophilic (π
F
= +0.14, π
CF3
=
+0.88) and this can lead to an increased absorption of the drug into membranes, while
increasing the half life.
19
Fluorine can also form intra- and intermolecular hydrogen
bonds, although these bonds are weaker than traditional hydrogen bonds (~2.4 kcal/mol).
Organofluorine groups have also been found to act as bioisosteres for other groups more
commonly found in organic molecules. These properties have also been exploited in
rational drug design (Figure 1.2). For example, the difluoromethyl and fluoromethyl
5

groups have been shown to be bioisosteres for the ether group. Because many
perfluoroalkyl groups have the ability to be inert within the body and have oxygen
solibility, many of them are used as anesthetics and as blood substitutes.
18,22

Figure 1.2 Popular Fluorinated Drugs
One of the important applications of fluorine is in positron emission tomography
(PET) imaging.
14,19

18
F, which is a radioactive isotope of fluorine, has a half life of 109
min is used as a marker in medical imaging. PET imaging is used to diagnose diseases
such as cancer, and brain-related conditions such as Alzheimer’s disease and Parkinson’s
disease. The low half-life period of
18
F has led to the recent development of very
interesting research into late stage fluorination.
6

Organofluorine compounds constitute about 30% of all agrochemicals (Figure
1.3).
23
One of the biggest drawbacks of fluorine containing compounds is their longevity
and inertness. Many fluoro-organic compounds do not degrade on an environmental time
scale and can cause build-up in the soil over time.

Figure 1.3 Fluorinated Agrochemicals
1.3 Chapter 1: Fluoroalkylation Methods
The introduction of fluorine and fluoroalkyl groups is becoming increasingly
relevant as about 20% of pharmaceuticals and 30% of agrochemicals contain fluorine.
23,24

The synthesis of lightly fluorinated molecules, especially those with 1-3 fluorines, is
gaining importance largely due to the ability of fluorine to modulate physical and
biological properties of the parent molecule. Several research groups are developing new
and efficient methods to introduce fluorine or fluoroalkyl (monofluoromethyl,
difluoromethyl or trifluoromethyl) groups.
1.3.1 Trifluoromethylation Reactions
Among the various fluoroalkylation methods, selective trifluoromethylation is the
most extensively studied reaction. In the past 50 years, several reactions and reagents
7

have been studied that include nucleophilic, electrophilic and radical
trifluoromethylations (Figure 1.4).
25,26
The trifluoromethyl group (-CF
3
) is ubiquitous
among fluoroalkyl groups and is found in a large number of molecules with a variety of
applications. The first trifluoromethyl compound was made in 1898 by Swarts.
Benzotrifluoride was synthesized by the reaction between trichlorotoluene and antimony
trifluoride at 125
o
C.
27
In the years following this discovery, several other reagents such
as HF, XeF
2
, SF
4
, DAST, etc. were also used to synthesize benzotrifluoride from other
substrates.
24,28,29

Figure 1.4 Examples of Trifluoromethylation Reagents
In 1968, the first copper mediated coupling between perfluoroalkyl iodides and
aromatic iodides was described. It was suggested that the reaction proceeded via a
8

reactive trifluoromethylcopper (I) intermediate ([CuCF
3
]), but the presence of this species
was only proved in 1986. Burton and co-workers observed the presence of three different
‘[CuCF
3
]’ species in the
19
F NMR studies of the reaction mixture. The mechanism of the
reaction between haloarenes and [CuCF
3
]

has been widely debated and has only recently
been postulated to proceed via a non-radical pathway. Trifluoromethyl copper has been
generated from various reagents such as Cd(CF
3
)
2
, Hg(CF
3
)
2
, ClCF
2
COOMe,
FSO
2
CF
2
COOMe, TMS-CF
3
etc.
30
Recently, Grushin and co-workers reported the
generation of [CuCF
3
] from fluoroform (CF
3
H) under basic conditions.
31
The CuCF
3
thus
generated was reacted with haloarenes to yield the corresponding trifluoromethyl arenes.
Nucleophilic trifluoromethylation is the most widely used method to introduce the
CF
3
group into molecules. Nucleophilic introduction of the trifluoromethyl group has
been studied for a very long time. In 1984, Ruppert synthesized
(trifluoromethyl)trimethylsilane (TMS-CF
3
) through the nucleophilic
trifluoromethylation of halosilanes.
32
In 1989, Prakash and co-workers reported the first
efficient nucleophilic trifluoromethylation
33
of a wide variety of aldehydes and ketones
using TMS-CF
3
in the presence of tetrabutylammonium fluoride as the initiator (Scheme
1.1).This reagent has since become one of the most important reagents for nucleophilic
trifluoromethylation reactions, and several papers and reviews have been published by
the Prakash group demonstrating the versatility and wide utility of TMS-CF
3
,

leading to it
popularly being known as the Ruppert-Prakash reagent.
22,25,34
Prakash and co-workers
also discovered a new method for the synthesis of TMS-CF
3
via electrochemical methods
using an aluminum anode. A more efficient method for its synthesis was later discovered
9

using a magnesium mediated process.
35,36
The mechanism of the trifluoromethylation has
been shown to go through a pentavalent silicon species (Scheme 1).
37,38
TMS-CF
3
has
also been activated using other initiators such as K
2
CO
3
, phosphate, and trimethylamine
oxide.
39
Nucleophilic trifluoromethylations have also been carried out successfully using
fluorinated sulfur compounds such as sulfones, sulfoxides, and sulfides.
40

More recently, in 2013, Prakash and co-workers demonstrated the direct
nucleophilic trifluoromethylation in basic media starting from fluoroform (CF
3
H).
41,42

The trifluoromethide ion thus generated was also used to synthesize TMS-CF
3
in very
good yields. This method was the first direct nucleophilic trifluoromethylation reaction
reported. Further experiments and NMR studies showed the presence of a ‘free’ long-
lived trifluoromethide ion, which is the key intermediate for nucleophilic
trifluoromethylations.
43

Radical and electrophilic trifluoromethylations have also been extensively
studied. Trifluoromethylation of benzene and other aromatic compounds by the
trifluoromethyl radical was first reported in 1948. Since then, several reagents have been
developed as precursors of the CF
3
radical. These reagents include iodotrifluoromethane,
bromotrifluoromethane, bis(trifluoromethyl)mercury, diazotrifluoromethane, etc. Since
the trifluoromethyl radical is electrophilic in nature, it reacts well with electron-rich
aromatics. Often, aromatic trifluoromethylations with the radical are not very specific.
10

Scheme 1.1 Nucleophilic Trifluoromethylation using TMS-CF
3

Electrophilic trifluoromethylation is another effective method to introduce the
trifluoromethyl group into molecules.
44,45
Several reagents have been developed that
proceed via the generation of a ‘CF
3
+
’ ion. Although generation of a ‘CF
3
+
’ ion is
extremely difficult, there are several reagents that can successfully generate ‘CF
3
+
’.
Among them are reagents developed by Umemoto, Togni, Yagupol’skii, Shreeve and
Shibata to name a few.
44
The first electrophilic trifluoromethylating reagent was
discovered in 1984 by Yagupol’skii
46
and co-workers for the trifluoromethylation of
thiolates. Since this initial synthesis of S-trifluoromethyl diarylsulfonium salts, several
other electrophilic trifluoromethylating reagents based on other trifluoromethyl
sulfonium, selenium, tellurium, and iodide salts have been developed. These reagents
have gained prominence, and are commercially available largely due to their stability and
11

broad substrate scope. All these reagents produce an electrophilic CF
3
+
species that reacts
with soft and hard nucleophiles.
1.3.2 Difluoromethylation Reactions
Difluoromethylation reactions are more challenging reaction to accomplish than
trifluoromethylations. This can be attributed to the difference in reactivity of the CF
2
H
group relative to the CF
3
- group. Despite the challenges presented, several reagents and
methods have been developed to incorporate the difluoromethyl group (Figure 1.5).
Several fluorination reagents such as SF
4
, DAST, etc. have been traditionally used to
introduce the difluoromethyl group.

Figure 1.5 Examples of Difluoromethylation Reagents
12

The use of organometallic reagents such as difluoromethyl cadmium,
47,48

difluoromethyl zinc,
48
and difluoromethyl copper
49
for difluoromethylation has been long
studied. Burton and co-workers prepared the cadmium and zinc reagents by the reaction
of iodo- or bromodifluoromethane with the corresponding metal salts.
47
Difluoromethyl
copper was prepared from difluoromethyl cadmium, which is a very stable compound.
49

Unlike other perfluoroalkylcopper compounds, difluoromethylcopper is unstable above
-30
o
C. However, it was successfully reacted with various halides to yield corresponding
difluoromethyl products.
49

Recently, many research groups have successfully generated difluoromethyl
copper from easier to handle reagents such as difluoromethyltrimethylsilane
(TMSCF
2
H)
50–52
and difluoromethyltributylstannane (TBT-CF
2
H).
53
In the presence of
appropriate initiators they generate difluoromethylcopper in situ, which further reacts
with aryl halides,
50,53
vinyl halides,
50,53
and arenediazonium salts
51
yielding
difluoromethylated products.
Difluoromethyl and trifluoromethyl reagents have been used in direct
difluoromethylation in recent years. In 1995, Fuchikami
54
reported the first direct
difluoromethylation of carbonyl compounds using TMS-CF
2
H as the difluoromethylating
reagent under thermal conditions. While, the reaction yielded the difluoromethylated
product in good yields in the case of most aldehydes, the presence of a hydrogen α- to the
carbonyl group resulted in poor yields. In 2011, Hu et. al.
55
and Tyutyunov and co-
workers
56
independently described the difluoromethylation of carbonyl compounds and
13

imines using TMS-CF
2
H at ambient or low temperatures in the presence of a Lewis base.
TMS-CF
3
has also been used as a difluoromethylating reagent via a domino
trifuoromethylation/ Brook rearrangement/ fluoride-elimination pathway.
57
Although
difluoromethyl phenyl sulfone (PhSO
2
CF
2
H) was synthesized in the 1960s,
58
it was used
as a difluoromethylating reagent only around the 1990s.
40

In 2014, the Prakash group described the N-difluoromethylation of imidazoles
and benzimidazoles from TMSCF
3
.
59
In the presence of lithium iodide, several
imidazoles and benzimidazoles, including caffeine were selectively difluoromethylated at
the nitrogen atom. A recent popular difluoromethylating reagent is
chlorodifluoroacetate.
60
It has been used by several research groups as CF
2
X group
transfer reagent. Other difluorocarbene reagents such as chlorodifluoromethane
(CHClF
2
),
61,62
methyl chlorodifluoroacetate,
63
TMS-CF
2
Br,
64,65
etc. have been used as
reagents for the difluoromethylation of O-, N-, and S- nucleophiles. In 2007, the first
direct electrophilic difluoromethylation was reported by Prakash and co-workers using S-
(difluoromethyl)diarylsulfonium salts.
66
In 2013, Fier and Hartwig reported the synthesis
of difluoromethylethers from difluoromethyltriflate (CF
2
H-OTf) as a direct
difluoromethylating reagent.
67
In 2011, Prakash and co-workers developed another sulfur
based direct electrophilic reagent for the difluoromethylation of heteratom nucleophiles
using N,N-Dimethyl-S-difluoromethyl-S-phenylsulfoximinium tetrafluoroborate as a
mild reagent.
68

14

Besides nucleophilic and electrophilic reagents, radical difluoromethylation is
another method to incorporate the difluoromethyl group. CF
2
HI,
69
CF
2
Br
2
70
and
CF
2
BrCl
71
are reagents that act as a good source for the CF
2
X radical. Unfortunately,
these reagents are not very convenient to use and most are ozone depleting reagents.
Recently, Baran and co-workers reported the synthesis of a new zinc reagent that is a
source of difluoromethyl radical. Zn(SO
2
CF
2
H)
2
(DFMS) is an air-stable, free-flowing
white solid that has been used for the difluoromethylation of several heteroarenes.
72

However, difluoromethylation of simple arenes could not be achieved by Baran’s
reagent.
1.3.3 Monofluoromethylation Reactions
Monofluoromethylation reactions are even less studied than difluoromethylation
reactions. However, several research groups are pursuing this area of research (Figure
1.6). One of the most popular monofluoromethylating reagent is
fluorobis(sulfonyl)methane or FBSM.
73
It was discovered independently by Shibata
74
and
Hu
75
in 2006, and has since been used extensively for monofluoromethylation reactions
in the presence of an appropriate base. A related reagent, fluorobis(sulfonyl)nitromethane
(FNSM)
76
has also been developed for monofluoromethylation reactions.
77
In 2006, Hu
and co-workers reported the application of fluoromethyl phenyl sulfone for the
stereoselective nucleophilic monofluoromethylation of sulfinylaldimines.
78

The first monofluoromethylation reaction was carried out by Olah and Pavlath
in 1953 using fluoromethanol in an acid-catalyzed reaction.
79,80
In 2008, Prakash and co-
15

workers reported one of the few electrophilic monofluoromethylation reactions mediated
by S-(monofluoromethyl)diarylsulfonium salts.
81
More recently, in 2013, Hu and co-
workers
82
used a sulfoximine (PhSO(NTs)CH
2
F) for the monofluoromethylation of O-,
S-, N-, and P- nucleophiles.

Figure 1.6 Examples of Monofluoromethylation Reagents
1.4 Chapter 1: Aim and Scope of Current Work
As described in the previous sections, fluorine has long-reaching applications in
the pharmaceutical, materials, agrochemical, and specialty chemicals industries. In the
pharmaceutical industry specifically, several studies have demonstrated the benefits of
incorporating fluorine, either as a single atom, or as fluoroalkyl groups. The position and
nature of the organofluorine moiety can favorably affect properties such as lipophilicity
and pharmacokinetics of a drug molecule. This makes it increasingly important for
synthetic routes and reagents to be developed that incorporate fluorine and fluoroalkyl
groups successfully and efficiently.
16

While many methods and reagents exist for the introduction of fluorine and
fluoroalkyl groups, their applications are more often than not hampered by limitations
ranging from difficulty in handling and performing reactions to cost of reagents.
Scientific research to discover new reagents and methods that are cost-effective, efficient,
and wide-reaching is still thriving. Fluoroalkylation reactions and reagents have been of
particular interest in our group for the past 30 years. In particular,
(trifluoromethyl)trimethylsilane or TMS-CF
3
, also called the Ruppert-Prakash reagent
has been extensively developed as an efficient nucleophilic trifluoromethyating reagent.
In an effort to expand the utility of this widely used and relatively inexpensive reagent,
we have developed convenient methods to use TMS-CF
3
as a source of singlet
difluoromethylene (:CF
2
). In this thesis in particular, we describe the generation of
difluoromethylene (:CF
2
) from TMS-CF
3
selectively by tuning reaction conditions to
synthesize a variety of difluorocyclopropanes. This work also describes one of the most
efficient methods to generate :CF
2
under low temperature conditions.
Thus, this thesis not only succeeds in expanding the utility of a widely available
reagent, but also provides new, efficient and versatile methodologies towards the
synthesis of an exciting class of organofluorine molecules that can have a great impact on
medicinal and pharmaceutical science.

17

1.5 Chapter 1: References
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Nicolas, F. J. Fluor. Chem. 2007, 128, 285.
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(11) George A. Olah, G. K. Surya Prakash, Jean Sommer, A. M. 2009, Superacid
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(20) Schmitz, A.; Kalicke, T.; Willkomm, P.; Grunwald, F.; Kandyba, J.; Schmitt, O. J.
Spinal Disord. 2000, 13, 541.
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Smart, B.E., Tatlow, J. C., Ed.; 1994, Springer.
(24) Hiyama, T. Organofluorine Compounds Chemistry and Applications; Yamamoto,
H., Ed.; 2000, Springer.
(25) Prakash, G. K. S.; Mandal, M. J. Fluor. Chem. 2001, 112, 123.
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Am. Chem. Soc. 2011, 133, 20901.
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393.
(34) Prakash, G. K. S.; Yudin, A. K. Chem. Rev. 1997, 97, 757.
(35) Prakash, G. K. S.; Hu, J.; Olah, G. A. J. Org. Chem. 2003, 68, 4457.
(36) Prakash, S. G. K.; Hu, J.; Olah, G. A. 2003 Magnesium mediated preparation of
fluorinated alkylsilanes, WO2003048033A2.
(37) Maggiarosa, N.; Tyrra, W.; Naumann, D.; Kirij, N. V; Yagupolskii, Y. L. Angew.
Chem. Int. Ed. 1999, 38, 2252.
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(38) Kolomeitsev, A.; Movchun, V.; Rusanov, E.; Bissky, G.; Lork, E.; Roschenthaler,
G.-V.; Kirsch, P. Chem. Commun. 1999, 1017.
(39) Prakash, G. K. S.; Mandal, M. J. Fluor. Chem. 2001, 112, 123.
(40) Prakash, G. K. S.; Hu, J. Acc. Chem. Res. 2007, 40, 921.
(41) Prakash, G. K. S.; Jog, P. V; Batamack, P. T. D.; Olah, G. A. Science 2012, 338,
1324.
(42) Prakash, G. K. S.; Jog, P. V; Batamack, P. T. D.; Olah, G. A. 2012 Direct
trifluoromethylations using trifluoromethane, WO2012148772A1.
(43) Prakash, G. K. S.; Wang, F.; Zhang, Z.; Haiges, R.; Rahm, M.; Christe, K. O.;
Mathew, T.; Olah, G. A. Angew. Chemie, Int. Ed. 2014, 53, 11383.
(44) Shibata, N.; Matsnev, A.; Cahard, D. Beilstein J. Org. Chem. 2010, 6, 65.
(45) Barata-Vallejo, S.; Lantaño, B.; Postigo, A. Chemistry 2014, 20, 16806.
(46) Yagupol’skii, L. M.; Kondratenko, N. V; Timofeeva, G. N. Zhurnal Org. Khimii
1984, 20, 115.
(47) Hartgraves, G. A.; Burton, D. J. J. Fluor. Chem. 1988, 39, 425.
(48) Burton, D. J.; Hartgraves, G. A. J. Fluor. Chem. 2007, 128, 1198.
(49) Burton, D. J.; Hartgraves, G. A.; Hsu, J. Tetrahedron Lett. 1990, 31, 3699.
(50) Fier, P. S.; Hartwig, J. F. J. Am. Chem. Soc. 2012, 134, 5524.
(51) Matheis, C.; Jouvin, K.; Goossen, L. J. Org. Lett. 2014, 16, 5984.
(52) Xu, P.; Guo, S.; Wang, L.; Tang, P. Synlett 2015, 26, 36.
(53) Prakash, G. K. S.; Ganesh, S. K.; Jones, J.-P.; Kulkarni, A.; Masood, K.; Swabeck,
J. K.; Olah, G. A. Angew. Chemie, Int. Ed. 2012, 51, 12090.
(54) Hagiwara, T.; Fuchikami, T. Synlett 1995, 717.
(55) Zhao, Y.; Huang, W.; Zheng, J.; Hu, J. Org. Lett. 2011, 13, 5342.
(56) Tyutyunov, A. A.; Boyko, V. E.; Igoumnov, S. M. Fluor. Notes 2011, 78, 1.
20

(57) Brigaud, T.; Doussot, P.; Portella, C. J. Chem. Soc. Chem. Commun. 1994, 2117.
(58) Hine, J.; Porter, J. J. J. Am. Chem. Soc. 1960, 82, 6178.
(59) Surya Prakash, G. K.; Krishnamoorthy, S.; Ganesh, S. K.; Kulkarni, A.; Haiges,
R.; Olah, G. A. Org. Lett. 2014, 16, 54.
(60) Mehta, V. P.; Greaney, M. F. Org. Lett. 2013, 15, 5036.
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2011, 1243.
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(65) Yudin, A. K.; Prakash, G. K. S.; Deffieux, D.; Bradley, M.; Bau, R.; Olah, G. A. J.
Am. Chem. Soc. 1997, 119, 1572.
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(68) Prakash, G. K. S.; Zhang, Z.; Wang, F.; Ni, C.; Olah, G. A. J. Fluor. Chem. 2011,
132, 792.
(69) Cao, P.; Duan, J. X.; Chen, Q. Y. J. Chem. Soc. Chem. Commun. 1994, 737.
(70) Gonzalez, J.; Foti, C. J.; Elsheimer, S. J. Org. Chem. 1991, 56, 4322.
(71) Wegert, A.; Miethchen, R.; Hein, M.; Reinke, H. Synthesis 2005, 1850.
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M. R.; Blackmond, D. G.; Baran, P. S. J. Am. Chem. Soc. 2012, 134, 1494.
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21

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2010, 131, 1007.
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22

2. Chapter 2: Synthesis of gem-Difluorinated
Cyclopropanes: (Trifluoromethyl)trimethylsilane as a
Difluorocarbene Source

2.1 Chapter 2: Introduction
Cyclopropanes and cyclopropenes constitute an important class of compounds in
alicyclic chemistry. Introduction of fluorine on a cyclopropane ring is known to alter the
structure and reactivity of the three-membered ring. This is due to higher
electronegativity, small size of the fluorine and consequent increase in C-F bond polarity.
Therefore, difluorocyclopropanes and difluorocyclopropenes Fluorine substituents also
increase the biological activity, bioavailability and in some cases potency of known
biologically active molecules.
1–3
Several groups have introduced the gem-
difluorocyclopropyl moiety into biological molecules.
1,4
Wang et. al. synthesized the
difluorocyclopropyl analogues of nucleobases such as adenine and guanine and
discovered that these molecules are effective against certain viruses, leukemia and some
solid tumors.
5–7
The difluoromethylene group (:CF
2
) is also considered as a bioisostere
for an “oxygen” atom in biological studies.
8,9
Prakash and co-workers discovered
8
that
replacing the oxygen atoms with difluoromethylene groups in triphosphoric acids led to
less enzymatic hydrolysis while still maintaining overall polarity and steric bulk (Figure
2.1).
Recently, a unique application of difluorocyclopropanes to trap the 1,3-diradical
formed during the mechanochemical activation of the polybutadiene backbone was
reported.
10
Besides biological and polymeric applications, difluorocyclopropanes are
23

synthetically useful substrates for variety of reactions such as thermal rearrangements,
bimolecular reactions, carbocation, carbanion and free radical chemistry.
11

Figure 2.1 Polarities of bridging units in triphosphate anion and CF
2
substituted analog
The synthesis of difluorocyclopropanes and difluorocyclopropenes can be
achieved in various ways. However, a [2+1] cycloaddition reaction of difluorocarbene to
an alkene or an alkyne has proven to be the most efficient method so far.

This has led to
considerable efforts in developing reagents that can act as a source of difluorocarbene.
Difluorocarbene (:CF
2
) is a relatively stabilized carbene species with a singlet ground
state that is destabilized by the negative inductive effect of the fluorine atoms and
stabilized due to the interaction of the lone pairs of the fluorine substituents with the
carbene center (Figure 2.2). The singlet state is ~50 kcal/mol more stable than the triplet
4

state, and is a moderately electrophilic species. This could be one of the reasons why
difluorocarbenes do not react well with electron-poor alkenes to yield the [2+1] addition
product. Often, higher temperatures are required for the generation as well as efficient
reactions of difluorocarbene with alkenes. Difluorocarbene reacts under more ambient
and low-temperature conditions with very electron-rich alkenes and heteroatom
nucleophiles.
24

Figure 2.2 Stabilization of singlet :CF
2
species
Several reagents have been developed for the generation of singlet
difluorocarbene and its subsequent addition to alkenes and alkynes has been studied by
many groups. In 1960, Birchall et. al. reported the first transfer of difluorocarbene (:CF
2
)
to alkenes albeit in poor to moderate yields.
12
The :CF
2
, generated at 165
o
C by the
thermal decomposition of sodium chlorodifluoroacetate, reacted with several alkenes to
yield the difluorocyclopropane in moderate yields (Scheme 2.1, eq. 1). Since this
discovery, other metal salts
13
of chlorodifluoroacetic acid and even the methyl ester
14,15

have been shown to generate the difluorocarbene. The thermal decomposition of sodium
chlorodifluoroacetate yields the chlorodifluoromethyl anion which upon losing the
chloride ion yields :CF
2
. In recent years, chloro and bromodifluoroacetate has been used
as difluorocarbene sources under microwave irradiation as well.
16

Seyferth and co-workers developed organometallic reagents of tin
17
and
mercury
18,19
that were also used as sources of difluorocarbene (Scheme 2.1, eq. 2).
PhHgCF
3
and (CH
3
)
3
SnCF
3
upon treatment with sodium iodide (NaI) at 80
o
C transferred
difluorocarbene to alkenes forming difluorocyclopropanes in good yields. Eujen and
Hoge also used bis(trifluoromethyl)cadmium ((CF
3
)
2
Cd) as a source of difluorocarbene at
lower temperatures (-25-0
o
C) (Scheme 2.1, eq. 6).
20,21
It should be noted here that
(CF
3
)
2
Cd is explosive at room temperature.
21
Addition of the :CF
2
generated from
25

(CF
3
)
2
Cd to various alkenes yielded the difluorocyclopropanes in yields greater than
95%. However, since :CF
2
is an electrophilic species, addition to electron poor alkenes
yielded the product in only very poor yields.
In a reaction analogous to the Simmons-Smith reaction, Dolbier and co-workers
reported a room-temperature addition of :CF
2
, generated from difluorodibromomethane
and zinc, to alkenes in yields upto 96%.
22
Excess of the reagent had to be used in order to
obtain good yields of the cyclopropane product, and electron-poor alkenes react to give
very low yields (Scheme 2.1, eq. 5). In 1995, Chen reported the discovery of his reagent
for the generation of difluorocarbene.
23
In 2000, Dolbier and co-workers also reported the
synthesis of a reagent,
24
trimethylsilyl(fluorosulfonyl)difluoroacetate (F-SO
2
-CF
2
-
COOTMS; TFDA), which was a variant of Chen’s reagent. When subjected to reaction
with alkenes at 105
o
C, difluorocarbene generated from TFDA added in a [2+1] fashion
with good yields of the cyclopropane products. Even very electron deficient alkenes
reacted to give the desired product in good yields (Scheme 2.1, eq. 3). More recently,
Dolbier and co-workers demonstrated the generation of :CF
2
from fluoroform and its
subsequent insertion into the O-H bond of phenolic compounds (Scheme 2.1, eq. 7).
25

Recently, Hu et al. reported that (chlorodifluoromethyl)trimethylsilane
(Me
3
SiCF
2
Cl) can act as an efficient difluorocarbene precursor under chloride-ion
catalysis at 110 C.
26
However, (chlorodifluoromethyl)trimethylsilane (Me
3
SiCF
2
Cl) is
not commercially available and its preparation requires ozone depleting
bromochlorodifluoromethane (CBrClF
2
).

26

Scheme 2.1 Generation of :CF
2
under thermal and low/room temperature conditions
27

While there are many methods and reagents to generate difluorocarbene, its
addition to alkenes is mostly carried out at high temperatures. For the substrates which
are thermally unstable, the above mentioned methods/reagents could be a serious
limitation and development of better difluorocarbene precursors, that are able to generate
difluorocarbenes at lower temperatures are required. There are only few reports which
discuss difluorocarbene generation at room temperature with Ph
3
P/CF
2
Br
2
27
or
Zn/CF
2
Br
2
,
22
or at low temperatures (below 0 C), with bis(trifluoromethyl)cadmium-
base (a highly pyrophoric reagent) as a source. Again, use of cadmium or phosphines and
lack of commercial availability of these reagents is a severe limitation. The synthesis of
many reagents is also fraught with issues, such as the use of ozone-depleting compounds
(CF
2
Br
2
and CBrClF
2
), toxic metals (Hg and Sn), dangerous reagents ((CF
3
)
2
Cd).
Trifluoromethyltrimethylsilane (Me
3
SiCF
3
or TMSCF
3
, 1), commonly known as
Ruppert-Prakash reagent, is readily commercially available and is the most widely used
nucleophilic trifluoromethylating agent for a variety of applications.
28–33
Silicon based
systems have been increasingly used for transition metal based (Cu, Pd, Ni)
trifluoromethyl group transfer.
34,35
Importantly, TMSCF
3
(1) can be used as a
trifluoromethyl anion source at low temperatures and the decomposition of
trifluoromethyl anion to difluorocarbene and fluoride ion at low temperature is well
recognized as a side decomposition reaction. Based on this, the cyclopropanation reaction
of alkenes with TMSCF
3
at low temperatures using nonmetallic fluoride initiator sources
was studied. Additionally, it was also discovered that TMSCF
3
(1) can be easily activated
28

at room and/or higher temperature, and reactions of this reagent with alkenes was
explored at higher temperature (65 C) using iodide ion-based activation.

2.2 Chapter 2: Results and Discussion
We previously presented initial results on the reaction between alkenes and
TMSCF
3
at -50
o
C using tetrabutylammonium triphenyldifluorosilicate (TBAT) as the
initiator. However, product isolation was found to be difficult and only accomplished for
one compound. Initial reaction conditions used TMSCF
3
as the limiting reagent and the
alkene was added in excess. A more systematic and thorough study was then carried out
to determine optimal reaction conditions for the synthesis of gem-difluorocyclopropanes
using TMSCF
3
as a source of difluorocarbene.
In our initial attempts to synthesize difluorocyclopropanes, we carried out
reactions based on the hypothesis that excess of TMSCF
3
would generate an excess of
difluorocarbene and therefore yield higher conversion to the desired product. With this in
mind, the reaction between 4-F-α-methylstyrene 2d and excess TMSCF
3
(5 equiv.) was
carried out using TBAT as initiator at -50
o
C in THF as solvent (Table 2.1, entry 1).
19
F
NMR analysis showed 82% conversion of 2d to the desired difluorocyclopropane
product. Encouraged by this result, reactions with other initiators were attempted. The
profound effect of the initiator used to activate TMSCF
3
was observed when
tetrabutylammonium fluoride (TBAF), tetramethylammonium fluoride (TMAF), and
trimethylamine oxide (TMAO) were used to initiate the reaction, but yields of the desired
29

product were inferior or nil (37%, 0%, and 0%, respectively) (Table 2.1, entries 2, 3, and
4).
Table 2.1 Optimization of reaction conditions for the reaction between TMSCF
3
(1) and
alkene 2d

Entry Molar Equiv (1) Solvent

Initiator

Yield (%)
[a]

1 5 THF TBAT
[b]
82
2 5 THF TBAF
[c]
37
3 5 THF TMAF
[d]
0
4 5 THF TMAO
[e]
0
5 5 THF NaI 0
6 5 Monoglyme TBAT 54
7 5 Diethyl ether TBAT 21
8 5 Toluene TBAT 0
9 5 Acetonitrile TBAT 0
10 1 THF TBAT 40
11 2 THF TBAT 80
12 2.5 THF TBAT 83
30

Other solvents were used to expand the utility of the reaction. Ethereal solvents
like THF, monoglyme and diethyl ether (Table 2.1, entries 1, 6, and 7) facilitated the
generation of difluorocarbene and the subsequent [2+1] cycloaddition to alkenes.
Solvents like toluene and acetonitrile didn’t show any cycloaddition product or
tetrafluoroethylene (product of the dimerization of :CF
2
) in the
19
F NMR. Further
experiments led to the final reaction conditions for the synthesis of gem-
difluorocyclopropanes starting from 1 equiv. alkene, 2.5 equiv. TMSCF
3
, 5 mol% TBAT
and THF as solvent at -50
o
C (Table 2.1, entry 12) (Table 2.2, Method A). This method
was then applied to a variety of alkenes and the results are shown in Table 2.2.
Both aromatic and alkyl substituted alkenes gave desired cyclopropanes in good
yields. As expected, for the electron-deficient singlet difluorocarbene (:CF
2
), electron-
rich alkenes (Table 2.2, entries 2, 3, 4, 10, using Method A) gave better yields compared
to electron-poor alkenes (Table 2.2, entries 5 and 7, Method A). Unfortunately, some
alkenes either did not react or gave poor yields (Table 2.2, entries 6 and 9, using Method
A) under these low temperature reaction conditions. Isolation of some of the
difluorocyclopropane products was found to be difficult using standard column
chromatographic techniques and therefore distillation was used as a purification method
of choice (Table 2.2, entries 5, 7, 8, 9 using Method A)
Following the poor yields products starting from electron poor alkenes, it was
envisioned that TMSCF
3
could also be activated at higher temperatures using a suitable
initiator. Higher temperature reactions would increase the versatility of the reagent and
improve the scope of the reaction. In following the work of Seyferth and co-workers,
31

TMSCF
3
1 was activated with sodium iodide as the initiator. The use of fluoride ion (in
TBAF or TBAT) as an initiator failed to yield any desired product and fluoroform (CF
3
H)
was the only observed product. Our initial efforts were directed towards increasing the
yield of the product and hence we chose acetonitrile as a solvent with greater than
stoichiometric amount (2.2 eq) of NaI and high temperatures (110 C). However, through
further optimization it was discovered that addition of 0.2 equiv. of sodium iodide
successfully activated TMSCF
3
and yielded good to excellent yields of the desired
difluorocyclopropane product. The reaction temperature was 65
o
C, which is still lower
than the temperature used in many prior methodologies. Alkenes that were unreactive or
poorly reactive under the low temperature conditions (Method A) yielded good to
excellent yields of the product (Table 2.2, entries 5, 6, 7, 9, Method A vs Method B). α-
Bromostyrene (Table 2.2, entry 6) was completely unreactive under the low temperature
conditions but was converted in >97% of the desired cyclopropane product when initiated
with sodium iodide (NaI) at 65
o
C. This could be due to thermal activation of the parent
difluorocarbene and/or alkene under the chosen reaction conditions. The results are
summarized in Table 2.2, Method B.

32

Table 2.2 [2+1] cycloaddition reaction between alkenes 2 and difluorocarbene (:CF
2
)
generated from TMSCF
3
1

33

Table 2.2 continued.

34

Boronic acids are used extensively in organic chemistry as chemical building
blocks, particularly in the Suzuki coupling reaction.
36,37
The boronic acid moiety is also
present in Bortezomib, which is a drug used in chemotherapy.
38
As has been mentioned
previously in this chapter, fluorine containing compounds, particularly the gem-
difluoromethylene group, have the potential to be advantageous in pharmaceutically
important compounds. In 2008, Amii and co-workers reported the synthesis of gem-
difluorocyclopropyl boronate esters starting from vinylboronate esters and chloro and
bromodifluoroacetate salts. The desired products were obtained in good yields and they
were subjected to further reactions, including homologation and hydrolysis.
16,39

The utility of the boronate ester group led us to extend the methodology of
difluorocyclopropanation using TMSCF
3
to vinylboronic acid and esters. Reaction
between boronic acids (Table 2.3, entry 1) and TMSCF
3
(1) proved to be unsuccessful,
yielding only CF
3
H as the sole product. This is probably due to the presence of acidic
hydrogens on the boronic acid. To overcome this, boronate esters (Table 2.3, entry 5)
were used as substrates. Other boronate salts, such as trifluoroborate salts (Table 2.3,
entries 2, 3, and 4), were also attempted to be used as substrates; however, they also did
not yield any of the desired gem-difluorocyclopropyl product. Optimization of reaction
conditions led to conditions that were slightly different from that used in the synthesis of
difluorocyclopropanes from alkenes (Table 2.2). The pinacol ester of phenylvinylboronic
acid reacts with 1 in the presence of excess NaI (2.2 equiv.) as initiator, and the reaction
mixture had to be heated to 110
o
C for 12h in order to obtain good conversions to the
desired product (Table 2.3, entry 5). The results are summarized in Table 2.3.
35

Table 2.3 Optimization of conditions for the [2+1] cycloaddition reaction between
vinylboronic acids/ vinylboronate esters with :CF
2

[a] Yield was determined by
19
F NMR spectroscopy using C
6
F
6
as an internal standard
The final optimized reaction conditions were then extended to various
vinylboronate esters 4 and the results are summarized in Table 2.4. As was seen in earlier
experiments, aliphatic and electron deficient alkenes did not perform very well under the
reaction conditions (Table 2.4, entries 2 and 3). This is probably due to the boronate ester
moiety behaving as an electron withdrawing group. 1-Phenylvinylboronic acid, pinacol
ester (Table 2.4, entry 1) gave the best conversion (94% isolated yield) to the gem-
difluorocyclopropyl product. 4f, which has two double bonds, gave a mixture of two
products. The major product was obtained from the [2+1] addition of :CF
2
with the
internal double bond.
Entry Substrate Molar
Equiv (1)
Reaction Conditions

Yield
(%)
[a]

1

2 2.2 equiv. NaI, THF,
2h, 65
o
C
0
2

2
2.2 equiv. NaI, THF,
2h, 110
o
C
0
3

2 2.2 equiv. NaI, CH
3
CN
2h, 110
o
C
0
4

2.5 0.2 equiv. NaI, THF,
2h, 110
o
C
0
5

2 2.2 equiv. NaI, THF,
12h, 110
o
C
99
36

During a scaled-up synthesis of 5a, it was observed that conversion to the desired
product was very much dependent on the of the concentration of the reaction medium. A
more concentrated reaction mixture yielded the desired product in very poor to zero
yields. From our observations, a solution greater than 0.5M resulted in no product being
formed. This observation is contrary to observations made by other research groups. For
example, Dolbier et. al. discovered during the synthesis of gem-difluorocyclopropanes
using TFDA that dilution of the reaction mixture resulted in poor yields of the product.
Thus, reactions were either carried out in the absence of solvent or in very highly
concentrated media.
The gem-difluoromethylated product of 4a, was subjected to further Suzuki coupling
reactions and to a multi-component Petasis reaction. However, the reactivity of the
carbon attached to the boron is diminished due to the boronate ester group being attached
to a sp
3
carbon.

37

Table 2.4 Substrate scope for the reaction between vinylboronate esters 4 and :CF
2

[a] conversion was determined by
19
F NMR using C
6
F
6
as an internal standard

38

2.3 Chapter 2: Conclusions
In conclusion, an efficient new method for the generation of difluorocarbene from
Ruppert-Prakash reagent TMSCF
3
(1) has been discovered, which has enabled the
synthesis of gem-difluorocyclopropanes from alkenes. Tetrabutylammonium
difluorotriphenyl silicate (TBAT), a nonmetallic fluoride was able to initiate
decomposition of 1 to generate difluorocarbene (:CF
2
) at low temperatures to result in the
formation of the corresponding gem-difluorocyclopropane in good yields. This is
noteworthy as this could be a very attractive synthetic protocol for the synthesis of
thermally unstable gem-difluorocyclopropanes. Sodium iodide (NaI) was found to play a
crucial role in promoting the [2 + 1] cycloaddition reactions of alkenes at higher
temperatures. The generation of difluorocarbene (:CF
2
) from TMSCF
3
using sodium
iodide as initiator was also exploited in the synthesis of gem-
difluorocyclopropylphenylboronate esters in moderate to good yields. Since the Ruppert-
Prakash reagent is readily available and much less toxic than the Seyferth reagents
(Me
3
SnCF
3
and PhHgCF
3
), this synthetic protocol promises to find many applications in
the synthesis of difluoromethylene-containing compounds.

2.4 Chapter 2: Experimental
2.4.1 General
Commercially available trifluoromethyltrimethylsilane (TMSCF
3
) (SynQuest
Labs), tetra-n-butylammonium triphenyldifluorosilicate (TBAT) (Sigma-Aldrich),
sodium iodide (NaI) (Sigma-Aldrich), tetra-n-butylammonium fluoride (TBAF, 1.0 M
39

solution in THF) (Sigma- Aldrich), tetramethylammonium fluoride (TMAF) (Sigma-
Aldrich), tetramethylammonium oxide (TMAO) (Sigma-Aldrich) were used as received.
Tetrahydrofuran (THF) and diethyl ether were freshly distilled over Na/ benzophenone.
Dimethoxyethane (glyme) was distilled over calcium hydride. Commercially available
toluene (DriSolv
®
, EMD Chemicals) and acetonitrile (DriSolv
®
, EMD Chemicals) were
used as received. All reactions were carried out under inert atmosphere unless otherwise
mentioned.
1
H,
13
C and
19
F NMR (CFCl
3
as reference and C
6
F
6
as internal standard) was
recorded on a Varian Inova 400 MHz instrument with CDCl
3
and/or TMS as reference.
C
6
F
6
was used as internal reference for
19
F NMR wherever required. Chemical shifts
were reported in ppm. HRMS data was obtained from the University of Arizona Mass
Spectrometry Facility.
2.4.2 Experimental Procedures
1. Generation of difluorocarbene at low temperature for the synthesis of gem-
difluorocyclopropanes using TMSCF
3
(Method A):
To a 25 mL Schlenk flask charged with a magnetic stir bar was added anhydrous
TBAT (0.099 g, 0.18 mmol, 5 mol%), 5 mL of freshly distilled THF as solvent, and 4-
fluoro- α-methylstyrene (2d) (0.5 g, 3.67 mmol, 1 eq) in that order. The reaction mixture
was cooled to - 50
o
C and stirred at this temperature for 10 min. To this was added drop
wise TMSCF
3
(1) (1.36 mL, 9.18 mmol, 2.5 eq) over 10 min. The reaction mixture was
then stirred at – 50
o
C for 2 hours. After this, it was allowed to warm up to room
temperature and stirred at room temperature for 4 hours.
40

Work-up:
The reaction mixture was evaporated to dryness under reduced pressure to remove
THF. The residue was then extracted with hexanes (3 X 5 mL). The organic solution was
then evaporated under reduced pressure to obtain the crude product as oil.
2. Generation of difluorocarbene at high temperature for the synthesis of gem-
difluorocyclopropanes using TMSCF
3
(Method B):
To a 25 mL pressure tube charged with a magnetic stir bar was added anhydrous
NaI (0.110 g, 0.73 mmol, 0.2 eq), 5 mL of freshly distilled THF as solvent, and 4-fluoro-
α-methylstyrene (2d) (0.5 g, 3.67 mmol, 1 eq) in that order under inert atmosphere. To
this was added TMSCF
3
(1) (1.36 mL, 9.18 mmol, 2.5 eq). The reaction vessel was sealed
and heated to 65
o
C in an oil bath for a period of 2 hours.
Work-up:
The reaction mixture was evaporated to dryness under reduced pressure to remove
THF. The crude was extracted with ether (15 mL) and washed with water (15 mL),
saturated sodium sulfite solution (15 mL), saturated sodium bicarbonate solution (15
mL), and water (15 mL), in that order. The ethereal layer was then collected and dried
over anhydrous magnesium sulfate. The ethereal layer was evaporated under reduced
pressure to obtain the crude as oil.

41

3. Generation of difluorocarbene at high temperature for the synthesis of gem-
difluorocyclopropylboronate esters:
To a 25 mL pressure tube charged with a magnetic stir bar was added anhydrous
NaI ( ), 1-phenylvinylboronic acid, pinacol ester (4a) ( ) and the reaction was made up to
0.25 M by the addition of THF as solvent, in that order under inert atmosphere. To this
was added TMSCF
3
(1) ( ). The reaction vessel was sealed and heated at 110
o
C for 12
hours. The reaction was worked up in the same manner as with Method B.
Purification of crude product was done in three different ways depending on the
substrate:
Procedure A: The crude was purified on a silica gel column using hexanes (100%) as
eluent. The column fractions were collected together and evaporated under reduced
pressure to obtain the pure gem-difluorocyclopropane product.
Procedure B: The ethereal extract was subjected to distillation under reduced pressure to
obtain the pure product.
Procedure C: The ethereal extract was distilled under atmospheric pressure using a
vigoureux column to obtain the pure product.
2.4.3 Spectral Data and Representative Spectra
The
1
H,
13
C, and
19
F NMR spectra for compounds 3a-c, 3g-i, and 5a were
consistent with those reported in literature.

42

1-(2,2-difluoro-1-methylcyclopropyl)-4-fluorobenzene (3d)

Purification procedure: A; yield 82% (Method A), 85% (Method B);
19
F NMR (376
MHz):  -115.76 (m, 1F), -133.00 (dd, J = 150.7, 13.9 Hz, 1F), -138.25 (dd, J = 148.9,
12.4 Hz, 1F);
1
H NMR (400 MHz):  7.25-7.31 (m, 2H), 6.98-7.05 (m, 2H), 1.64 (ddd, J
= 13.6, 8.0, 4.0 Hz, 1H), 1.48 (dd, J = 2.8, 1.6 Hz, 3H), 1.40 (ddd, J = 12.4, 7.6, 4.4 Hz,
1H);
13
C NMR (100.5 MHz):  161.89 (d, J = 245.9 Hz, 1C), 134.91, 130.01 (dd, J = 8.1,
1.8 Hz, 2C), 115.42 (d, J = 21.5 Hz, 2C), 114.35 (dd, J = 289.7, 287.1 Hz, 1C), 30.54 (t, J
= 9.9 Hz, 1C), 22.66 (t, J = 9.9 Hz, 1C), 21.44 (d, J = 6.3 Hz, 1C). High Resolution MS
(EI): m/z for (C
10
H
9
F
3
): calculated 186.0656 found 186.0664.
1-(2,2-difluorocyclopropyl)-4-fluorobenzene (3e)

Purification procedure: B; bp 59-61
o
C at 35mm; yield 23% (Method A), 78% (Method
B);
19
F NMR (376 MHz):  -115.84- -115.71 (m, 1F), -126.76 (dtd, J = 154.1, 12.7, 3.7
Hz, 1F), -142.79 (ddd, J = 154.1, 12.7, 4.8 Hz, 1F);
1
H NMR (400 MHz):  7.23-7.15 (m,
2H), 7.02 (tt, J = 8.4, 3.2 Hz, 2H), 2.80-2.67 (m, 1H), 1.90-1.76 (m, 1H), 1.63-1.51 (m,
1H);
13
C NMR (100.5 MHz):  161.98 (d, J = 245.9 Hz, 1C), 129.69 (td, J = 8.1, 1.7 Hz,
2C), 129.36 (d, J = 3.2 Hz, 1C), 115.37 (d, J = 21.5 Hz, 2C), 112.36 (dd, J = 286.9, 283.7
43

Hz, 1C), 26.38 (t, J = 11.5 Hz, 1C), 17.09 (t, J = 10.6 Hz, 1C). High Resolution MS (EI):
m/z for (C
9
H
7
F
3
): calculated 172.0500 found 172.0501.
(1-bromo-2,2-difluorocyclopropyl)benzene (3f)

Purification procedure: A; yield 79% (Method B);
19
F NMR (376 MHz):  -127.20 (ddd,
J = 148.8, 10.5, 4.5 Hz, 1F), -132.12 (ddd, J = 149.2, 13.1, 4.5 Hz, 1F);
1
H NMR (400
MHz):  7.53-7.44 (m, 2H), 7.42-7.31 (m, 3H), 2.25 (ddd, J = 14.0, 9.6, 4.8 Hz, 1H), 2.09
(ddd, J = 14.0, 9.6, 4.8 Hz, 1H);
13
C NMR (100.5 MHz):  136.16, 129.21, 128.86,
109.49 (t, J = 292.1 Hz, 1C), 34.10 (t, J = 11.9 Hz, 1C), 26.90 (t, J = 10.7 Hz, 1C). High
Resolution MS (EI): m/z for (C
9
H
7
BrF
2
): calculated 231.9699 found 231.9706.
1-(2,2-difluorocyclopropyl)-4-methoxybenzene (3j)

Purification procedure: B; bp 92-95
o
C at 11mm; yield 82% (Method A), 85% (Method
B);
19
F NMR (376 MHz):  -126.72 (dtd, J = 153.4, 13.1, 3.7 Hz, 1F), -142.85 (ddd, J =
153.4, 12.4, 4.5 Hz, 1F);
1
H NMR (400 MHz):  7.16 (td, J = 8.8, 3.2 Hz, 2H), 6.87 (td, J
= 8.8, 2.8 Hz, 2H), 3.80 (s, 3H), 2.64-2.76 (m, 1H), 1.71-1.85 (m, 1H), 1.48-1.61 (m,
1H);
13
C NMR (100.5 MHz):  158.73, 129.152 (t, J = 1.1 Hz, 2C), 125.57, 113.87,
112.71 (dd, J = 286.8, 283.8 Hz, 1C), 55.20, 26.42 (t, J = 11.3 Hz, 1C), 16.86 (t, J = 10.5
44

Hz, 1C). High Resolution MS (EI): m/z for (C
10
H
10
F
2
O): calculated 134.0907 found
134.0907.
(2,2-difluoro-1-(2-methyl-2-phenylpropyl)cyclopropyl)benzene (3k)

Purification procedure: A; yield 78% (Method A), 83% (Method B);
19
F NMR (376
MHz):  -133.10 (ddd, J = 148.1, 13.1, 4.8 Hz, 1F), -136.83 (dd, J = 147.7, 12.4 Hz, 1F);
1
H NMR (400 MHz):  7.01-6.78 (m, 10H), 2.11 (d, J = 15.2 Hz, 1H), 1.82 (d, J = 14.0
Hz, 1H), 1.29-1.19 (m, 1H), 0.95 (s, 3H), 0.83-0.76 (m, 1H), 0.82 (s, 3H);
13
C NMR
(100.5 MHz):  148.49, 137.52 (t, J = 2.7 Hz, 1C), 129.36 (d, J = 2.2 Hz, 2C), 128.11,
127.88, 126.95, 125.91, 125.58, 113.66 (dd, J = 289.6, 286.3 Hz, 1C), 46.62 (dd, J = 4.4,
2.2 Hz, 1C), 38.26 (d, J = 2.1 Hz, 1C), 33.86 (t, J = 9.6 Hz, 1C), 30.45, 27.98, 21.16 (t, J
= 9.6 Hz, 1C) . High Resolution MS (EI): m/z for (C
19
H
20
F
2
): calculated 286.1533 found
286.1533.
2',2'-difluoro-6,6-dimethylspiro[bicyclo[3.1.1]heptane-2,1'-cyclopropane] (3l)

Purification procedure: B; bp 81-84
o
C at 10mm; yield 79% (Method A), 88% (Method
B);
19
F NMR (376 MHz):  -138.50- -137.90 (m, 1F), -141.00- -140.35 (m, 1F);
1
H
NMR (400 MHz):  2.16-2.33 (m, 2H), 1.82-2.04 (m, 3H), 1.65-1.72 (m, 1H), 1.42 (d, J
45

= 10.0 Hz, 1H), 1.25-1.35 (m, 1H), 1.23 (m, 1H), 1.03-1.11 (m, 2H), 0.97 (s, 3H);
13
C
NMR (100.5 MHz):  144.43 (dd, J = 292.5, 285.8 Hz, 1C), 43.72, 40.37, 39.77 (d, J =
3.6 Hz, 1C), 30.11 (t, J = 9.7 Hz, 1C), 27.33, 26.25, 23.93 (t, J = 9.4 Hz, 1C), 23.25,
21.46, 20.16 (dd, J = 5.5, 1.1 Hz, 1C). High Resolution MS (EI): m/z for (C
11
H
16
F
2
):
calculated 184.0700 found 184.0697.

46

1
H
13
C
(3f)
47

19
F
48

1
H
13
C
(3m)
49

19
F
50

1
H
13
C
(3n)
51

19
F
52

2.5 Chapter 2: References
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(28) Ruppert, I.; Schlich, K.; Volbach, W. Tetrahedron Lett. 1984, 25, 2195.
(29) Prakash, G. K. S.; Krishnamurti, R.; Olah, G. A. J. Am. Chem. Soc. 1989, 111,
393.
(30) Prakash, G. K. S.; Yudin, A. K. Chem. Rev. (Washington, D. C.) 1997, 97, 757.
(31) Prakash, G. K. S.; Mandal, M. J. Fluor. Chem. 2001, 112, 123.
(32) Prakash, G. K. S.; Hu, J.; Olah, G. A. J. Org. Chem. 2003, 68, 4457.
(33) Liu, X.; Xu, C.; Wang, M.; Liu, Q. Chem. Rev. 2014.
(34) Tomashenko, O. A.; Grushin, V. V. Chem. Rev. (Washington, DC, United States)
2011, 111, 4475.
(35) Lundgren, R. J.; Stradiotto, M. Angew. Chemie, Int. Ed. 2010, 49, 9322.
54

(36) Miyaura, N.; Yamada, K.; Suzuki, A. Tetrahedron Lett. 1979, 20, 3437.
(37) Miyaura, N.; Suzuki, A. J. Chem. Soc. Chem. Commun. 1979, 866.
(38) Adams, J.; Kauffman, M. Cancer Invest. 2004, 22, 304.
(39) Fujioka, Y.; Amii, H. Org. Lett. 2008, 10, 769.

55

3. Chapter 3: An Introduction to the Mizoroki-Heck
Coupling Reaction

3.1 Chapter 3: Introduction
Palladium catalyzed cross-coupling reactions have an enormous impact in
synthetic organic chemistry. Despite being an expensive metal, palladium catalysts have
been widely used, largely due to their ease of handling and storage, and low toxicity.
While early research with palladium involved its use in stoichiometric amounts, its high
price led to the development of various catalytic reactions. Several carbon-carbon bond
forming reactions employ Pd-catalyzed reactions and many of these reactions have
attained immense popularity and widespread use and have led to more than a dozen
‘Name’ reactions, and several books and reviews.
1–4
In 2010, in recognition “for
palladium catalyzed cross-coupling reactions in organic synthesis”, R. F. Heck, E-i
Negishi, and A. Suzuki were jointly awarded the 2010 Nobel Prize in Chemistry.
5
Since
the invention of the palladium catalyzed Wacker process in 1958,
6,7
the field of
organopalladium chemistry has grown exponentially, beginning with the discovery of the
Mizoroki-Heck reaction. Discovered independently by Mizoroki
8
and Heck
9
in 1971, the
cross coupling between aryl iodides and alkenes was the first palladium-catalyzed
carbon-carbon bond forming reaction.
10

The discovery of the Mizoroki-Heck reaction led the way for the development of
other palladium catalyzed cross-coupling reactions including the Negishi reaction
11
(aryl
56

halides and organozinc reagents), Suzuki reaction
12–14
(arylboronic acids and aryl/vinyl
halides), Stille coupling
15
(organotin compounds), and Sonogoshira coupling
16,17

(organosilicate compounds) to name a few. These reactions predominantly occur between
two sp
2
hybridized carbon atoms, and recent research is expanding the scope of these
reactions to include sp
3
hybridized carbon atoms as well.
This chapter will discuss various aspects of the Mizoroki-Heck coupling reaction,
including the mechanism, solvent effects, modern techniques, and applications in organic
synthesis.
3.2 Chapter 3: Mizoroki-Heck Coupling Reactions
3.2.1 History
In 1967, Fujiwara and co-workers discovered that pre-synthesized styrene-
palladium(II) chloride complex with benzene in acetic acid under reflux led to the
formation of stilbene.
18
This was the first carbon-carbon bond forming reaction mediated
by an organopalladium species, but palladium(II) chloride had to be used in a
stoichiometric amount to generate the ‘active’ complex. In 1969, Heck developed another
reaction utilizing stoichiometric palladium salts with olefins and organomercury
compounds to facilitate the corresponding carbon-carbon bond formation and synthesize
various olefinic compounds.
19

In an extension of this work, Mizoroki in 1971 discovered a palladium-catalyzed
process using palladium(II) chloride (PdCl
2
) and potassium acetate as an acceptor for the
57

HI formed in the reaction (Scheme 3.1, eq. 1).
8
Heck, in 1972, independently reported the
palladium- catalyzed reaction of iodobenzene and substituted iodobenzenes with various
olefins using palladium(II)acetate (Pd(OAc)
2
) as the catalyst (Scheme 3.1, eq. 2).
9
The
reaction yielded the coupled product in good yields and Heck discovered that aryl iodides
were much more reactive than aryl bromides while aryl chlorides remained unreactive.
Benzyl and styryl halides were also found to react under the reaction conditions, although
longer reaction times and lower yields of product were obtained. In 1974, Heck extended
the methodology and used phosphine ligands to further improve the scope of the reaction.
In the presence of tetrakistriphenylphosphine palladium (Pd(PPh
3
)
4
), bromobenzene
reacted with highly electron deficient alkenes such as methyl acrylate to give the coupled
product in very good yields.
20

Scheme 3.1 Intital Reactions Performed by Mizoroki and Heck

58

3.2.2 Mechanism
The reaction between organomercury salts (ArHgX, X= Cl, OAc) and alkenes in
the presence of stoichiometric amounts of palladium salts (PdCl
2
or Pd(OAc)
2
) was
shown to result in the carbon-carbon coupled product (Ar-alkene) in good yields.
19
A
mechanism was proposed involving the in situ formation of arylpalladium salts (Ar-Pd-X,
X= Cl, OAc) from ArHgX and PdX
2
(X= Cl, OAc). The alkenes were then proposed to
undergo a syn insertion into the aryl-palladium bond, followed by a β-hydride elimination
and expulsion of the hydridopalladium species (H-Pd-X) yielding the coupled product.
19

In 1971, as mentioned earlier, Mizoroki and co-workers demonstrated a similar
coupling reaction involving aryl halides and alkenes, with palladium(II) chloride as a
catalyst. They also proposed that palladium(0) particles, formed in situ in the reaction
mixture was the active catalyst. In 1972, Heck and co-workers demonstrated a similar
reaction using palladium(II) acetate as a catalyst and tri-n-butylamine (n-Bu
3
N) as base
(Scheme 3.1). Based on prior research on the formation of a palladium(II) species,
obtained by the oxidative addition of palladium into the Ar-X bond, Heck proposed a
mechanism, wherein palladium inserts into the Ar-I bond of iodobenzene in the initial
step of the coupling reaction.
9,20

The complete mechanism of the Heck reaction was proposed by Dieck and Heck
in 1974 for reactions catalyzed by palladium associated with a phosphine ligand.The
catalytic cycle involves the following steps (Figure 3.1).
10,20,21

59

1. Following the reduction of the Pd(II) catalyst to a Pd(0) species, the first step of
the catalytic cycle is an oxidative addition of the aryl halide to the Pd(0) species.
Under identical reaction conditions, the order of reactivity for aryl halides has
been found to be Ar-I>Ar-Br>>Ar-Cl. Based on this, the oxidative addition step
has been suggested as the rate determining step for less reactive arylhalides. The
oxidative addition yields σ-arylpalladium(II) halide (trans-ArPdXL
2
) (Figure 3.1,
A).
2. A then undergoes disassociation of one of the ligands, followed by complexation
to the alkene and a syn insertion of the alkene leading to the formation of a σ-
alkylpalladium(II) halide (Figure 3.1, B). This step of the catalytic cycle is
referred to as carbopalladation.
3. An internal carbon-carbon bond rotation in B sets up a β-hydride syn to Pd, which
then leads to a syn-β-hydride elimination resulting in the expulsion of the H-Pd-
XL
2
(Figure 3.1, D) species and the formation of the desired coupled product.
4. In the final step, the base reduces the H-Pd-XL
2
(Figure 3.1, D) species to Pd(0)
in the reductive elimination step. The regeneration of the active Pd(0) species sets
up the next cycle.

60

Figure 3.1 Mechanism of the Mizoroki-Heck Reaction
3.2.3 Regioselectivity in the Mizoroki-Heck Reaction
Of the four steps in the catalytic cycle of the Mizoroki-Heck coupling reaction,
the formation of the π-complex and the subsequent insertion to form the σ-
alkylpalladium(II) halide (B) is key in determining the regiochemical outcome of the
reaction.
22,23
There are two possible regiochemical outcomes of the coupling reaction;
61

one where the R group yields an internal alkene- the α-product, or where the R group
yields the terminal alkene- the β-product.
Steric and electronic factors determine the regiochemical outcome of the coupling
reaction. Electron-poor alkenes react very well, and undergo a syn β-hydride elimination
to yield the trans-isomer with the β-substituted compound. The regiochemistry of the
product is not as clear-cut in the case of electron-rich alkenes. The product is usually a
mixture of the α-substituted product along with the cis- and trans- isomers of the β-
product.
24

The formation of the palladium(II) complex is the central factor that determines
the stereoselectivity, regioselectivity, reaction rate, and even the yield of a given reaction.
The active complex in the Mizoroki-Heck coupling reaction is a 14-electron Pd(0)L
2

species. The geometry of the complex is square planar and the insertion of the alkene
requires the palladium and the alkene to be coplanar, and this results in a syn-insertion in
a stereoselective manner.
22,23

There are two distinct pathways for the insertion of alkenes into the palladium(II)
complex (Figure 3.1; A). In the first scenario, the alkene complexes with the palladium
via the disconnection of one of the ligands L. In the second scenario, the alkene
complexes via the dissociation of the halide of the starting haloarene. These two
scenarios lead to the formation of two different types of palladium(II) complexes- a
neutral species in the first case and a cationic species in the second (Figure 3.2).
22,23

62

Figure 3.2 The Cationic and Neutral Mizoroki-Heck Routes for Electron Rich Alkenes
(Copied with permission from The Mizoroki-Heck Reaction, WILEY-VCH, Figure 3.1)
It has been shown both by experimental work and by computational studies that
the nature of the palladium complex determines the product outcome when an electron-
rich alkene is involved. In case of the positively charged complex, the complex is
stabilized by an electron-rich ligand such as a phosphine or an amine. This leads to the
formation of the α-product. In the case of the neutral complex, the palladium is stabilized
by one ligand and the halide, and yields a mixture of α- and β- substituted products.

63

3.3 Chapter 3: Mizoroki-Heck Reactions with Modern Solvent
Systems and Techniques
One of the biggest challenges in organic synthesis these days is waste
management. It is becoming increasingly important to reduce the amount of waste
material generated from a reaction after the isolation of the product. One way to address
this issue is to use catalytic systems in place of stoichiometric systems. Efficiencies of
chemical reactions are measured on the basis of three characteristics- reaction volume,
atom economy and the E-factor. The E-factor is defined as the ratio of kilograms of by-
product per kilogram of product. The lower the E-factor, the lower the amount of waste
generated from the process.
25,26
The Mizoroki-Heck coupling when carried out on a large
scale uses stoichiometric amount of base and as a result, a large amount of acid is
generated at the end of the reaction that needs to be neutralized.
27
Traditional solvents
used in the Mizoroki-Heck coupling are also seldom reused and long reaction times at
high temperatures results in higher energy costs.
In recent times, several research groups are working on improving the preparative
utility of the Mizoroki-Heck reaction by the use of alternate solvents such as ionic
liquids, supercritical fluids (SCFs), and water among others. Energy efficiency has also
been improved by the use of microwave systems and ultrasound.
3.3.1. Modern Solvent Systems:
The Mizoroki-Heck coupling reaction usually employs polar solvents along with
salt additives, which help to stabilize the active metal catalyst. With a focus on green
64

chemistry, newer solvent systems are being developed and used. Among these are ionic
liquids, supercritical liquids (SCFs), fluorous solvents, and water.
Ionic liquids are salts that exist in a liquid state. Their physical properties are
tunable depending on the properties of the anion or cation. Most ionic liquids dissolve
organometallic catalyst precursors, which makes it an effective reaction medium.
28,29
The
product separation from such a reaction is simple and the catalyst recovery is also fairly
simple as it stays dissolved in the ionic liquid for further reactions. The first Mizoroki-
Heck coupling reaction using ionic liquids was carried out by Kaufmann et. al. in 1996.
30

Since this initial reaction several other research groups have successfully utilized ionic
liquids both as reaction media and as ligands on palladium metal to increase reaction
efficacy.
Supercritical fluids have also been used as convenient solvents for large scale
synthesis for a long time. Supercritical CO
2
(scCO
2
) and water (scH
2
O) are the most
commonly used solvents in this category.
31
Supercritical fluids conform very well with
the principles of ‘green’ or sustainable chemistry. They are non-flammable and non-toxic
materials and this provides environmental and safety advantages, but the cost of
equipment and energy needed to carry out reactions are big drawbacks.
31
scCO
2
has a
critical temperature of 31
o
C and a critical pressure of 73.8 bar which are relatively mild
conditions to carry out reactions.
32,33
The non-toxicity of scCO
2
and its inertness to
chemical transformation also make it an appealing ‘green’ solvent. However, Mizoroki-
65

Heck coupling reactions carried out in scCO
2
are comparable to results of similar
reactions in toluene in the presence of specific ligands.
3.3.2. Mizoroki-Heck Reactions in Water as the Solvent:
In efforts to make organometallic coupling reactions greener, the use of water as
solvent is always favorable. However, this is not a very easy task as most substrates and
reagents in reactions are hydrophobic, as are the catalyst systems and ligands. The
stability of active catalyst species in water is also another limitation. Despite the
difficulties of using water as a suitable solvent in coupling reactions, many research
groups have worked on this problem. Several research articles and reviews document the
use of water in Mizoroki-Heck coupling reactions.
34–37
As will be shown below, most of
this research involves the use of some additional compounds such as phase transfer
catalysts (PTC), micelles, resins, or polymer supports for the catalysts.
38,39

One of the early instances of the Mizoroki-Heck coupling reaction with water as
the reaction medium was reported by Jeffry in 1994 (Scheme 3.2, eq. 1).
40
He
demonstrated that methyl acrylate and iodobenzene could be successfully coupled using a
catalytic amount of palladium acetate and triphenylphosphine (PPh
3
), in neat water with
alkali metal carbonate as base, albeit in the presence of tetraalkylammonium salts as
phase transfer agents (PTA). The reaction was carried out at room temperature and good
yields of the coupled product were obtained. In the absence of the PTA, almost no
product was observed, even with heating.
40
It can be inferred that the PTA provides an
‘organic interface’ for the reaction to successfully take place. In the following year,
66

Bumagin and co-workers reported the Heck coupling between haloarenes and styrene or
acrylic acid at 100
o
C in neat water with no PTA and sodium carbonate as base (Scheme
2, eq. 2). Palladium acetate or palladium chloride was used as the catalyst in fairly low
loading with PPh
3
as the ligand.
41

Scheme 3.2 Mizoroki-Heck Reactions in Water as the Only Solvent
Bhattacharya
42
et. al. and Lipshutz
43
et. al. are among research groups that have
popularized the use of surfactant in coupling reactions. The first micellar system for the
Heck coupling was reported by Bhattacharya et. al. when they used stoichiometric
amounts of the cationic surfactant CTAB to stabilize the palladium nanoclusters that were
formed during the course of the reaction (Scheme 3.3, eq. 1).
42
Lipshutz and co-workers
have used an amphiphilic surfactant called PTS in upto 15 wt% with respect to water in
the room temperature coupling reaction between iodobenzenes and acrylates. Upon
further investigation, they were also able to reduce the amount of PTS to less than 5 wt%
in water (Scheme 3.3, eq. 2).
43

67

Scheme 3.3 Mizoroki-Heck Reactions in Water Mediated by Surfactants
Several other groups have also researched the use of polymer supported palladium
catalysts in Heck coupling reactions. These heterogeneous palladium catalysts have a
distinct advantage of easy removal and recycling by simple filtration of the reaction
mixture.
44
However, the catalysts can also leach out some metal particulates upon
increased reuse and this can prove to be a problem. In 2002, Uozumi
45
reported the use of
polymer supported palladium catalysts in the reaction between iodobenzene and acrylic
acid. Of the various polymeric supports that he tested, the most active one was a
68

palladium chloride catalyst supported through a chelating phosphine to an amphiphilic
polymer support consisting of a polystyrene-polyethyleneglycol (PS-PEG) resin (Scheme
3.4, eq. 1). The reaction was completed in 20h at room temperature. The catalyst was
recovered by simple filtration and reused in five consecutive runs yielding the coupled
product in an average yield of 90%.
45,46
In another instance, a self assembled palladium
catalyst was used in extremely low loading in the coupling reaction of iodoarenes and
acrylates with TONs up to 1150000 and TOFs between 1200 and 12000 h
-1
(Scheme 3.4,
eq. 2).
47

Scheme 3.4 Polymer Supported Catalysts in Mizoroki-Heck Coupling Reactions in
Water

69

3.3.3. Modern Techniques:
Lowering of energy costs is of broad interest in organic synthesis. The Mizoroki-
Heck coupling reaction is usually carried out over a long period of time at high
temperatures. Alternate sources of energy can offer new possibilities for different
reaction pathways and different reaction outcomes and are being increasingly studied.
The use of ultrasound is one of the newer methods for energy input being studied.
Ultrasound has been shown to change reaction pathways and influence mechanical
effects of reaction systems.
48
Reactions proceeding via single electron transfer are
particularly affected by the application of ultrasound.
49
In one example of a Mizoroki-
Heck coupling catalyzed by palladium nanoparticles, it has been shown that a reaction
between iodobenzene and methyl acrylate in water yielded 86% of the desired product
under sonochemical conditions versus 10% under conventional methods.
50

Microwave irradiation is another method that is used to improve the energy
efficiency of a reaction. It is important to note here that microwave irradiation does not
change the reaction pathway or chemistry of a reaction. In microwave heating, molecules
align according to the electric field through the orientation of their dipoles. This allows
for more uniform and faster heating by heating throughout the reaction volume. This can
lead to reduction in energy costs and reaction times.
51

The first microwave promoted Mizoroki-Heck coupling was reported in 1996 by
Larhed and Hallberg (Scheme 3.5).
52
They carried out various coupling reactions under
70

both conventional heating methods and by microwave irradiation. Results showed a 100-
fold reduction of reaction times by the use of microwaves without affecting yields of
desired products. Since then, many reactions have been reported describing the use of
microwave irradiation in Mizoroki-Heck coupling. Newer strategies in this regard
involve the use of solid-supported catalysts combined with microwaves.
53

Scheme 3.5 First Example of a Microwave Assisted Mizoroki-Heck Reaction
3.4 Chapter 3: Mizoroki-Heck Reactions in Domino Processes
The term ‘domino reactions’ was coined by Tietze and is defined as processes of
two or more bond forming reaction under identical reaction conditions, in which the
latter transformations take place at the functionalities obtained in the former bond
forming reactions.
54
The value of a domino process is measured in terms of the number
of transformations that occur; the greater the number of steps, the more valuable the
domino process. Domino processes are in general very useful in industrial applications
due to their ability to build complex molecules with minimal waste of material and
energy resources and time.
25-27

The Mizoroki-Heck reaction is one of many reactions that are catalyzed by
palladium catalysts, and thus can be easily be incorporated as part of a domino sequence
71

with reactions such as the Suzuki, Stille, and Sonogoshira coupling reactions, among
others.
57,58
Other palladium (0) catalyzed reactions such as the Tsuji-Trost reaction can
also be successfully applied.
59
The elegance and ease of domino reactions has been
demonstrated in the synthesis of estradiol (Figure 3.3).
60
The core tetracyclic system was
constructed in two steps from enantiopure starting materials via two palladium (0)
catalyzed Heck coupling reactions in excellent yields. The difference in reactivities of
aryl bromides to vinyl bromides has been exploited in this synthesis.

Figure 3.3 Total Synthesis of Estradiol via a Domino Heck/Heck Coupling Reaction
(Copied with permission from The Mizoroki-Heck Reaction, WILEY-VCH, Figure 8.1)

3.5 Chapter 3: Aim and Scope of Present Work
The award of the 2011 Nobel Prize in Chemistry to Heck, Suzuki and Negishi has
emphasized the importance of palladium catalyzed cross coupling reactions in organic
72

synthesis. This chapter describes the importance of the Mizoroki-Heck coupling reaction
in particular. Despite the large number of publications on the Heck coupling reaction, its
importance in synthetic organic chemistry remains unchanged. The palladium catalyzed
Heck ccoupling reaction is one of the most efficient methods to form a bond between two
sp
2
hybridized carbon atoms. The following chapters describe the Heck coupling reaction
as one of the key reactions in a domino process to synthesize important intermediates in
materials, agrochemical, and medicinal chemistry.
A newer application of the Mizoroki-Heck coupling reaction is in domino
reactions. The name ‘Domino’ reactions emerged due to the property of this reaction
sequence proceeding as if multiple pins in a domino. Several natural products and
biologically relevant molecules with complex architecture have been synthesized using a
domino sequence of reactions. Our aim in the following work was to synthesize
molecules that could serve as starting materials in pharmaceutical, agrochemical, and
materials sciences using a domino sequence of reactions.
In the following chapters, the Mizoroki-Heck reaction is the key reaction in a
domino sequence to synthesize various substituted styrenes. Groups that have heretofore
been difficult to incorporate into molecules such as the sulfonate, trifluoromethyl, and
fluoride have been successfully synthesized. The use of reagents that can easily handled
and a simple reaction set-up are the hallmark of this reaction sequence.

73

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(52) Larhed, M.; Hallberg, A. J. Org. Chem. 1996, 61, 9582.
(53) Kingston, H. M. S.; Haswell, S. J., Eds. Microwave-Enhanced Chemistry:
Fundamentals, Sample Preparation, and Applications. 1997, American Chemical
Society.
(54) Tietze, L. F.; Beifuss, U. Angew. Chemie Int. Ed. English 1993, 32, 131.
(55) Tietze, L. F. Chem. Rev. 1996, 96, 115.
76

(56) Domino Reactions: Concepts for Efficient Organic Synthesis; Tietze, L. F., Ed.;
Wiley-VCH, 2014.
(57) Vlaar, T.; Ruijter, E.; Orru, R. V. A. Adv. Synth. Catal. 2011, 353, 809.
(58) Tietze, L. F.; Levy, L. M. The Mizoroki-Heck reaction in domino processes.;
Oestreich, M., Ed.; 2009, John Wiley & Sons Ltd.
(59) Negishi, E.; Coperet, C.; Ma, S.; Liou, S.-Y.; Liu, F. Chem. Rev. 1996, 96, 365.
(60) Tietze, L. F.; Noebel, T.; Spescha, M. J. Am. Chem. Soc. 1998, 120, 8971.

77

4. Chapter 4: A Domino Approach (Hydrolysis/
Elimination/Mizoroki-Heck Coupling) Towards the
Synthesis of Styrene Sulfonate Salts

4.1 Chapter 4: Introducttion
Polymers functionalized with certain groups such as ammonium (NH
4
+
), and
sulfonate (SO
3
-
) are finding applications in multiple fields such as protein and
biomolecular synthesis, inks and coatings, and in material chemistry applications.
Polymers containing the sulfonate group, particularly, have found applications in a
variety of fields ranging from membranes in fuel cells, battery electrolytes and ion-
exchange membranes.
1
The sulfonate group is also being used to help build protein
libraries with new functional groups.
2
Separation of transition metal catalysts from
reaction mixtures of atom transfer radical polymerization (ATRP) is one of the main
applications of polymers containing the sulfonate group as it is more economically viable
than other technologies.
3,4,5
A big part of current research into these materials involves
their use as proton exchange membranes (PEMs) for fuel cells. The most common
membrane used in fuel cells are perfluorosulfonic acid (PFSA) polymer membranes such
as Nafion
®
(DuPont).
6
These membranes are readily available, and have good mechanical
strength and stability. However, they are expensive and the difficulty in their synthesis
and processing is a major drawback. Sulfonated styrenes co-polymerized with other
monomers have been shown as efficient alternatives to Nafion
®
.
1,7

78

As a part of our continuing interest in making proton exchange membranes for
fuel cell and material chemistry applications,
6,8
we have focused on the development of
new synthetic methodologies for the direct synthesis of styrenesulfonic acid salts. These
styrenesulfonic acid salts can serve as monomers for the synthesis of various polymer
sulfonates that can serve as novel proton exchange membranes in the direct methanol fuel
cell (DMFC).
The synthesis of styrenesulfonate salts have been carried out by other research
groups in the past. Quilico et. al.
9
reported the first synthesis, wherein styrene was reacted
with sulfamic acid (NH
2
SO
3
H) at 150
o
C and upon work-up with ether gave the
ammonium salt of styrene sulfonic acid (Scheme 4.1, eq. 1). Following this paper, other
groups reacted ammonium sulfate and sodium sulfite with styrene to obtain the
ammonium
10
and sodium
11
salts, respectively. Bordwell et. al.,
12,13
and Terent’ev et. al,
14

independently came up with the idea of using complexes of SO
3
to sulfonate styrene, by
using dioxane:SO
3
and pyridine:SO
3
complexes, respectively (Scheme 4.1, eq. 2).
Makarova et. al. synthesized the potassium salt of styrene sulfonic acid via a two-step
process. 2-Bromoethylbenzene was treated with chlorosulfonic acid in the first step to
yield the ethanesulfonic acid, which in the presence of excess alcoholic base underwent
elimination and hydrolysis to yield the potassium styrenesulfonate (Scheme 4.1, eq. 3).
15

In our efforts to realize a convenient method for the synthesis of styrenesulfonate
salts, we decided to look into the Mizoroki-Heck coupling reaction as the key step. The
Heck reaction is one of the most efficient routes for the addition of a vinyl group to aryl
halides or triflates. Herein, we report the synthesis of potassium styrene sulfonate salts
79

from easily accessible iodoarenes (and bromobenzene) and 2-chloroethanesulfonyl
chloride via a novel domino, hydrolysis/ dehydrohalogenation/ Heck coupling pathway
using phosphine free palladium catalyst in only water with no additives.

Scheme 4.1 Methods for the synthesis of styrenesulfonate salts

4.2 Chapter 4: Results and Discussion:
Our initial idea was to synthesize styrene sulfonate salts via traditional Heck
coupling of iodoarenes and commercially available sodium vinyl sulfonate (Figure 4.1).
Commercially sourced sodium vinyl sulfonate is available as a 25% (w/w) solution in
water, and the initial reaction was therefore carried out in water as solvent

80

Figure 4.1 Proposed Synthetic Route for Styrene Sulfonate Salts
The initial reaction was carried out using iodobenzene, sodium vinyl sulfonate (1
equiv.), potassium carbonate (K
2
CO
3
) (1 equiv.) as base, and palladium acetate
(Pd(OAc)
2
) (2 mol%) as the catalyst. The Heck reaction is usually carried out at higher
temperatures (>100
o
C), and requires longer reaction times. Reactions carried out in
microwave reactors have been shown to reduce reaction times significantly. With this in
mind, the reaction was carried out in a microwave reactor at 180
o
C for 10 min (Scheme
4.2, (a)). While we were able to synthesize the corresponding styrene sulfonate salt from
a reaction between iodobenzene and commercially available sodium vinyl sulfonate in
moderate yield (~50%), purification of the product was a daunting task due to the
presence of an undesirable side product already present in the commercially available
sodium vinyl sulfonate. Analysis of the
1
H NMR of the starting material showed that the
undesirable compound was a mixture of salts of (2-hydroxyethane)sulfonic acid.
The difficulties in purifying the starting material led us to rethink our strategy of
using the commercially available alkene. Conventional Heck coupling is usually carried
out in strongly basic medium; incidentally, alkenes (or olefins) can also be formed via
dehydrohalogenation of a suitably substituted alkyl halide in strongly basic medium. We,
81

therefore, envisioned an initial dehydrohalogenation of a suitably substituted alkyl halide
to generate the olefin/ alkene in situ followed by a Pd-catalyzed Heck coupling under the
identical basic reaction conditions. We thought this would give us easy access to
arylation of olefins in a novel domino dehydrohalogenation/ Heck coupling reaction
(Figure 4.2). To the best of our knowledge, this was the first time that such a domino
reaction sequence was attempted.

Scheme 4.2 (a) Synthesis of Sodium Styrenesulfonate; (b) Hydrolysis of Sodium
Vinylsulfonate 1

Figure 4.2 Retrosynthetic Analysis of the Proposed Domino Sequence for the Synthesis
of Styrene Sulfonate Salts
82

To test our hypothesis of such a domino process, we set up a reaction between
iodobenzene and 2-chloroethanesulfonyl chloride (1 equiv.) (Commercially available) in
water (solvent) using palladium(II) acetate (2 mol%) as the precatalyst and potassium
carbonate (2 equiv.) as base. Once again, the reaction was carried out in a microwave
reactor to reduce the reaction time

Scheme 4.3 Hydrolysis/Elimination/Heck Domino Sequence for the Synthesis of Styrene
Sulfonate Salts

The initial reaction under these conditions showed promising results with the
formation of the desired styrenesulfonate salt product in ~45% yield (by analysis of the
crude
1
H NMR of the reaction mixture). The impurities, sodium(2-hydroxyethane
sulfonate) 1a and 1b observed in the initial Heck reaction was only observed in trace
amounts (<2%). Further optimization of the reaction was carried out to improve the yield
of the product (Table 4.1). While decreasing the equivalents of base had a detrimental
effect on the formation of the Heck coupled product, an increase in the amount of base
from 2 equiv. to 3 equiv. (Table 4.1, entry 1 vs. 2) showed an increase in the formation
of the desired product to ~85% yield by analysis of the crude
1
H NMR. Use of a weaker
inorganic base (NaHCO
3
) or organic base (triethylamine) resulted in inferior conversions
to the final product (via the Heck coupling reaction) (Table 4.1, entries 4 and 5). This
83

was confirmed by the presence of potassium vinyl sulfonate peaks (and complete absence
of 2-chloroethane sulfonyl chloride peaks) in the crude reaction mixture, which led us to
conclude that dehydrohalogenation had occurred successfully. Use of sodium carbonate
instead of potassium carbonate gave slightly lower yield (69% Na vs 85% K, Table 4.1,
entries 1 and 2).
In order to confirm the sequence of reactions- hydrolysis of the sulfonyl chloride
4, followed by elimination and Heck coupling, the domino sequence was carried out step-
by-step and the progress monitored via
1
H NMR. 2-Chloroethanesulfonylchloride 4 and
potassium carbonate (2 equiv.) were heated in a microwave reactor at 180
o
C for 10 min.
1
H NMR analysis showed the complete conversion of 4 to vinyl sulfonate salt 1, the
product of the hydrolysis and elimination reaction. Iodobenzene (1 equiv.), Pd(OAc)
2

(2mol%) and another equivalent of K
2
CO
3
were added and the same reaction mixture was
once again subjected to standard reaction conditions.
1
H NMR analysis showed the
presence of the desired styrene sulfonate product in ~82% conversion. The similar yields
obtained (single step vs. step-by-step) revealed that the reaction proceeds via a domino
process.
Buoyed by the success of the domino sequence of reactions, the methodology was
extended to other iodoarenes, but with limited success. Phosphine free palladium
catalysts, such as the one used here (palladium (II) acetate), have been shown to be very
active and efficient for Heck coupling prompting for the minimum catalyst loading in the
reaction. However, in the absence of any ligands, deactivation of the Pd(0) species to
generate ineffective palladium black in the reaction mixture is a well known process. This
84

could be due to various reasons such as difference in the reaction rates of the individual
steps of the catalytic cycle, temperature and change in concentration as well as
composition of the reaction mixture. However addition of fresh catalyst (1 mol%) to the
same reaction mixture followed by heating in microwave for another 10 min at 180 C
was found to be the solution to overcoming lower yields of products. The modified
protocol was applied to a variety of iodoarenes with different substituents on the aromatic
ring in order to study the steric and electronic effects on the outcome of the reaction
(Table 4.2).
Table 4.1 Optimization of Base for the Synthesis of Styrene Sulfonate Salts

Iodobenzene gave the desired styrene sulfonate salt in excellent yield (85%, Entry
1). Substituted iodobenzenes, with both electron-withdrawing (Table 4.2, entries 2, 11,
Entry Base Equivalents Conversion by
1
H NMR
(%)
1 K
2
CO
3
2 45
2 K
2
CO
3
3 85
3 Na
2
CO
3
3 69
4 NaHCO
3
3 55
5 Et
3
N 4 65
85

and 14) and electron-donating (Table 4.2, entries 3, 4, and 6) groups were also well
tolerated in this domino reaction sequence yielding corresponding styrene sulfonate salts
in moderate to excellent yields. 2-Aminoiodobenzene and 3-iodophenol (Table 4.2,
entries 13 and 17) did not react as expected, probably due to the electron rich amine
nitrogen and oxygen, which presumably poisons the palladium catalyst. The same is
probably the case with 2-iodobenzoic acid also, which completely fails to react. 2,6-
Dimethyl iodobenzene yields the product in only 61%, probably due to the steric
hindrance of two methyl groups during or after the palladium insertion into the arylC-I
bond and consequent coordination of the palladium species to vinyl sulfonate. On the
other hand, iodonaphthalene produced desired sulfonate salt in excellent yield (Table 4.2,
entry 9). Under the reaction conditions, 4-vinyliodobenzene (Table 4.2, entry 10)
underwent vinyl polymerization resulting in an inseparable mixture of the desired product
and the polymer.
Table 4.2 Substrate Scope of the Hydrolysis/Elimination/Heck Domino Reaction to
Synthesize Styrene Sulfonate Salts

86

Table 4.2 Continued

87

Table 4.2 Continued

88

To increase the scope of the title reaction, other halobenzenes were subjected to
identical reaction conditions. Unfortunately, bromobenzene gave the desired styrene
sulfonate salt in only 52% yield while chlorobenzene was completely unreactive under
the reaction conditions (Table 4.3). This follows the expected rate of reactivity of
haloarenes in the order ArI>ArBr>>ArCl.
Table 4.3 Comparison of Reactivities of Various Halobenzenes

.
Heteroaromatic sulfonate salts were also synthesized using this method albeit, in
lower yields. 2-Iodopyridine, 2-iodothiophene, and 2- iodopyrazine (Table 4.4, entries 1,
3, and 5) gave complex mixtures and were difficult to purify. Again, in all these cases
low yields could be due to catalyst poisoning because of presence of heteroatom at the
ortho position of C-I bond. Both 3-iodopyridine (Table 4.4, entry 2) and 5-iodoindole
(Table 4.4, entry 4), where the heteroatom is present farther away from the C-I bond
yielded the desired product in moderate yields. Unfortunately, 2-bromoimidazole did not
produce any of the desired product.
Entry Compound Isolated Yield (%)
1 Ph-I 86
2 Ph-Br 52
3 Ph-Cl 0
89

Table 4.4 Synthesis of Heteroaryl Sulfonate Salts

We also extended this methodology to disubstituted iodobenzenes and the results
are shown in Table 4.5. While 1,2-diiodobenzene gave a mixture of the desired
disulfonate salt and monosulfonate product (Table 4.5, entry 1), 1,3-diiodobenzene gave
corresponding desired product in good yield (Table 4.5, entry 2). In the case of 1,2-
diiodobenzene, formation of two simultaneous palladium insertion complexes at the 1
and 2 positions could be sterically demanding. Due to this steric hindrance, both Pd -
complexes cannot undergo β-hydride elimination which probably results in a side
reaction to produce monosubstituted product. Surprisingly, the biphenyl system (Table
4.5, entry 3) gave desired product only in 29% yield. Substituted diiodobenzenes such as
90

2,3,5,6-tetrafluoro- and 2,3,5,6-tetramethyl-1,4-diiodobenzene (Table 4.5, entries 4 and
5, respectively) gave the corresponding products in moderate to good yields. However,
for all the diiodo substrates longer reaction times (30 mins) were required to obtain better
conversions and yields.
Table 4.5 Synthesis of Aryl-bis-Sulfonate Salts

91

In an attempt to generate precursors for proton exchange membranes for the fuel
cell material applications, compounds 1, 11, and 14 were hydrogenated to give the
corresponding ethane sulfonate salts in excellent yields.

4.3 Chapter 4: Conclusions
In summary, we have shown that various styrene sulfonates can be conveniently
synthesized by a novel domino approach, which involves the initial formation of the
alkene in situ followed by Heck coupling. This synthetic protocol does not involve any
phosphine catalysts, uses only water as solvent and it does not require any further
additives. Therefore, it can draw significant attention as an efficient, environmentally
friendly synthetic method towards the synthesis of styrenesulfonate salts.
Mechanistically, we propose the hydrolysis of 2-chloroethanesulfonyl chloride to the
corresponding sulfonate salt to be the initial step under aqueous basic conditions. This is
followed by base induced elimination (dehydrohalogenation) of corresponding 2-
chloroethanesulfonate at higher temperatures to generate vinyl sulfonate in situ which
would be inserted into the well-known Heck coupling catalytic cycle to give desired
Heck-coupled product in an overall three-step reaction.

4.4 Chapter 4: Experimental
4.4.1 General
Commercially available palladium (II) acetate, potassium carbonate, and 2-
chloroethanesulfonyl chloride (Aldrich) were used without further purification. All
92

reactions were carried out using deionized water as solvent. Biotage Initiator 1 was used
as a source of microwave irradiation.
1
H,
13
C,
19
F NMR (CFCl
3
as reference) was
recorded on Varian Inova 400 MHz instrument with D
2
O as reference (few drops of
Acetone-d6 for
13
C as reference). For compounds with low solubility in D
2
O, water
suppressed
1
H NMR (wet 1D) experiment was performed. Unless otherwise specified, all
the
1
H NMR spectra were run as regular (water non-suppressed)
1
H NMR experiments.
Chemical shifts are reported in ppm. HRMS data were obtained from University of
Arizona Mass Spectrometry Facility. IR spectra for all compounds were recorded on a
Jasco FTIR-4100 instrument using KBr pellets. IR absorption values are reported in cm
-1
.
4.4.2 General Experimental Procedure
To a 20 ml microwave vial with a magnetic stir bar was added anhydrous K
2
CO
3

(1.015 g, 7.35 mmol), palladium(II) acetate

(Pd(OAc)
2
) (0.011 g, 0.049 mmol, 2 mol%)
and iodobenzene (0.5 g, 2.45 mmol) in that order followed by 15 ml of deionized water.
This reaction mixture was stirred at room temperature until all of the K
2
CO
3
was
dissolved, after which 2- chloroethanesulfonyl chloride (0.281 ml, 2.45 mmol, neat) was
added to the reaction mixture dropwise. The vial was sealed and heated in a microwave
for 10 min at 180
o
C. The vial was then opened and a fresh portion of Pd(OAc)
2
(5.5 mg,
0.024 mmol, 1 mol%) was added to the reaction mixture. The vial was then resealed and
heated in a microwave under the same conditions.
Work-Up Procedure:
The reaction mixture was filtered under vacuum to remove Pd(0) and the vial was
washed with water and dichloromethane. The filtrate was then extracted with
93

dichloromethane (3 x 10 ml) and the water extract was evaporated under reduced
pressure to obtain the crude product as a solid. Purification of the crude product was done
in three different ways depending on the substrate.
Procedure A: The solid was redissolved in a 1:1 v/v mixture of acetone and water
to remove an impurity which was formed in the form of oil. This process was repeated
until all the traces of impurity were removed. The supernatant liquid was then
evaporated under reduced pressure to obtain a light yellow solid. The solid was dissolved
in 3-5 ml water and acetone (3 x 25 ml) was then added to precipitate out the desired
product as a crystalline white solid. The solid was collected by vacuum filtration, air
dried.
Procedure B: Crude product obtained after workup was dissolved in minimum
amount of water (1-1.5 ml), recrystallized, and filtered to collect pure product which was
washed with 1-2 ml of acetone and air-dried.
Procedure C: Crude product obtained after workup was put under soxhlet
extraction apparatus for 24-48 hours with acetone as solvent to remove unreacted
potassium vinyl sulfonate. Crude obtained after soxhlet extraction, was dissolved in
minimum amount of water (1-1.5 ml) and filtered to collect pure product which was
washed with 1-2 ml of acetone and air-dried.

4.4.3 Spectral Data and Representative Spectra
The
1
H and
13
C NMR spectra for compound 3a was consistent with that reported in
literature
13

94

Potassium (E)-2-(3-nitrophenyl)ethenesulfonate (3b)

Purification method: A;
1
H NMR (400 MHz):  8.38 (s, 1H), 8.23 (dd, J = 8.3, 2.3 Hz,
1H), 7.92 (d, J = 7.8 Hz, 1H), 7.64 (t, J = 8.0 Hz, 1H), 7.36 (d, J = 15.7 Hz, 1H), 7.14 (d,
J = 15.7 Hz, 1H);
13
C NMR (100.5 MHz):  150.94, 138.73, 136.46, 135.24, 135.15,
132.93, 126.26, 124.60; IR(cm
-1
): 1638, 1535, 1350, 1251, 118, 1177, 1052, 957, 813,
728, 643; High resolution MS (EI): m/z for (C
8
H
6
KNO
5
S): calculated 227.9972 found
227.9972.
Potassium (E)-2-(2-methoxyphenyl)ethenesulfonate (3c)

Purification method: A;
1
H NMR (400 MHz):  7.56 (m, 2H), 7.46 (m, 1H), 7.09 (m,
3H), 3.92 (s, 3H);
13
C NMR (100.5 MHz):  157.37, 131.77, 131.44, 128.72, 128.28,
121.73, 121.00, 111.78, 55.54; IR (cm
-1
): 1623, 1594, 1491, 1461, 1431, 1255, 1196,
1052, 971, 876, 750; High resolution MS (EI): m/z for (C
9
H
9
KO
4
S): calculated 213.0227
found 213.0228.
Potassium (E)-2-m-tolylethenesulfonate (3d)

Purification method: A;
1
H NMR (400 MHz):  7.33 (m, 3H), 7.27 (d, J = 15.7 Hz, 1H),
7.20 (m, 1H), 6.99 (d, J = 15.7 Hz, 1H) , 2.32 (s, 3H);
13
C NMR (100.5 MHz):  138.84,
95

136.28, 133.36, 130.64, 128.89, 128.21, 127.82, 124.84, 20.36; IR (cm
-1
):1653, 1579,
1413, 1376, 1214, 1177, 964, 838,772; High resolution MS (EI): m/z for (C
9
H
9
O
3
S):
calculated 197.0278, found 197.0278.

Potassium (E)-2-o-tolylethenesulfonate (3f)

Purification method: A;
1
H NMR (400 MHz):  7.60 (m, 2H), 7.32 (m, 3H), 6.91 (d, J =
15.6 Hz, 1H), 2.40 (s, 3H);
13
C NMR (100.5 MHz):  137.22, 133.04, 132.61, 130.75,
129.96, 129.66, 126.54, 126.32, 18.98; IR (cm
-1
): 3463, 3059, 1631, 1487, 1245, 1196,
1050, 736, 642; High resolution MS (EI): m/z for C
9
H
9
O
3
S, calculated 197.0278, found
197.0274.
Potassium (E)-2-(2,6-dimethylphenyl)ethenesulfonate (3g)

Purification method: A;
1
H NMR (400 MHz):  7.43 (d, J = 16 Hz, 1H), 7.17 (m, 3H),
6.59 (d, J = 16 Hz, 1H), 2.35 (s, 6H);
13
C NMR (100.5 MHz):  138.94, 138.00, 136.20,
134.73, 130.49, 130.25, 22.75; IR (cm
-1
): 1627, 1472, 1446, 1384, 1244, 1192, 1159,
1045, 982, 761; High resolution MS (EI): m/z for (C
10
H
11
O
3
S): calculated 211.0434,
found 211.0434.

96

Potassium (E)-2-(4-methoxy-3-nitrophenyl)ethenesulfonate (3h)

Purification method: A;
1
H NMR (400 MHz):  8.13 (d, J = 2.3 Hz, 1H), 7.92 (dd, J =
8.8, 2.3 Hz), 7.41 (d, J = 8.9 Hz, 1H), 7.29 (d, J = 15.7 Hz, 1H), 7.06 (d, J = 15.7 Hz,
1H), 4.06 (s, 3H);
13
C NMR (100.5 MHz):  156.01, 141.24, 136.80, 135.67, 131.90,
127.35, 117.21, 59.33; IR (cm
-1
): 3469, 3056, 2950, 1623, 1533, 1275, 1240, 1195, 1055,
1006, 916, 635, 532; High resolution MS (EI): m/z for C
9
H
8
NO
6
S, calculated 258.0078,
found 258.0073.
Potassium (E)-2-(naphthalen-1-yl)ethenesulfonate (3i)

Purification method: A;
1
H NMR (400 MHz):  8.72 (d, J = 8.5 Hz, 1H), 8.54 (d, J = 15.4
Hz, 1H), 8.40 (m, 2H), 8.28 (d, J = 7.2 Hz, 1H), 8.10 (m, 1H), 8.03 (m, 2H), 7.54 (d, J =
15.4 Hz, 1H);
13
C NMR (100.5 MHz):  133.60, 133.07, 131.55, 131.15, 130.89,
129.35, 128.53, 126.78, 126.17, 125.76, 124.69, 123.43; IR (cm
-1
): 1642, 1407, 1238,
1190, 1051, 970, 955, 790; High resolution MS (EI): m/z for C
12
H
9
O
3
S, calculated
233.0278, found 233.0274.
Potassium (E)-2-(2-fluorophenyl)ethenesulfonate (3k)

Purification method: A;
1
H NMR (400 MHz):  7.63 (dt, J = 7.7, 1.6 Hz, 1H), 7.45 (m,
2H), 7.27 (t, J = 7.7 Hz, 1H), 7.19 (m, 1H), 7.12 (d, J = 15.8 Hz, 1H);
13
C NMR (100.5
97

MHz):  160.82 (d, J

= 272 Hz, C-F), 131.68 (d, J

= 9 Hz), 129.17, 127.94, 125.07,
121.58, 116.06 (d, J

= 21 Hz);
19
F NMR (376 MHz):  -116.35 (ddd, J = 11.2, 7.6, 5.4
Hz, 1F); IR (cm
-1
): 1634, 1579, 1495, 1455, 1403, 1223, 1183, 1054, 951, 830, 753; High
resolution MS (EI): m/z for C
8
H
6
FO
3
S, calculated 201.0027, found 201.0025.
Potassium (E)-2-(4-fluorophenyl)ethenesulfonate (3m)

Purification method: A;
1
H NMR (400 MHz):  7.62 (dd, J = 8.6, 5.6 Hz, 2H), 7.35 (d, J
= 15.7 Hz, 1H), 7.22 (t, J = 8.9 Hz, 2H), 7.00 (d, J = 15.7 Hz, 1H);
13
C NMR (100.5
MHz):  163.37 (d, J

= 247 Hz, C-F), 135.33, 129.80 (d, J

= 9 Hz), 129.73 (d, J

= 3 Hz),
127.55, 115.81 (d, J

= 22 Hz);
19
F NMR (376 MHz):  -110.4 (sep, 1F); IR (cm
-1
): 1638,
1509, 1410,1374, 1212, 1186, 1164, 973; High resolution MS (EI): m/z calculated for
201.0027 found 201.0027.
Potassium (E)-2-(3-(trifluoromethyl)phenyl)ethenesulfonate (3n)

Purification method: A;
1
H NMR (400 MHz):  7.62 (s, 1H), 7.56 (d, J = 7.7 Hz, 1H),
7.45 (d, J = 7.7 Hz, 1H), 7.36 (t, J = 7.8 Hz, 1H), 7.12 (d, J = 15.7 Hz, 1H), 6.89 (d, J =
15.7 Hz, 1H);
13
C NMR (100.5 MHz):  134.80, 134.56, 131.26, 130.49 (d, J

= 32 Hz),
130.13, 129.73, 126.21 (d, J

= 4 Hz), 124.37 (d, J

= 4 Hz), 124.02 (CF
3
, J

= 272 Hz);
19
F
NMR (376 MHz):  -61.6 (s, 3F); IR (cm
-1
): 1649, 1439, 1336, 1236, 1185, 1118, 1052,
960, 853, 787; High resolution MS (EI): m/z calculated for 250.9995 found 250.9994.

98

Potassium (E)-2-(3,5-bis(trifluoromethyl)phenyl)ethenesulfonate (3o)

Purification method: A;
1
H NMR (400 MHz):  8.22 (s, 2H), 7.89 (s, 1H), 7.53 (d, J =
15.7 Hz, 1H), 7.41 (d, J = 15.7 Hz, 1H) ;
13
C NMR (100.5 MHz):  136.98, 133.45,
132.14, 131.59 (d, J

= 33 Hz), 127.86, 123.32 (d, J

= 272 Hz), 121.95;
19
F NMR (376
MHz):  -63.5 (s, 6F); IR (cm
-1
): 3602, 3514, 3098, 3052, 1627, 1381, 1283, 1244, 1195,
1131, 1048, 960, 664; High resolution MS (EI): m/z for C
10
H
5
F
6
O
3
S, calculated 318.9869
found 318.9865.
Potassium (E)-2-(3-carboxy-4-hydroxyphenyl)ethenesulfonate (3p)

Purification method: A;
1
H NMR (400 MHz):  7.81 (d, J = 2.2 Hz, 1H), 7.53 (dd, J =
8.7, 2.3 Hz, 1H), 7.06 (d, J = 15.7 Hz, 1H), 6.82 (d, J = 8.7 Hz, 1H), 6.72 (d, J = 15.7 Hz,
1H);
13
C NMR (100.5 MHz):  171.94, 161.17, 135.17, 134.45, 130.57, 126.46, 125.26,
117.65, 113.38; IR (cm
-1
): 3388, 1665, 1590, 1448, 1345, 1227, 1176, 1040, 688, 611,
513; High resolution MS (EI): m/z for C
9
H
7
O
6
S, calculated 243.0 found 243.0.
Potassium (E)-2-(pyridin-3-yl)ethenesulfonate (6)

Purification method: C;
1
H NMR (400 MHz):  8.65 (s, 1H), 8.51 (s, 1H), 8.06 (d, J = 8.1
Hz, 1H), 7.49 (dd, J = 8.0, 4.9 Hz, 1H), 7.32 (d, J = 15.8 Hz, 1H), 7.13 (d, J = 16.4 Hz,
99

1H);
13
C NMR (100.5 MHz):  124.9,130.8,133.1, 136.0,148.6, 149.8, 160.7; IR (cm
-1
):
1642, 1402, 1364, 1191, 1006, 832; High resolution MS (EI): m/z for C
7
H
6
NO
3
S,
calculated 184.0073 found 184.0073.
Potassium (E)-5-(2-sulfonatovinyl)indol-1-ide (8)

Purification method: C;
1
H NMR (400 MHz):  7.79 (s, 1H), 7.49 (d, J = 8.6 Hz, 1H),
7.39 (dd, J = 10.2, 5.9 Hz, 3H), 6.92 (d, J = 15.6 Hz, 1H), 6.58 (d, J = 2.3 Hz, 1H);
13
C
NMR (100.5 MHz):  138.01, 136.59, 127.73, 126.42, 124.64, 124.53, 121.41, 120.47,
112.01, 101.89; IR (cm
-1
): 3089, 2689, 1680, 1612, 1427, 1370, 1189, 1004, 974, 834,
702, 668; High resolution MS (EI): m/z for C
10
H
8
NO
3
S, calculated 222.0228 found
222.0230.
Potassium (1E,1'E)-2,2'-(1,3-phenylene)diethenesulfonate (11):

Purification method: C;
1
H NMR (400 MHz):  7.78 (s, 1H), 7.64 (m, 2H), 7.51 (s, 1H),
7.35 (d, J = 15.7 Hz, 2H), 7.10 (d, J = 15.7 Hz, 2H);
13
C NMR (100.5 MHz):  135.87,
134.09, 129.55, 129.07, 128.56, 127.02; IR (cm
-1
): 1638, 1409, 1187, 1043, 969, 832;
High resolution MS (EI): m/z for C
10
H
9
O
6
S
2
, calculated 288.9846 found 288.9845.

100

Potassium (1E,1'E)-2,2'-(biphenyl-4,4'-diyl)diethenesulfonate (12)

Purification method: C;
1
H NMR (400 MHz):  7.69 (dd, J = 22.4, 8.2 Hz, 8H), 7.35 (d, J
= 15.7 Hz, 2H), 7.07 (d, J = 15.7 Hz, 2H);
13
C NMR (100.5 MHz):  140.76, 135.57,
133.06, 128.44, 128.20, 127.13; IR(cm
-1
): 3452, 2250, 1623, 1495, 1249, 1216, 1190,
1047, 981, 804, 647; High resolution MS (EI): m/z for C
16
H
12
O
6
S
2
, calculated 182.0043
found 182.0044.
Potassium (1E,1'E)-2,2'-(perfluoro-1,4-phenylene)diethenesulfonate (13)

Purification method: B;
1
H NMR (400 MHz):  7.31 (m, 4H);
13
C NMR (100.5 MHz):
19
F NMR (376 MHz):  -142.15 (s, 2F), -141.94 (br, 1F), -139.94 (br, 1F); IR (cm
-1
):
1455, 1234, 1186, 955, 826; High resolution MS (EI): m/z for C
10
H
4
F
4
O
6
S
2
, calculated
179.9698 found 179.9699.
Potassium (1E,1'E)-2,2'-(2,3,5,6-tetramethyl-1,4-phenylene)diethenesulfonate (14)

Purification method: B;
1
H NMR (400 MHz):  7.36 (d, J = 15.9 Hz, 1H), 6.33 (d, J =
15.9 Hz, 1H), 2.15 (s, 12H);
13
C NMR (100.5 MHz):  136.42, 133.73, 133.69, 132.01,
16.54; IR (cm
-1
): 3475, 2961, 1635, 1412, 1219, 1182, 1046, 672, 541; High resolution
MS (EI): m/z for C
14
H
16
O
6
S
2
, calculated 172.0200 found 172.0197.
101

1
H NMR of (3b):

102

13
C NMR of (3b):

103

1
H NMR of (6):

104

13
C NMR of (6):

105

4.5 Chapter 4: References
(1) Chen, S.-L.; Krishnan, L.; Srinivasan, S.; Benziger, J.; Bocarsly, A. B. J. Memb.
Sci. 2004, 243, 327.
(2) Ibba, M.; Stathopoulos, C.; Soll, D. Curr. Biol. 2001, 11, R563.
(3) Gil-Molto, J.; Karlstroem, S.; Najera, C. Tetrahedron 2005, 61, 12168.
(4) De Lucas, A.; Canizares, P.; Rodriguez, J. F. Sep. Sci. Technol. 1995, 30, 125.
(5) Djinovic, V. M.; Antic, V. V; Djonlagic, J.; Govedarica, M. N. React. Funct.
Polym. 2000, 44, 299.
(6) Surampudi, S.; Narayanan, S. R.; Vamos, E.; Frank, H. A.; Halpert, G.; Olah, G.
A.; Prakash, G. K. S. Aqueous liquid feed organic fuel cell using solid polymer
electrolyte membrane. 1997, US5599638A.
(7) Oren, Y.; Freger, V.; Linder, C. J. Memb. Sci. 2004, 239, 17.
(8) Prakash, G. K. S.; Olah, G. A.; Smart, M. C.; Narayanan, S. R.; Wang, Q. S.;
Surumpudi, S.; Halpert, G. Novel polymer electrolyte membranes for use in
methanol fuel cells. 1998, WO9822989A1.
(9) Quilico, A.; Fleischner, E. Atti della Accad. Naz. dei Lincei, Cl. di Sci. Fis. Mat. e
Nat. Rend. 1928, 7, 1050.
(10) Kharasch, M. S.; Schenck, R. T. E.; Mayo, F. R. J. Am. Chem. Soc. 1939, 61,
3092.
(11) Suter, C. M.; Milne, H. B. J. Am. Chem. Soc. 1943, 65, 582.
(12) Bordwell, F. G.; Suter, C. M.; Holbert, J. M.; Rondestvedt, C. S. J. Am. Chem.
Soc. 1946, 68, 139.
(13) Bordwell, F. G.; Rondestvedt Jr., C. S. J. Am. Chem. Soc. 1948, 70, 2429.
(14) Terent’ev, A. P.; Dombrovskii, A. V. Zhurnal Obs. Khimii 1950, 20, 1875.
(15) Makarova, S. B.; Roizen, K. M.; Vlasov, L. G.; Aptova, T. A.; Korovina, T. N.;
Makovskaya, V. I.; Lavrikov, E. S.; Bazhenov, V. I. 1976, 1974-2082463-530024.
106

5. Chapter 5: A Domino Approach (Elimination/Mizoroki-
Heck Coupling) Towards the Synthesis of β-
Trifluoromethylstyrenes and Related Compounds

5.1 Chapter 5: Introduction
Organofluorine compounds are known for their ability to alter the lipophilicity,
metabolic activity and bioavailability of host compounds. The trifluoromethyl group is
one of the most widely used functional groups in drug development.
1
The electron
withdrawing nature of the trifluoromethyl group is also an added advantage for further
chemical transformations due to significant changes in the electron density around the
adjacent carbon center. Many compounds with the 3,3,3-trifluoropropenyl (CF
3
CH=CH-)
group have found important applications in medicinal chemistry (cephalosporin
derivatives)
2–4
and agrochemicals (pyrethroid insecticides).
5,6
Introduction of this group
has been found to enhance the volatility of aliphatic compounds.
7
Conjugated aromatic
systems with trifluoromethyl groups such as β-trifluoromethylstyrene derivatives have
found wide use in organic light emitting diodes (OLED’s)
8
and in other material
chemistry applications. β-trifluoromethylstyrenes and related compounds also serve as
important intermediates in the synthesis of more complex molecules.
The synthesis of 3,3,3-trifluoropropene derivatives has been explored by several
research groups and can be classified into tree main types of reactions. First, by transition
metal catalyzed trifluoromethylation of β-halostyrenes using various trifluoromethylating
107

reagents (Figure 5.1, disconnection 1). The second approach involves either a traditional
Horner reaction or a Wittig olefination reaction (Figure 5.1, disconnection 2). The third
type of reaction involves a desulfitative approach to yield the desired
trifluoromethylolefins.
The first approach requires access to alkenyl or aryl halides and in some cases,
synthesis of the trifluoromethylating reagent as an added step.
9–13
These processes suffer
from poor atom economy and the production of noxious gases such as SO
2
as major
drawbacks. The Wittig reaction approach involves the synthesis of corresponding ylides,
which can be cumbersome. In some cases where a trifluoromethyl yilde was prepared as
the reacting species, the ylide itself is unstable and a considerable amount of reactant was
lost due to decomposition.
7,14,15
Török and co-workers used a slightly different approach
by using benzyltriphenylphosphonium ylides and trifluoroactealdehyde (generated in
situ) in a Wittig process to yield the desired trifluoromethyl alkenes in good yields.
16

However, they observed a mixture of (E)- and (Z)- isomers in all cases. In the third
approach, the starting materials were either sulfones or sulfides that yielded the desired
trifluoromethylalkenes upon desulfitative coupling reactions. In 2005, Vogel and co-
workers reported the palladium catalyzed cross coupling reaction between styrene (5
equiv.) and trifluoromethanesulfonyl chloride to synthesize β-trifluoromethylstyrene
derivatives albeit in 50% yield, with limited substrate scope.
17

In 1981, Fuchikami et al. reported one of the earliest papers that described the
synthesis of β-trifluoromethylstyrene in high yields via palladium catalyzed coupling of
aromatic halides and 3,3,3-trifluoropropene (Figure 5.1, disconnection 3).
18
This method
108

requires the use of gaseous 3,3,3-trifluoropropene as a reaction component in an
autoclave and the substrate scope is limited.

Figure 5.1 Various approaches towards synthesis of β-trifluoromethylstyrenes
Based on the success of our previously reported (vide supra) synthesis of various
styrene sulfonate salts via the Mizoroki-Heck coupling in a domino process,
19
we decided
to approach the synthesis of β-trifluoromethylstyrenes following a similar strategy. As
mentioned, this approach involves a palladium catalyzed Mizoroki-Heck reaction
between haloarenes and commercially accessible 1-iodo-3,3,3-trifluoropropane under
highly basic conditions ( >3 equiv.). Under such conditions, 1-iodo-3,3,3-
trifluoropropane underwent dehydrohalogenation to produce 3,3,3-trifluoropropene
(vinyl-CF
3
) in situ, which then reacted with the haloarene in the presence of palladium(II)
acetate as catalyst to yield the desired β-trifluoromethylstyrenes. This approach has many
advantages. Firstly, 1-iodo-3,3,3-trifluoropropane is a liquid at room temperature and
hence can be easily handled, and commercially available. Secondly, the reaction setup
109

does not require an autoclave or any other sophisticated equipment. Another advantage is
that this reaction can be performed under microwave irradiation conditions, which
reduces the reaction time drastically compared to other methods such as the one reported
by Fuchikami et al.
18
(14-97 h depending on substrate vs 1 h reported here).

5.2 Chapter 5: Results and Discussion
The reaction between iodobenzene and 1-iodo-3,3,3-trifluoropropane (1.4 equiv.)
was selected as the initial reaction for optimization. Based on Fuchikami’s report,
18
we
began our study of the optimization of the reaction conditions with methanol:water (1:1)
as the solvent. Potassium carbonate (K
2
CO
3
) was used in excess (3.5 equiv.) as the base
for both the dehydrohalogenation and the Mizoroki-Heck reaction, and palladium acetate
(Pd(OAc)
2
) (2 mol%) was chosen as the catalyst. As the Heck reaction usually requires
high temperatures and long reaction times, we decided to carry out the reactions using a
microwave reactor in an attempt to try and reduce reaction times. Upon irradiating the
reaction mixture at 130
o
C for 1h, ~50% of the desired trifluoromethylstyrene product
was observed by
19
F NMR. Further optimization studies were carried out with various
solvents, including water, 1:1 (v/v) mixture of methanol and water, and DMF, all other
conditions remaining the same. The results from these reactions led us to continue using
DMF as the solvent as choice for all further reactions (Table 5.1). Different palladium
catalysts such as Pd
2
(dba)
3
and Pd(PPh
3
)
2
Cl
2
were also tested for their efficacy with no
observed improvement in yields (Table 5.2).

110

Table 5.1 Screening of solvents for the reaction between iodobenzene and 1-iodo-3,3,3-
trifluoropropane

Solvent Temperature (
o
C) Conversion by
19
F NMR
(%)
a

Methanol- Water (1:1) 130
o
C 49
Water 180
o
C 36
DMF 200
o
C 83
a
C
6
F
6
was used as an internal standard

Table 5.2 Screening of palladium catalysts for the reaction between 3-iodotoluene and 1-
iodo-3,3,3-trifluoropropane

Catalyst Conversion by
19
F NMR (%)
a

Pd(OAc)
2
83
Pd
2
(dba)
3
62
Pd(PPh
3
)
2
Cl
2
69

111

Analysis of the results of various reactions yielded the optimized conditions for
the title reaction, which were applied to a variety of substituted iodobenzenes. The results
are shown in Table 5.3. Bromobenzene and chlorobenzene were also subjected to the
same domino reaction under identical conditions. As expected, the reaction with
bromobenzene was much slower and less efficient yielding the desired β-
trifluoromethylstyrene product in only 10% yield and chlorobenzene did not yield any of
the desired product as evidenced by
19
F NMR analysis of the reaction mixture.
Iodobenzene (Table 5.3, entry 1) gave the corresponding trifluoromethylstryene
in 76% isolated yield. Both electron-withdrawing and electron donating substituents are
well tolerated by this method, however electron donating substituents tend to give
slightly better yields than electron withdrawing substituents (Table 5.3, entries 13 vs. 8
and 9). Steric effects also do not seem to affect the overall yield significantly (Table 5.3,
entry 5 vs 6). 2-Aminoiodobenzene (Table 5.3, entry 10), which is generally known to
poison palladium catalysts, possibly due to lone pair on the nitrogen atom (a Lewis base),
surprisingly gave 52% isolated yield of the corresponding trifluoromethylstryene.
However, 3-iodophenol and 2-iodobenzoic acid (Table 5.3, entries 12 and 4,
respectively) failed to give any of the desired product, which could be due to catalyst
poisoning under the utilized reaction conditions.

112

Table 5.3 Synthesis of β-trifluoromethylstyrenes via elimination/Mizoroki-Heck reaction

113

Table 5.3 continued

In addition, heterocyclic iodoarenes also gave desired trifluoromethylated
styrenes in low to moderate yields (Figure 5.2). The previously unknown compound,
(E)-5-(3,3,3-trifluoroprop-1-en-1-yl)-1H-indole (7) could be an interesting substrate for
biological studies and therapeutic analysis. 3-Iodopyridine also gave moderate yield of
the desired Heck-coupled product. However, both 2-iodopyridine and 2-iodopyrazine did
not react under identical reaction conditions (Figure 5.2, 4 and 8). Diiodoarenes gave the
corresponding bis(trifluoromethyl) styrene derivatives in moderate to good isolated yields
114

(Figure 5.2, 9, 10, 10a, 11, and 13), with the exception of 2,3,5,6-tetrafluoro-1,4-
diiodobenzene, which did not yield any desired product (Figure 5.2, 12). In all cases,
isolated yields were less than those recorded by NMR due to either low boiling points of
the products or difficulties in purification and product loss during column
chromatography. During purification of 10, another product 10a was also isolated (8%
yield). This product could be the result of two simultaneous reactions, Heck coupling at
one position and aryl-aryl homocoupling (side reaction) occurring at the other position of
1,3-diiodo benzene.

Figure 5.2 Heterocyclic and bis( β-trifluoromethyl)styrenes
115

During optimization studies, with iodobenzene (Table 5.3, entry 1) as a substrate,
an interesting product was observed under certain reaction conditions. Unfortunately, we
were not able to isolate this product as a pure material. However, GC-MS analysis of the
reaction mixture and crude product indicated it to be the “double” Heck product,
probably resulting via elimination-Heck-Heck domino reaction sequence (Scheme 5.1).
Crude
19
F NMR analysis of the reaction mixture also suggested that the probable
“double” Heck product could be exclusively the Z-isomer. This product was observed
only as a minor product.
Scheme 5.1 Elimination-Heck-Heck coupling domino reaction pathway
5.3 Chapter 5: Conclusions
In conclusion, a very easy to perform, efficient and simple method of synthesizing
β-trifluoromethylstyrene derivatives using elimination/Mizoroki-Heck domino reaction
sequence has been developed. Additionally, the reported method gives us access to some
interesting and previously unknown β-trifluoromethylstryrenes. The method avoids the
use of the gaseous 1,1,1-trifluoropropene reagent as one of the reactants and is easy to set
up and carry out. The substrate scope of this reaction is broad, which increases its
116

applicability in synthesizing various trifluoromethylated styrenes as potential monomers
in polymer and material synthesis.

5.4 Chapter 5: Experimental
5.4.1 General
Commercially available palladium (II) acetate, potassium carbonate, and 1-Iodo-
3,3,3-trifluoropropane (Synquest Labs) were used without further purification. All
reactions were carried out using dry Dimethylformamide (DMF) as the solvent. Biotage
Initiator 1 was used as a source of microwave irradiation. Products were identified using
1
H,
13
C,
19
F NMR and HRMS.
1
H,
13
C,
19
F NMR were recorded on Varian Inova 400
MHz NMR spectrometer using CDCl
3
as solvent.
1
H and
13
C shifts were determined
relative to tetramethylsilane (TMS) at  0.0 ppm or to the residual solvent peak at  7.26
ppm for CDCl
3
.
13
C NMR shifts were determined relative to TMS at  0.0 ppm or to the
residual solvent peak at  77.16 ppm for CDCl
3
.
19
F chemical shifts were determined
relative to internal standard CFCl
3
at  0.0 ppm. Chemical shifts are reported in ppm.
HRMS data was obtained from University of Arizona Mass Spectrometry Facility.

5.4.2 General Experimental Procedure for the Synthesis of β-
Trifluoromethylstryrenes

To a 20 ml microwave vial charged with a magnetic stir bar was added anhydrous
K
2
CO
3
(1.015g, 7.35 mmol), palladium(II) acetate

(Pd(OAc)
2
) (0.011 g, 0.049 mmol, 2
mol%) and iodobenzene (0.5 g, 2.45 mmol) in that order. The vial was sealed and 15 ml
117

dry DMF was added to the vial under argon. This reaction mixture was stirred at room
temperature for few minutes after which 1-Iodo-3,3,3-trifluoropropane (0.281 ml, 2.45
mmol, neat) was added to the reaction mixture dropwise. The reaction mixture was
heated in a microwave for 60 min at 200
o
C. Upon cooling the reaction mixture, it was
vacuum filtered to remove Pd(0) and the vial was washed with water and pentane. The
filtrate was then extracted with pentane (3 X 10 ml) and the combined pentane extract
was evaporated under reduced pressure to obtain the crude product as an oil. The crude
product was purified using column chromatography with pentane or pentane:ether (8:2)
as eluent.

5.4.3 Spectral Data and Representative Spectra
The
1
H,
13
C, and
19
F NMR spectra for compounds 3a,
18
3c,
16
3g,
20
3k,
18
3m,
7
and
5
20
were consistent with those reported in literature.
(E)-1-Methoxy-3-(3,3,3-trifluoroprop-1-en-1-yl)benzene (3b)

1
H NMR (400 MHz):  7.31 (t, J = 8.2 Hz, 1H), 7.12 (dq, J = 16.0, 2.2 Hz, 1H), 7.06-
6.92 (m, 3H), 6.19 (dq, J = 16.0, 6.5 Hz, 1H), 3.84 (s, 3H);
13
C NMR (100.5 MHz): 
160.0, 137.6 (q, J = 6.8 Hz, 1C), 134.8, 130.0, 123.6 (q, J = 268.3 Hz, 1C), 120.1, 116.2
(q, J = 33.4 Hz, 1C), 112.7, 55.3;
19
F NMR (376 MHz):  -63.84 (dd, J = 6.5, 2.0 Hz,
3F); High resolution MS (EI): m/z for C
10
H
9
F
3
O, calculated 202.0605, found 202.0603.
118

(E)-1-Methyl-2-(3,3,3-trifluoroprop-1-en-1-yl)benzene (3e)

1
H NMR (400 MHz):  7.47 (d, J = 7.6 Hz, 1H), 7.42 (dq, J = 15.7, 2.3 Hz, 1H), 7.31-
7.21 (m, 3H), 6.12 (dq, J = 15.7, 6.8 Hz, 1H), 2.40 (s, 3H);
13
C NMR (100.5 MHz): 
136.9, 135.5 (q, J = 7.4 Hz, 1C), 132.5, 130.7, 129.8, 126.4, 126.2, 123.6 (q, J = 268.9
Hz, 1C), 117.1 (q, J = 35.3 Hz, 1C), 19.6;
19
F NMR (376 MHz):  -63.81 (dd, J = 6.5, 2.4
Hz, 3F); High resolution MS (EI): m/z for C
10
H
9
F
3
O, calculated 186.0656, found
186.0650.
(E)-1,3-Dimethyl-2-(3,3,3-trifluoroprop-1-en-1-yl)benzene (3f)

1
H NMR (400 MHz):  7.25 (dq, J = 16.5, 2.3 Hz, 1H), 7.15 (m, 1H), 7.09 (m, 2H), 5.84
(dq, J = 16.5, 6.3 Hz, 1H), 2.32 (s, 6H);
13
C NMR (100.5 MHz):  136.0, 135.9 (q, J =
7.0 Hz, 1C), 133.0, 128.2, 128.1, 123.2 (q, J = 269.2 Hz, 1C), 121.7 (q, J = 33.1 Hz, 1C),
20.7;
19
F NMR (376 MHz):  -64.6 (dd, J = 6.3, 2.2 Hz, 3F); High resolution MS (EI):
m/z for C
11
H
11
F
3
, calculated 200.0813 found 200.0813.

119

(E)-1-Fluoro-4-(3,3,3-trifluoroprop-1-en-1-yl)benzene (3h)

1
H NMR (400 MHz):  7.47-7.42 (m, 2H), 7.12 (dq, J = 16.2, 2.1 Hz, 1H), 7.11-7.06 (m,
2H), 6.13 (dq, J = 16.2, 6.9 Hz, 1H);
13
C NMR (100.5 MHz):  163.7 (d, J = 250.3 Hz,
1C), 136.4 (q, J = 6.6 Hz, 1C), 129.6 (d, J = 4.1 Hz, 1C), 129.4 (d, J = 8.6 Hz, 2C), 123.5
(q, J = 268.7 Hz, 1C), 116.1 (d, J = 22.0 Hz, 2C), 115.6 (qd, J = 34.2, 2.2 Hz, 1C);
19
F
NMR (376 MHz):  -63.82 (dd, J = 6.7, 2.0 Hz, 3F).
(E)-N-(4-(3,3,3-Trifluoroprop-1-en-1-yl)phenyl)acetamide (3i)

1
H NMR (400 MHz):  7.62 (d, J = 8.7 Hz, 2H), 7.51 (d, J = 8.7 Hz, 2H), 7.16 (dq, J =
16.2, 2.1, Hz, 1H), 6.37 (dq, J = 16.2, 7.04, 1H), 2.13 (s, 3H);
13
C NMR (100.5 MHz): 
171.8, 141.7, 138.5 (q, J = 6.50 Hz, 1C), 130.4, 129.4, 125.5 (q, J = 268.7 Hz, 1C),
121.0, 115.4 (q, J = 33.3 Hz, 1C), 23.9;
19
F NMR (376 MHz):  -60.75 (dd, J = 6.9, 2.1
Hz, 3F).
(E)-2-(3,3,3-Trifluoroprop-1-en-1-yl)aniline (3j)

1
H NMR (400 MHz):  7.31-7.28 (m, 1H), 7.28 (dq, J = 16.0, 2.2 Hz, 1H), 7.21-7.17 (m,
1H), 6.81 (t, J = 7.9 Hz, 1H), 6.73 (d, J = 8.2 Hz, 1H), 6.14 (dq, J = 16.0, 6.75, 1H), 3.85
120

(br s, 2H);
13
C NMR (100.5 MHz):  144.7, 133.3, 130.9, 127.9, 123.6 (q, J = 269.5 Hz,
1C), 119.4, 119.3, 116.8, 116.6 (q, J = 33.5 Hz);
19
F NMR (376 MHz):  -63.64 (dd, J =
6.5, 2.3 Hz, 3F); High resolution MS (EI): m/z for C
9
H
8
F
3
N, calculated 187.0656 found
187.0650.
(E)-3-(3,3,3-Trifluoroprop-1-en-1-yl)pyridine (5)

1
H NMR (400 MHz):  8.68 (s, 1H), 8.61 (d, J = 4.1 Hz, 1H), 7.76 (dt, J = 8.0, 1.9 Hz,
1H), 7.32 (dd, J = 7.9, 4.8 Hz, 1H), 7.13 (dq, J = 16.2, 2.1 Hz, 1H), 6.27 (dq, J = 16.2,
6.4 Hz, 1H);
13
C NMR (100.5 MHz):  150.8, 149.2, 134.3 (q, J = 6.7 Hz, CF
3
-C-C),
133.8, 129.1, 124.4 (q, J = 269.0, CF
3
), 123.7, 118.2 (q, J = 34.3, CF
3
-C);
19
F NMR (376
MHz):  -64.3 (dd, J = 6.4, 2.1 Hz, 3F).
(E)-5-(3,3,3-Trifluoroprop-1-en-1-yl)-1H-indole (7)

1
H NMR (400 MHz):  8.13 (br, 1H), 7.63 (m, 1H), 7.23 (m, 4H), 6.49 (m, 1H), 6.06
(dq, J = 16.0, 6.6 Hz, 1H);
13
C NMR (100.5 MHz):  138.8 (q, J = 6.7 Hz, CF
3
-C-C),
136.6, 128.0, 125.5, 125.2, 124.0 (q, J = 268.4, CF
3
), 121.4, 120.9, 112.6 (q, J = 34.3,
CF
3
-C), 111.5, 103.3;
19
F NMR (376 MHz):  -63.0 (dd, J = 6.6, 1.9 Hz, 3F); High
resolution MS (EI): m/z for C
11
H
8
F
3
N, calculated 211.0609 found 211.0616.
121

1,2-bis((E)-3,3,3-Trifluoroprop-1-en-1-yl)benzene (9)

1
H NMR (400 MHz):  7.50 (m, 2H), 7.43 (m, 3H), 7.39 (q, J = 2.2 Hz, 1H), 6.14 (dq, J
= 16.0, 6.4 Hz, 2H);
13
C NMR (100.5 MHz):  134.5 (q, J = 6.8 Hz, CF
3
-C-C), 132.8,
130.0, 127.5, 123.0 (q, J = 269.3, CF
3
), 119.7 (q, J = 33.9, CF
3
-C);
19
F NMR (376 MHz):
 -64.2 (dd, J = 6.4, 2.2 Hz, 3F); High resolution MS (EI): m/z for C
12
H
8
F
6
, calculated
266.0530 found 266.0519.
1,3-bis((E)-3,3,3-Trifluoroprop-1-en-1-yl)benzene (10)
(Major product)
1
H NMR (400 MHz):  7.47 (m, 4H), 7.17 (dq, J = 16.2, 2.2 Hz, 2H), 6.25 (dq, J = 16.2,
6.4 Hz, 2H);
13
C NMR (100.5 MHz):  136.8 (q, J = 6.8 Hz, CF
3
-C-C), 134.2, 129.5,
128.7, 126.6, 124.7 (q, J = 269.3, CF
3
), 117.0 (q, J = 34.0, CF
3
-C);
19
F NMR (376 MHz):
 -64.0 (dd, J = 6.4, 2.1 Hz, 3F); High resolution MS (EI): m/z for C
12
H
8
F
6
, calculated
266.0530 found 266.0522.

122

3,3'-bis((E)-3,3,3-Trifluoroprop-1-en-1-yl)-1,1'-biphenyl (10a)
(Minor product)
1
H NMR (400 MHz):  7.64 (m, 2H), 7.59 (dt, J = 6.3, 2.4 Hz, 2H), 7.48 (m, 4H), 7.22
(dq, J = 16.1, 2.1 Hz, 2H), 6.29 (dq, J = 16.1, 6.5 Hz, 2H);
13
C NMR (100.5 MHz): 
141.2, 137. 4 (q, J = 6.7 Hz, CF
3
-C-C), 134.0, 129.5, 128.7, 126.6, 126.3, 124.8 (q, J =
268.8, CF
3
), 116.6 (q, J = 33.9, CF
3
-C);
19
F NMR (376 MHz):  -63.9 (dd, J = 6.4, 2.1
Hz, 3F); High resolution MS (EI): m/z for C
18
H
12
F
6
, calculated 342.0843 found
342.0844.
4,4'-bis((E)-3,3,3-Trifluoroprop-1-en-1-yl)-1,1'-biphenyl (11)

1
H NMR (400 MHz):  7.56 (d, J = 8.34 Hz, 4H), 7.47 (d, J = 8.34 Hz, 4H), 7.09 (dq, J =
16.1, 2.1 Hz, 2H), 6.19 (dq, J = 16.1, 6.57 Hz, 2H);
13
C NMR (100.5 MHz):  141.6,
137.0 (q, J = 6.8 Hz, CF
3
-C-C), 132.9, 128.1, 127.4, 123.6 (q, J = 268.9, CF
3
), 116.1 (q, J
= 33.9, CF
3
-C);
19
F NMR (376 MHz):  -63.7 (dd, J = 6.5, 2.0 Hz, 3F); High resolution
MS (EI): m/z for C
10
H
12
F
6
, calculated 342.0843 found 342.0826.

123

1,2,4,5-Tetramethyl-3,6-bis((E)-3,3,3-trifluoroprop-1-en-1-yl)benzene (13)

1
H NMR (400 MHz):  7.30 (dq, J = 16.1, 2.18 Hz, 2H), 5.70 (dq, J = 16.1, 6.3 Hz, 2H),
2.19 (s, 12H);
13
C NMR (100.5 MHz):  138.0 (q, J = 6.9 Hz, CF
3
-C-C), 134.0, 131.8,
122.9 (q, J = 269.9 Hz, CF
3
-C), 122.4 (q, J = 33.2 Hz, CF
3
-C), 17.3;
19
F NMR (376
MHz):  -64.7 (dd, J = 6.3, 2.2 Hz, 3F); High resolution MS (EI): m/z for C
16
H
16
F
6
,
calculated 322.1156 found 322.1152.

124

19
F

1
H

125

13
C

126

19
F

1
H

127

13
C

128

19
F

1
H

129

13
C

130

5.5 Chapter 5: References
(1) Cho, E. J.; Senecal, T. D.; Kinzel, T.; Zhang, Y.; Watson, D. A.; Buchwald, S. L.
Science 2010, 328, 1679.
(2) Schmidt, G.; Metzger, K. G.; Zeiler, H. J.; Endermann, R.; Haller, I. Preparation of
cephalosporins as antibacterials for humans and animals. 1988, EP292808A2.
(3) Serizawa, N.; Nakagawa, K.; Kamimura, S.; Miyadera, T.; Arai, M. J. Antibiot.
1979, 32, 1016.
(4) Watanabe, T.; Kawano, Y.; Tanaka, T.; Hashimoto, T.; Miyadera, T. Chem.
Pharm. Bull. 1980, 28, 62.
(5) Hanack, M.; Korhummel, C. Synthesis 1987, 944.
(6) Mack, H.; Hanack, M. Liebigs Ann. der Chemie 1989, 833.
(7) Kobayashi, T.; Eda, T.; Tamura, O.; Ishibashi, H. J. Org. Chem. 2002, 67, 3156.
(8) Shimizu, M.; Takeda, Y.; Higashi, M.; Hiyama, T. Angew. Chem. Int. Ed. Engl.
2009, 48, 3653.
(9) Kitazume, T.; Ishikawa, N. J. Am. Chem. Soc. 1985, 107, 5186.
(10) Chen, Q.; Wu, S. J. Chem. Soc. Chem. Commun. 1989, 705.
(11) Chen, Q.; Duan, J. J. Chem. Soc. Chem. Commun. 1993, 1389.
(12) Duan, J.-X.; Su, D.-B.; Chen, Q.-Y. J. Fluor. Chem. 1993, 61, 279.
(13) Duan, J.; Dolbier, W. R.; Chen, Q. J. Org. Chem. 1998, 63, 9486.
(14) Hanamoto, T.; Morita, N.; Shindo, K. European J. Org. Chem. 2003, 4279.
(15) Umemoto, T.; Gotoh, Y. Bull. Chem. Soc. Jpn. 1991, 64, 2008.
(16) Landge, S. M.; Borkin, D. A.; Török, B. Lett. Org. Chem. 2009, 6, 439.
(17) Dubbaka, S. R.; Vogel, P. Chemistry 2005, 11, 2633.
(18) Fuchikami, T.; Yatabe, M.; Ojima, I. Synthesis 1981, 1981, 365.
131

(19) Prakash, G. K. S.; Jog, P. V; Krishnan, H. S.; Olah, G. A. J. Am. Chem. Soc. 2011,
133, 2140.
(20) Furuta, S.; Kuroboshi, M.; Hiyama, T. Bull. Chem. Soc. Jpn. 1999, 72, 805.

132

6. Chapter 6: A Domino Approach (Elimination/Mizoroki-
Heck Coupling) Towards the Synthesis of α-
Fluorostyrenes

6.1 Chapter 6: Introduction
Organofluorine compounds are an important class of molecules due to their
enormous significance in varied areas such as pharmaceuticals, agrochemicals, material
chemistry, fuel cell membranes, etc.
1–4
The development of new synthetic routes to
introduce fluorine into organic molecules is an important area of research. The
introduction of a single fluorine atom into an organic molecule has long been an
important and interesting challenge for research groups. Monofluorinated olefins have
many significant applications in materials, medicinal chemistry, etc.
5
In medicinal
chemistry, monofluoroalkenes are known peptide bond bioisosteres (Figure 6.1).
5

Figure 6.1 Monofluoroalkenes as bioisosteres of peptide bonds
133

α-Fluorostyrenes are an important class of olefins that have potential applications
in medicinal chemistry due to their prominent biological activity.
6–8
Polymers derived
from α-fluorostyrene as a monomer have been used for various applications in materials
chemistry, such as proton exchange membranes (PEM) in fuel cells,
9,10
optical
compensation films in LCDs, etc.
11
The presence of a fluorine atom in the α-position
results in many changes in structural and electronic properties of a molecule and hence
mechanistic studies have been carried out extensively with this moiety.
12,13

Many groups have previously worked on the synthesis α-fluorostyrene and its
derivatives. The earliest method for their synthesis involves the addition of HF to
phenylacetylene or α-chlorostyrene to yield the α,α-difluoroethylbenzene, which under
pyrolysis at 350-400
o
C yields the α-fluorostyrene in moderate yields.
14
McCarthy et. al.
first described a method for β-fluoro phenylselenylation from olefins.
15
These compounds
upon oxidative deselenylation yielded the corresponding fluoroolefins. This method was
further developed by Stang et. al. using PhSeF
3
, PhSeF
5
, and PhTeF
5
to include styrenes
(among other olefins), to yield α-fluorostyrenes in about 20-30% overall yield.
16
One of
the more widely used methods for the synthesis of α-fluorostyrene is one involving the
halofluorination of styrene using HF and N-halosuccinimide followed by
dehydrohalogenation under basic conditions, using bases such as potassium tert-butoxide
(t-BuO
-
K
+
).
17–20
The first step, i.e, the halofluorination is usually regioselective with
fluorination on the α-carbon.
19
The second step, dehydrohalogenation is also selective
leaving the fluorine intact. Several research groups have worked on this idea and have
134

optimized the process so it is now the method of choice to synthesize α-fluorostyrenes
(Scheme 6.1, a-c).
All the above reactions are multi-step processes involving the use of reagents such
as HF and extreme reaction conditions. In 1991, Heitz and Knebelkamp synthesized α-
fluorostyrenes in a one-step process using a Pd-catalyzed Heck coupling reaction
between iodobenzenes and 1,1-difluoroethylene.
21,22
N-Methylcaprolactam was used as
the solvent and the reaction mixture was heated in an autoclave at 115
o
C for 18h. α-
Fluorostyrene was isolated in 39% yield. One of the reagents, 1,1-Difluoroethylene,
being a gas, makes the handling of the reaction mixture somewhat difficult. After this
initial report, other syntheses of α-fluorostyrene using other cross coupling reactions
starting from 1-stannyl,
23
and 1-silyl
24
1-fluoroethylenes were reported. The synthesis of
the 1-stannyl-1-fluoroethylene was accomplished in 3 steps and the 1-silyl-1-
fluoroethylene was synthesized in a single step
25
from gaseous 1,1-difluoroethylene
(Scheme 6.1, d).
Based on our previous work which involved the Heck coupling reaction in a
domino approach,
26,27
we decided to extend this methodology towards the synthesis of α-
fluorostyrene and its derivatives. As described in our previous reports, the basic reaction
media required to carry out the Heck coupling reaction are the same as that for
elimination. Our goal was to synthesize α-fluorostyrenes in a one-pot fashion from
simple, commercially available materials. From our previous work, we have seen that the
135

setting up of the domino process involving the Heck reaction is simple, and reaction
mixtures can be easily purified to yield the desired products.

Scheme 6.1 Previous methods for the synthesis of α-fluorostyrenes
6.2 Chapter 6: Results and Discussion
We began our initial optimization reactions for the synthesis of α–fluorostyrenes
using iodobenzene (2a) and commercially available 1-iodo-2-fluoroethane (1). When we
conducted the initial reaction under the conditions for base mediated elimination,
followed by the Heck coupling, we observed styrene as the only product. The reaction
was carried out under various reaction conditions, such as varying the solvent,
136

temperature and equivalents of reagents. However, in all cases, styrene 4 was obtained as
the only product. From these experimental results, we determined that instead of a syn-β-
hydride elimination during the Heck coupling, a syn-β-fluoride elimination occurred,
leading to the formation of styrene as the sole product (Scheme 6.2, C, D).

Scheme 6.2 Mechanism of the Heck reaction between Ar-I 2 and 1-iodo-2-fluoroethane 3
137

In order to overcome this difficulty, we decided to perform the reaction with the
commercially available 1-iodo-2,2-difluoroethane 5. In the initial reaction, iodobenzene
(2a) and 5 were taken with 3 equiv. of K
2
CO
3
as base in DMF as solvent and subjected to
heating in a microwave reactor at 200
o
C for 1h. As expected, we observed α-
fluorostyrene (6) as one of the products, albeit in very poor yield. Again, as observed in
the previous reaction with 1-iodo-2-fluoroethane (3), syn-β-fluoride elimination was
taking place with the loss of the complex F-Pd-I

(Scheme 6.3, D), yielding the
monofluorinated α-fluorostyrene 6 as the product. It is noteworthy that the expected
product of a Heck coupling under these reaction conditions would be the β-fluorostyrene
instead of α-fluorostyrene. However, in this case, the alkene (CH
2
=CF
2
) 7 undergoes a
trans-addition to Pd, rather than a syn-addition leading to the observed α-fluorostyrene
(Scheme 6.3, B vs. Bʹ).

Scheme 6.3 Mechanism of Heck reaction between Ar-I 2 and 1-iodo-2,2-difluoroethane 5

138

Scheme 6.3 continued

Several optimization reactions were carried out in an attempt to improve the yield
of the α-fluorostyrene 6, as shown in Table 6.1. Different palladium catalysts, solvents
and bases were employed. Despite all our attempts, we were unable to achieve higher
yields. The highest conversion to product was observed when 1-iodo-2,2-difluoroethane
was taken as the limiting reagent and reacted with an excess of 4-iodoanisole (Table 6.1,
entry 9), using Pd(OAc)
2
as catalyst and 3 equiv. of K
2
CO
3
as base at 200
o
C. Even then,
139

we were unable to isolate the pure product due to difficulties of separating the product
from a mixture of side products and unreacted 4-iodoanisole.
Table 6.1 Optimization of reaction conditions for the reaction between 2 and 5

Entry Ar-I
2 (Equiv.)
Catalyst
(Equiv.)
Base
(Equiv.)
Solvent Conversion
1 Ph-I (0.8) Pd(OAc)
2
(0.1) K
2
CO
3
(2) DMF 10
2 Ph-I (0.8) Pd(OAc)
2
(0.1) Et
3
N(2) DMF < 3
3 Ph-I (0.8) Pd(OAc)
2
(0.1) Cs
2
CO
3
(2) DMF < 3
4 Ph-I (0.8) Pd(OAc)
2
(0.1) Na
2
CO
3
(2) DMF < 3
5 Ph-I (0.8) Pd(OAc)
2
(0.1) Li
2
CO
3
(2) DMF 0
6 Ph-I (0.9) Pd(PPh
3
)
2
Cl
2

(0.1)
K
2
CO
3
(2) DMF 0
7 Ph-I (0.9) Pd(PPh
3
)
4
K
2
CO
3
(2) DMF 4
8 Ph-I (0.8) Pd(OAc)
2
(0.1) K
2
CO
3
(2) NMP 4
9 4-OMe-Ph-I
(2.2)
Pd(OAc)
2
(0.05) K
2
CO
3
(3) DMF 25
140

We then decided to investigate the reasons for the poor yield. Our investigation
began based on earlier results,
22
which showed that the Heck coupling reaction between
iodobenzene and 1,1-difluoroethylene occurred with some success (40% conversion to
product) at 115
o
C. Despite heating our reaction mixture to 200
o
C for 1h, we were unable
to access the desired product in comparable yields. This led us to conclude that the poor
yield was due to one of two reasons- 1. The dehydrohalogenation reaction of 1-iodo-2,2-
difluoroethane to 1,1-difluoroethylene was not efficient even at 200
o
C, or 2. the
complexation of the alkene 7 to the Pd-complex A is inefficient.
Based on previous research, we believe that at ~115
o
C, the initial step of the
Heck coupling reaction, namely oxidative addition takes place i.e. the Pd(0) inserts into
the Ar-I bond forming the Ar-Pd-I complex A. However, at this temperature, 5 does not
undergo complete elimination when K
2
CO
3
is used as base. In an attempt to overcome
this difficulty, we repeated the reaction using a stronger base, t-BuOK. The reaction was
carried out in both one-pot and step-wise fashion, with t-BuOK and 1-iodo-2,2-
difluoroethane 5 subjected to reaction first, followed by the addition of K
2
CO
3
,
Pd(OAc)
2
, and iodobenzene 2a, and allowed to react further. These reactions also did not
yield any desired product, probably because t-BuOK is a very strong base and rendered
the palladium catalyst inactive. Therefore, three control experiments were carried out. In
the first reaction, 4-fluoroiodobenzene 2b was subjected to reaction in a microwave
reactor with 1-iodo-2,2-difluoroethane 5, K
2
CO
3
, and Pd(OAc)
2
in DMF at 200
o
C for 1h
(Table 6.2, Entry 1). The
19
F NMR showed less than 5% of the desired α-fluorostyrene 6
product. All of 5 had reacted to give the alkene 7 and other unidentified products. The 4-
141

fluoroiodobenzene 2a underwent homocoupling to yield the 4,4’-difluorobiphenyl 8,
along with protodeiodination to yield fluorobenzene 9 (Figure 6.2).
Table 6.2 Control experiments between 2b and alkene

142

Figure 6.2 Reaction of 2b with 5 at 200
o
C for 1h

Scheme 6.4 Formation of side-products during the Elimination/Heck Reaction
143

In the second reaction, a reaction mixture identical to that in the first reaction was
subjected to heating in a microwave reactor at 130
o
C for 1h (Table 6.2, Entry 2) and the
19
F NMR spectrum was recorded. At this lower temperature, as expected, the NMR
showed that 5 did not undergo complete reaction to yield the alkene 7. The NMR
spectrum also showed that a significant amount of the starting material 2b had been
converted to either 8 or 9. The amount of the desired product 6 in this reaction was <1%
(Figure 6.3).

Figure 6.3 Reaction of 2b with 5 at 130
o
C for 1h

Finally, a third reaction mixture containing all other components except 4-
fluoroiodobenzene (2b) was conducted at 130
o
C for 1h in a microwave reactor (Table
6.2, Entry 3). Once again, it was observed that 5 did not undergo complete elimination to
144

7. Also observed were side products from the reaction of 5. They were identified as either
the protodeiodinated product or the product of a substitution at the C-1 center of 5
(Figure 6.4).

Figure 6.4 Reaction of 5 in the presence of base and catalyst at 130
o
C for 1h
It has been observed from prior experiments that the reaction of 2b with 1,1,1-
trifluoroprop-2-ene (Table 6.2, Entry 4) yields the desired coupled product in good
conversion (~65%). We can conclude in the case of that reaction that the complexation of
the alkene to the arylpalladium(II) iodide complex (A) is favorable and efficient. The
poor yields in the synthesis of α-fluorostyrenes 6 can therefore also be attributed to poor
complexation of the alkene 7 to the complex A.
145

From these control reactions, it can be deduced that the elimination reaction and
the Heck coupling reaction to synthesize α-fluorostyrenes 6 do not work in a ‘domino’
fashion. It is possible that the rate of the oxidative addition of the palladium catalyst into
the aryl-I bond is much faster than the rate of the elimination, leading to poor yields.
This, in combination with an inefficient complexation of the alkene 7 to the Pd-complex
A leads to very poor yields of the desired product.
6.3 Chapter 6: Conclusions
This chapter describes the attempted synthesis of α-fluorostyrenes via an
elimination/Mizoroki-Heck coupling domino reaction sequence. Contrary to the results
from most Heck coupling reactions, the alkene in this case undergoes a trans-alkene
insertion and yields the α-fluorostyrene as the only product. The reaction also favors a β-
fluoride elimination in the penultimate step of the coupling reaction instead of the
expected β-hydride elimination. Although the best conversion obtained for the domino
reaction process in only about 30%, NMR experiments were carried out to determine the
cause of the low yield. From the experiments, it was concluded that the reasons for poor
yield are either due to an inefficient complexation of the alkene to the aryl-palladium(II)
complex or the elimination reaction being slow or inefficient. At lower temperatures,
elimination is not complete, and homocoupling and protodeiodination are the
predominant reactions.

146

6.4 Chapter 6: References
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(13) Bogachev, A. A.; Kobrina, L. S.; Meyer, O. G. J.; Haufe, G. J. Fluor. Chem. 1999,
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(14) Matsuda, K.; Sedlak, J. A.; Noland, J. S.; Gleckler, G. C. J. Org. Chem. 1962, 27,
4015.
(15) McCarthy, J. R.; Matthews, D. P.; Barney, C. L. Tetrahedron Lett. 1990, 31, 973.
(16) Lermontov, S. A.; Zavorin, S. I.; Bakhtin, I. V; Pushin, A. N.; Zefirov, N. S.;
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147

(17) Eckes, L.; Hanack, M. Synthesis 1978, 217.
(18) Haufe, G.; Alvernhe, G.; Laurent, A.; Emet, T.; Goj, O.; Krorger, S.; Sattler, A.
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Abstract (if available)

Abstract This dissertation is divided into two parts. The first part describes the generation of the reactive species difluoromethylene (:CF₂) from (trifluoromethyl)trimethylsilane, also called the Ruppert-Prakash reagent, and its subsequent application in synthesizing gem-difluorocyclopropanes. The second part describes the synthesis of various substituted styrenes via a domino process involving the Mizoroki-Heck coupling reaction. ❧ Chapter 1 describes the history and significance of fluorine in organic chemistry, and its many applications in fields ranging from pharmaceuticals to materials sciences. Methods to incorporate fluorine as a single atom and various fluoroalkyl groups are also described. ❧ In Chapter 2, the utility of the nucleophilic trifluoromethylating reagent, (trifluoromethyl)trimethylsilane is expanded. The generation of difluoromethylene (:CF₂) from (trifluoromethyl)trimethylsilane under different reaction conditions is described. Difluorocarbene has been generated from (trifluoromethyl) trimethylsilane under low temperature conditions using a fluoride initiator and under high temperature conditions using an iodide initiator. The [2+1] addition of the difluorocarbene to alkenes yielding gem-difluorocyclopropanes is described. The procedure is extended to the synthesis of gem-difluorocyclopropyl boronates as well. ❧ Chapter 3 describes the history and many applications of the Mizoroki-Heck coupling reaction. Different aspects of the reaction such as regioselectivity, catalyst, and solvent scope are discussed. Also discussed are the applications of the Mizoroki-Heck reaction in microwave systems and domino processes. ❧ Chapter 4 describes the synthesis of potassium styrenesulfonate salts from aryl iodides and 2-chloroethansulfonyl chloride under basic conditions in the presence of a palladium catalyst. Three reactions are carried out in a one-pot fashion namely, hydrolysis, dehydrohalogenation and Mizoroki-Heck coupling. Several potassium styrenesulfonate salts with different steric and electronic properties have been isolated. Hydrogenation of a few substrates to yield potassium ethylbenzenesulfonate salts is also described. ❧ Chapter 5 describes an extension of work detailed in the previous chapter. The synthesis of β-trifluoromethylstyrenes via a domino process involving the Mizoroki-Heck reaction is discussed. Iodoarenes are reacted with 1-chloro-3,3,3-trifluoropropane in the presence of base and palladium catalyst in a microwave to yield the corresponding β-trifluoromethylstyrenes in good yields. ❧ Finally, in Chapter 6, the attempted synthesis of α-fluorostyrenes is discussed. A domino process involving the Mizoroki-Heck coupling is utilized in the synthesis of α-fluorostyrenes from iodoarenes and 1-iodo-2,2-difluoroethane. Initial results for the reaction between iodoarenes and 1-iodo-2-fluoroethane, and the reaction mechanism to yield the desired product are also described. An explanation for the poor yields of the product is also attempted.

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Creator Krishnan, Hema Sivaram (author)

Core Title Novel fluoroalkylation reactions and microwave-assisted methodologies

School College of Letters, Arts and Sciences

Degree Doctor of Philosophy

Degree Program Chemistry

Publication Date 07/20/2015

Defense Date 05/11/2015

Publisher University of Southern California (original), University of Southern California. Libraries (digital)

Tag cyclopropanes,difluorocarbenes,microwave-assisted methods,Mizoroki-Heck coupling,OAI-PMH Harvest,organofluorine chemistry

Format application/pdf (imt)

Language English

Contributor Electronically uploaded by the author (provenance)

Advisor Prakash, G. K. Surya (committee chair), Hogen-Esch, Thieo E. (committee member), Shing, Katherine (committee member)

Creator Email hema.sivaramakrishnan@gmail.com,hskrishn@usc.edu

Permanent Link (DOI) https://doi.org/10.25549/usctheses-c3-599535

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Legacy Identifier etd-KrishnanHe-3642.pdf

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Document Type Dissertation

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Rights Krishnan, Hema Sivaram

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Access Conditions The author retains rights to his/her dissertation, thesis or other graduate work according to U.S. copyright law. Electronic access is being provided by the USC Libraries in agreement with the a...

Repository Name University of Southern California Digital Library

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