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Novel nucleophilic and electrophilic fluoroalkylation reactions and related chemistry

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Novel nucleophilic and electrophilic fluoroalkylation reactions and related chemistry

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Content NOVEL NUCLEOPHILIC AND ELECTROPHILIC FLUOROALKYLATION
REACTIONS AND RELATED CHEMISTRY
by

Sujith Chacko

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)

May 2008

Copyright 2008 Sujith Chacko
ii
DEDICATION

My Parents, Simmy, and Eleena
iii
ACKNOWLEDGMENTS

I would like to express my gratitude to Professor G. K. Surya Prakash who
provided excellent support and guidance throughout my entire stay at USC. This
wouldn’t have been possible without his advice and endless motivation.
I would also like to thank Professor George A. Olah for his constant support and
encouragement. Both Prof. Prakash and Prof. Olah are responsible for inspiring me to
continually strive to higher levels of excellence in chemistry.
I am grateful to Dr. Gulam Rasul, who helped me to finish few of my projects
with his expertise in computational chemistry. I also would like to thank Dr. Thomas
Mathew, who helped me to establish myself as a chemist in the laboratory. The scientific
discussions I had with him always helped me to understand the concepts of chemistry. I
also would like to extend my appreciation to Dr. Robert Anizfeld for constant support
throughout the program.
My heartful thanks to my collegue and friend, Dr. Chiradeep Panja, for lending
me a helping hand, whenever and wherever needed. I learnt a lot from him both in
concepts as well as in techniques. I also would like to express my appreciation to Pragya,
who also was very supportive during this time. Colleagues at USC who have made
significant contributions to this work include Dr.Weber, Dr.Lednezki, Ms. Vaghoo, Mr.
Shao, Mr.Ghugre, Dr. Palale and Mr. Stewart. Dr. Weber was the integral part of the
project of “Difluoromethylation” and Ms. Vaghoo collaborated in the project in chapter
iv
6. Dr. Palale and Mr. Ghugre contributed to the nanotechnology project. Many thanks to
Ms. Vaghoo for the inspiration and friendship throughout my entire stay.
I must acknowledge many people in Olah-Praksh group for their help and support.
Among these people are Dr. Batamack, Dr. Saitoh, Dr. Kultyshev, Dr. Goeppert, Dr.
Etzkorn, Dr. Li, Dr. Mogi, Dr. Foggassy, Dr. Beir, Dr. Colmenares, Dr. McGrath, Dr.
Moran and Dr. Desousa. I am also thankful to my other collegues, Ms. Farzaneh Paknia,
Dr. Meth, Mr. Bo Yang, Mr. Federico Viva, Mr. Kevin Glinton, Mr. Clement Do, Ms.
Ying Wang, Ms. Rehana Ismail, Mr. Mike Zibinsky, Mr. Fang Wang, Mr. Frederick
Krause, Ms. Inessa Bychinskaya, and Mr. Kiah Smith.
I also take this opportunity to thank all the undergraduates who have worked with
me specially, Steven, Laxman, and Shashank. Without their active help it would have
been impossible for me to finish some of my projects in reasonable time.
I am really happy to have Kalyan, Somesh, Sayantan, Nam and Carsten as
collegues and I thank them for their helpful discussions. I would also like to thank many
other friends and colleagues including Kevin, Jeremie, Gosha, Rong, Deepshika, Jiby,
Jisha, Babu, Ramya, Mathew, Bindu, Philip, Ajey, Milan, Anurag and Sanju.
My appreciation to staff members of the chemistry department and Loker
Hydrocarbon Institute, especially Michele, Heather, Jessy, Carole, Ralph and David for
their kind support. Allan and Jim are also thanked for their technical help with NMR and
glassblowing.
v
All this wouldn’t have been possible without the support of my wife, Simmy, who
has been a never ending source of inspiration and encouragement. Finally, to my parents,
special thanks for their encouragement and constant help during the entire period.
vi
TABLE OF CONTENTS
DEDICATION ii
ACKNOWLEDGMENTS iii
TABLE OF CONTENTS vi
LIST OF FIGURES x
LIST OF SCHEMES xii
ABSTRACT xiii
1 Chapter 1: Introduction 1
1.1 Chapter 1: Introduction 1
1.2 Chapter 1: Aim and Scope of Present Work 10
1.3 Chapter 1: References 12
2 Chapter 2: Stereoselective Monofluoromethylation of Primary and
Secondary Alcohols Using a Fluorocarbon Nucleophile in Mitsunobu
Reactions 15
2.1 Chapter 2: Introduction 15
2.2 Chapter 2: Results and Discussion 17
2.3 Chapter 2: Conclusion 23
2.4 Chapter 2: Experimental 24
2.4.1 Typical procedure for Mitsunobu reactions of
fluorobis(phenylsulfonyl)methane with alcohols. 25
2.4.2 Crystal Structure of C
25
H
21
O
4
S
2
F 30
2.4.3 Typical procedure for reductive desulfonylation of
fluorobis(phenylsulfonyl) derivatives 32
2.4.4 Synthesis of monoflouromethyl vitamin D
3
. 34
2.5 Chapter 2: Representative Spectra 37
2.6 Chapter 2 References 43
vii
3 Chapter 3: New Electrophilic Difluoromethylating Reagent 46
3.1 Chapter 3: Introduction 46
3.2 Chapter 3: Results and Discussion 48
3.3 Chapter 3: Conclusion 56
3.4 Chapter 3: Experimental 56
3.4.1 General 56
3.4.2 Preparation of 2-(Difluoromethylsulfanyl)bromobenzene 57
3.4.3 Preparation of 2-(Difluoromethylsulfanyl)biphenyl 57
3.4.4 Preparation of 2-(Difluoromethylsulfinyl)bromobenzene 58
3.4.5 Preparation of 2-(Difluoromethylsulfinyl)biphenyl 59
3.4.6 Reaction of 2-(Difluoromethylsulfinyl)biphenyl (7) with
Trifluoromethanesulfonic Anhydride 60
3.4.7 Reaction of 2-(Difluoromethylsulfinyl)bromobenzene (6) with
Benzene in the Presence of Triflic Anhydride. 61
3.4.8 Preparation of Difluoromethyl Phenyl Sulfide 61
3.4.9 Preparation of Difluoromethyl Phenyl Sulfoxide 62
3.4.10 Preparation of S-Difluoromethyl-S-phenyl-2,3,4,5-
tetramethylphenylsulfonium Tetrafluoroborate 63
3.4.11 Preparation of Phenyl 2,3,4,5-Tetramethylphenyl Sulfide 64
3.4.12 General Method for the Difluoromethylation of Aryl and Alkyl
Sulfonic Acids 64
3.5 Chapter 3: Representative Spectra 71
3.6 Chapter 3: References 85
4 Chapter 4: New Solid-phase Bound Electrophilic Difluoromethylating
Reagent 87
4.1 Chapter 4: Introduction 87
4.2 Chapter 4: Results and Discussion 90
4.3 Chapter 4: Conclusion 96
4.4 Chapter 4: Experimental 97
4.4.1 General 97
4.4.2 Preparation of Difluoromethyl Phenyl Sulfide 97
4.4.3 Preparation of Difluoromethyl Phenyl Sulfoxide 98
4.4.4 Preparation of Solid-phase Polymer Bound S-
Difluoromethyl(diphenyl)sulfonium Tetrafluoroborate 99
4.4.5 Difluoromethylation of Alkyl- and Arylsulfonates Using Solid
Phase Bound Reagent 100
4.4.6 Difluoromethylation of Imidazoles Using Solid-Phase Polymer
Bound Reagent 103
4.4.7 Preparation of Solid-phase Bound S Trifluoromethyl(diphenyl)
sulfonium Tetrafluoroborate 105
viii
4.4.8 Reaction of the Resin-bound S trifluoromethylsulfonium Triflate
with Aniline 106
4.4.9 Reaction of the Resin-bound S-trifluoromethylsulfonium Triflate
with Thiophenol 106
4.5 Chapter 4: Representative Spectra 107
4.6 Chapter 4: References 115
5 Chapter 5: Regioselective Synthesis of Phenols and Halo phenols from
Arylboronic Acids Using Solid Poly(N-vinylpyrrolidone)/H
2
O
2
and poly(4-
vinyl pyridine)/H
2
O
2
Complexes 117
5.1 Chapter 5: Introduction 117
5.2 Chapter 5: Results and Discussion 120
5.3 Chapter 5: Density Functional Theory (DFT) Study of N-ethylpyrrolidone
-H
2
O
2
Complexes Compared with 4-ethyl Pyridine-H
2
O
2
Complexes as
Models for the Polymer- H
2
O
2
Complexes 128
5.3.1 Calculational Methods 130
5.4 Chapter 5: Conclusion 132
5.5 Chapter 5: Experimental 132
5.5.1 Preparation of the PVD-H
2
O
2
and PVP-H
2
O
2
complex 132
5.5.2 Typical procedure for ipso-hydroxylation of aryl boronic acids 133
5.5.3 Typical procedure for the synthesis of halophenols from
aryl boronic acids 133
5.6 Chapter 5: References 134
6 Chapter 6: Efficient 1, 4-addition of α-substituted α-fluoro-
(phenylsulfonyl)methane derivatives to α, β -unsaturated compounds 139
6.1 Chapter 6: Introduction 139
6.2 Chapter 6: Results and Discussion 140
6.3 Chapter 6: Conclusions 144
6.4 Chapter 6: Experimental 144
6.4.1 Typical Procedure for the 1, 4 addition of α-fluoro-
(phenylsulfonyl)methane derivatives to various Michael acceptors 144
6.5 Represenatative Spectra 151
6.6 Chapter 6: References 160
7 Chapter 7: Synthesis of Nano sized Magnetite coated Poly (Vinylpyridine)
Nanospheres of varying size and Applications 162
7.1 Chapter 7: Introduction 162
7.2 Chapter 7: Results and discussion 165
7.3 Chapter 7: Conclusions 177
ix
7.4 Chapter 7: Experimental 177
7.4.1 Synthesis of Poly(vinylpyridine) nanospheres 178
7.4.2 Magnetite nanoparticulate synthesis 178
7.4.3 Immobilization of Magnetite on PVP Nano-spheres 179
7.5 Chapter 7: References 180
BIBLIOGRAPHY 182

x
LIST OF FIGURES
Figure 1.1 Popular fluorine-containing drugs .............................................................. 4
Figure 1.2 Nucleophilic and electrophilic fluorinating reagents.................................. 6
Figure 1.3 Fluoroartemisinin derivatives ..................................................................... 8
Figure 2.1 Crystal structure of monofluoromethyl adduct of (S)-(-)- α-methyl-2-
naphthalenemethanol ................................................................................ 19
Figure 3.1 Electrophilic Trifluoromethylating Agents............................................... 47
Figure.4.1 Fluorine Containing Lead Compounds Identified by Screening .............. 88
Figure.4.2 Difluoromethyl Group Containing Drugs on the Market ......................... 89
Figure 5.1 (a) Surface of PVD (b) Surface of PVD-H
2
O
2
complex .......................... 121
Figure 5.2 (a) Surface of PVP (b) Surface of PVP-H
2
O
2
complex............................ 121
Figure 5.3 Schematic diagram for the preparation of phenols from boronic ................
acids........................................................................................................124
Figure 5.4 B3LYP/6-311+G** calculated structures of 1 - 3. ................................. 131
Figure 7.1 SEM pictures of 250 nm poly(vinylpyridine)nanopsheres ..................... 168
Figure 7.2 SEM pictures of 350 nm poly(vinylpyridine)nanopsheres ..................... 169
Figure 7.3 SEM pictures of 580 nm poly(vinylpyridine)nanopsheres ..................... 170
Figure 7.4 Fe
3
O
4
coated poly(vinyl pyridine)nanopsheres- 580 nm ........................ 171
Figure 7.5 Fe
3
O
4
coated poly(vinylpyridine)nanopsheres- 380 nm ......................... 172
Figure 7.6 Fe
3
O
4
coated poly(vinylpyridine)nanopsheres- 250 nm ......................... 173
Figure 7.7 XRD data of Fe
3
O
4
coated poly(vinylpyridine)nanopsheres .................. 174
Figure 7.8 Time dependant study of intake of Fe
3
O
4
coated
poly(vinylpyridine)nanopsheres in neuroblastoma cells ........................ 176
xi
LIST OF TABLES
Table 2.1 Mitsunobu reaction of various alcohols with 1-fluoro-
bis(phenylsulfonyl)methane.............................................................18
Table 2.2 Walden inversion of chiral alcohols using Mitsunobu reaction.......20
Table 2.3 Reductive desulfonylation using activated magnesium and
methanol...........................................................................................21
Table 2.4 Crystal data and structure refinement for C
25
H
21
O
4
S
2
F...................31
Table 3.1 Reaction of 13 with Sulfonate salts .................................................53
Table 4.1 Difluoromethylation of Sulfonic Acids Using Polymer
Bound Difluoromethylating Reagent...............................................92
Table 4.2 Difluoromethylation of Imidazoles Using Solid-phase
Polymer Bound Difluoromethyl Sulfonium Reagent. .....................94
Table 5.1 Regioselective hydroxylation of of arylboronic acids ...................125
Table 5.2 Efficiency of PVD-H
2
O
2
complex as solid H
2
O
2
equivalent
and recycling of PVD.....................................................................126
Table 5.3 Synthesis of halophenols from boronic acids ................................127
Table 5.4 Total energies (-au), ZPE
a
and relative energies (kcal/mol)
b
.......129
Table 6.1 K
2
CO
3
/DMF catalyzed 1, 4-addition of α-fluoro
(bisphenylsulfonyl)methane and α-nitro, α-fluoro
phenylsulfonylmethane to α, β -unsaturated esters,
ketones, sulfone, and nitriles..........................................................142
Table 6.2 K
2
CO
3
/DMF catalyzed 1, 4-addition of α-fluoro
(bisphenylsulfonyl)methane and α-nitro, α-fluoro
phenylsulfonylmethane to propynoates .........................................143
Table 7.1 Reaction conditions for the synthesis of poly(vinylpyridine)
nanospheres....................................................................................167

xii
LIST OF SCHEMES
Scheme 2.1 Mitsunobu Reaction of alcholos using 1-Fluoro-bis(phenyl
sulfonyl)methane..............................................................................16
Scheme 2.2 Monofluoromethylation of Vitamin D
3
...........................................22
Scheme 2.3 Mitsunobu reaction of 1,2,3,4-tetra-O-acetyl- β-D-gluco
pyranose ...........................................................................................22
Scheme 2.4 Monofluoronitromethylation of alcohols using Mitsunobu
reaction.............................................................................................23
Scheme 3.1 Preparation of S-(Difluoromethyl)dibenzotiophenonium................49
Scheme 3.2 Preparation of S-Difluoromethyl-S-phenyl-2,3,4,5
tetramethylphenylsulfonium tetrafluoroborate ................................50
Scheme 3.3 Reaction of (13) with Imidazoles, Phosphines and
Tertiary amines. ...............................................................................55
Scheme 4.1 Solution-phase Difluoromethylation of O-, N- and
P-nucleophiles with the New S-difluoromethyl Sulfonium
Reagent. ...........................................................................................90
Scheme 4.2 Preparation of Polystyrene-bound -S-Difluoromethyl phenyl .........91
Scheme 4.3 Preparation and Reactivity of Solid-phase Polymer Bound S-
Trifluoromethyl sulfonium reagent. The conversions are based on
the parent compounds. .....................................................................95
Scheme 5.1 Ipso-hydroxylation of arylboronic acids using solid H
2
O
2

complexes ......................................................................................123

xiii
ABSTRACT

This dissertation describes the development of new methodologies for
nucleophilic monofluoromethylation, electrophilic difluoromethylation,
ipsohydorxylation, nucleophilic addition reactions and synthesis of polymeric
nanospheres.
Chapter 1 summarizes a brief history of organofluorine chemistry with the
emphasis on application of organofluorine compounds and novel methodologies
developed for introducing fluorine in organic compounds.
Chapter 2 describes a new, efficient Mitsunobu reaction using fluorinated carbon
pronucleophile for the facile synthesis of monofluoromethyl derivatives of alcohols. This
reaction performed under mild conditions is found to be highly feasible for primary,
secondary, allylic, benzylic and alicyclic alcohols and excellent enantioselectivity is
observed for chiral alcohols.
Chapter 3 deals with the synthesis of S-(difluoromethyl)diphenylsulfonium and its
use as a convenient electrophilic difluoromethylating reagent for various oxygen,
nitrogen and phosphorus nucleophiles.
Chapter 4 includes the synthesis of first solid-phase bound electrophilic
difluoromethylating agent has been developed by an efficient, short, two step synthetic
route from commercially available reagents. It has been shown that the reagent can be
used for O-difluoromethylation of sulfonic acids and N-difluoromethylation of
imidazoles affording pure product without further purification. This reagent may provide
xiv
a valuable collection of molecules for pharmacological and materials screening through
target and/or diversity oriented manual or automated library synthesis.
Chapter 5 expounds a milder and new technique to regioselectively transform aryl
boronic acids to the corresponding phenols in excellent yields and high purity, using a
solid PVD-H
2
O
2
complex, which can be reused further for several runs. High level DFT
calculations were also performed on model systems to study and understand the nature of
these complexes
Chapter 6 delineates a convenient protocol for the nucleophilic addition of α-
fluoro- α-phenylsulfonyl-substituted methane derivatives to a variety of Michael acceptors
such as, α, β unsaturated esters, ketones, sulfone, and nitriles. This methodology has been
further extended to propynoates to give the corresponding adducts in moderate yields.
Chapter 7 describes the synthesis of poly(vinylpyridine) nanospheres using an
emulsifier-free emulsion polymerization technique. Poly(vinylpyridine) nanospheres
were used as stable support for coating the magnetite nanoparticles by a one step
adsorption from colloidal solution.

1
1 Chapter 1: Introduction
1.1 Chapter 1: Introduction

Fluorocarbon molecules possess unique properties that make them useful in
various facets of life. These properties are important, in part because atomic fluorine has
the highest electronegativity, with a van der Waals radius of 1.47 Å. Fluorine gas, which
is greenish yellow in color, boils at -188.1
o
C and melts at -219.6
o
C. The first
electrochemical synthesis of elemental fluorine was reported by H. Moissan, and its first
pure chemical synthesis was achieved by K. O. Christe in 1986.
1
The atomic volume
occupied by fluorine is smaller than a methyl, amino or hydroxyl group, but is larger than
hydrogen.
2,3
After the first laboratory preparation of fluorine in 1886, its untamed
reactivity restricted the use of fluorination reactions for the synthesis of various
organofluorine compounds. With the advent of novel, selective and safe fluorinating and
fluoromethylating reagents, the field of organofluorine chemistry started to flourish after
1970, which was reflected in the use of organofluorine compounds for various
applications.
Organofluorine compounds are found to have large impact on various fields such
as the polymer and lubricant industries, liquid crystal technology, and agrochemical
chemistry. Fluoropolymers remain the largest scale applications of organofluorine
compounds. Major fluoropolymers include poly(tetrafluoroethylene), poly(vinylidene
difluoride), and perfluoropolyethers. Fluoroaromatics, when compared to their non-
fluorinated analogues in liquid crystal display technology, are attractive, as they improve
2
solubility, depress the melting point and broaden the nematic phase range of the liquid
crystals. Fluorinated herbicides, insectcides, fungicides, and rodenticides have gained
significant attention in the agricultural field and their usage has increased to 17 % in 1999
from 8% in 1988.
There has been a growing interest in green chemistry in recent years. Fluorous
chemistry offers a great scope in carrying out reactions in the absence of any organic
solvents, as well as the recycling of the fluorous phase for further applications.
Perfluoroaliphatic solvents are usually not miscible with hydrocarbons at room
temperature. At elevated temperatures they form a single phase, which can be reversed by
cooling. This principle has been used extensively in fluorous biphasic catalysis. Fluorous
compounds or fluorous “pony-tailed” organic compounds are separated by fluorous
chromatography and have found wide use in combinatorial chemistry. The ability of non-
toxic, physically inert fluoroorganics to dissolve molecular oxygen makes them suitable
for artificial blood substitutes.
More recently, fluorine chemistry has had a major impact on the pharmaceutical
industry and biomedicinal research. The inductive effects, the enhancement of metabolic
stability and the profound change in binding affinity and selectivity are major advantages
of introducing fluorine into a drug molecule.
4
This in turn results in better lipophilcity,
improved bioavailability and modulated physiochemical properties. The increased lipid
solubility often leads to enhanced rates of absorption and transport of drugs in vivo.
5

The change in basicity derived from the introduction of fluorine into drug
molecules impacts membrane permeability and has a strong effect on the
3
pharmacokinetic properties of the drug as well as its binding affinity.

It also has
significant effects on the binding affinity in protein–ligand complexes. The specificity of
organofluorine compounds has been derived from intense structure activity relationship
(SAR) studies. Exploration of the specific influence of carbon-fluorine bonds on docking
interactions, through a direct contact with a protein, could have widespread implications.
The short-lived isotope of fluorine,
18
F (half life = 110 minutes), which decays by positron
emission is especially useful in positron emission tomography (PET), which is a valuable
tool for the survey of living tissue.
6
Fluorine-18 labeled fluorodopamine has been
successfully utilized to image the brain of patients with Parkinson’s disease to get new
insights into the chemistry and metabolism of the brain.
The concept of bioisosterism (interchanging atoms or functional groups with
similar sizes or shapes without substantially altering biological characteristics) has been
accepted as a powerful tool for drug development. There have been studies to quantify
the physiochemical effects such as electronegativity, steric size and lipophilicity, and to
correlate these values to the observed biological activity.
7
A series of tricyclic inhibitors
of thrombin have been developed using this concept.

The peptide bond can be replaced by
a fluorovinyl group as a non- hydrolyzable bioisotere, and is an important constituent in
pepitodomimetics.
8
Fluorine also acts as a substitute for hydrogen, while the
trifluoromethyl and isopropyl groups are interchangeable.
9
All of these exchanges affect
the conformational and stereoelectronic properties of the molecules, allowing them to be
fine-tuned for improved binding efficacy.
4
F
3
C
O
H
N
. HCl
Prozac
N
H
O
N
COO
F
OH OH
. 1/2 Ca
2+
Lipitor
HN
N N
OH
O O
F
. HCl
Ciprobay

Figure 1.1 Popular fluorine-containing drugs

Fluorinated drugs currently occupy 20 % of the total drug market, as well as being
the top five drugs sold in 2005. Lipitor, Prozac and Ciprobay are the fastest selling
fluorodrugs. (Figure 1.1) This surge can be attributed to a better understanding of
“fluorine effects” through extensive drug research and development also to the novel
methodologies designed to introduce fluorine in various organic molecules.
Organofluorine compounds are currently used as anticancer agents, antiviral agents,
5
cardiovascular drugs, anesthetics, central nervous system agents, antibiotics, anti-
inflammatory drugs, antidiabetics, and hypolipidemic agents. Fluorinated aminoacids
have also been synthesized and utilized as potential enzyme inhibitors and therapeutic
agents.
An increased number of selective fluorinating agents are currently available for
introducing fluorine in organic molecules. Rozen and coworkers have reported the use of
elemental fluorine (diluted with nitrogen) for the electrophilic fluorination of alkenes
10

and α, β - unsaturated ketones.
11
They also carried out electrophilic substitution of “F
+
”
with deactivated tertiary hydrogen centers using elemental fluorine and applied this
methodology for the synthesis of various fluorine-containing steroids.
12
Barton et al.
reported fluoroxytrifluoromethane as an electrophilic reagent.
13
Perchloryl fluoride
(FClO
3
), xenon difluoride (XeF
2
), nitrogen oxide fluorides (NOF, and NO
2
F), acetyl
hypofluorite and other hypofluorides were also reported as electrophilic fluorinating
reagents for various organic transformations.
14,15
A new class of N-F electrophilic
reagents have since gained popularity as stable, non toxic form of electrophilic fluorine.
Umemoto et al. synthesized the first stable N-fluoropyridinum salt and studied the effects
of the counteranion, which influences the stability, reactivity and selectivity of the
reagent.
16,17
A range of electrophilic N-F reagents were then developed and are available
through commercial sources. 1-Chloromethyl-4-fluorodiazoniabicyclo [2.2.2]octane
bis(tetrafluoroborate) (Selectfluor), N,N-difluoro-2,2'-bipyridinium bis(tetrafluoroborate)
(Synfluor), and N- fluorobenzenesulfonimide (NFSI) are the most widely used
6
commercial N-F reagents. DesMarteau and co-workers have reported the synthesis of N-
fluorobis[(trifluoromethyl)sulfonyl]imide and still is one of most powerful source of
electrophilic fluorine.
18,19

Beginning with Olah’s reagent, pyridinium polyhydrogen fluoride,
20,21,22,
reagents
are also available for the nucleophilic introduction of a fluorine moiety into various
organic compounds, including diethylaminosulfur

trifluoride (DAST), 2,2-difluoro-1,3-
dimethylimidazolidine

(DFI), and bis(2-methoxyethyl) aminosulfur trifluoride

(Deoxofluor). (Figure 1.2) Alkali metal fluorides, tetrabutylammonium fluoride, and
tetrabutylammonium (triphenyl)difluorosilicate were also used for nucleophilic
fluorination extensively.
O
2
S
N
SO
2
Ph Ph
F
N
N
Cl
F
BF
4
2
N-Fluorobenzenesulfonimide
Selectfluor
N
N
F
F
BF
4
2
Synfluor
Electrophilic fluorinating agents
N
SF
3
N
N
F F
N
O
O
SF
3
DAST
DFI
Dexofluor
Nucleophilic fluorinating agents

Figure 1.2 Nucleophilic and electrophilic fluorinating reagents.

7
Prakash and coworkers have focused on developing novel fluorinating and
fluoromethylating agents for almost two decades. Because of the instability of directly
generated trifluoromethyl Grignards and lithium reagents,
23
trifluoromethyl
trimethylsilane has been explored systematically as a nucleophilic trifluoromethylating
agent to introduce the triflouromethyl group into various functional groups such as
aldehydes, ketones, esters, organohalides, sulfur-based electrophiles, and organotin
compounds.
24,25
Due to the mild reaction conditions, this methodology is widely
applicable and is used for the synthesis of various carbohydrates, nucleotides and
steroids.
26
Fluorinated nucleosides have currently found applications in antiviral and
anticancer agents. 10-Deoxoartemisinin is a powerful antimalarial agent, and is active
against P. falciparum strains in vitro but loses its activity under in vivo conditions.
Trifluormethyltrimethylsilane has also been used to introduce the trifluoromethyl group
into this molecule, enabling it to be active under in vivo conditions. Based on these
inspiring results, 10-CF
3
analogues of dihydroartemisinin, artemether, arteether, and
artesunate have been synthesized. Some of them were found to have prolonged plasma
half-life, and better stability under acidic stomach conditions. Further more, two orally
active antimalarial drugs, 10-trifluoromethyl dihydroartemisinin, and 10-trifluoromethyl
deoxoartemisinin have been developed and currently in the preclinical phase of
development
27
(Figure 1.3).
8
O
O
CF
3
OH
O
O
10 - Trifluoromethyl dihydroartemisinin
O
O
CF
3
O
O
N
N
OH
10-trifluoromethyl deoxoatremisnin

Figure 1.3 Fluoroartemisinin derivatives

Trifluromethyl trimethyl silane chemistry has been extended to activated imines
and azirines. By using chiral N-sulfimines, stereoselective trifluoromethylation has been
achieved to generate trifluoromethyl chiral amines, which are potential intermediates in
pharmaceutical chemistry.
28,29
Known as “Ruppert-Prakash Reagent”, TMS-CF
3
is
currently the most widely used trifluoromethylating agent for synthetic applications. The
same group also extensively investigated trifluromethyl sulfones as efficient
trifluromethyating agents as an alternative to TMS-CF
3
. Dolbier and co-workers have
developed trifluoromethyliodide(CF
3
I)/tetrakis-(dimethylamino)ethylene (TDAE) as an
9
alternate approach to nucleophilic trifluoromethylation. The trifluoromethyl carbanion is
generated in situ by two electron reduction of CF
3
I by TDAE in the presence of
dimethylformamide as the solvent. Using this chemistry, they successfully introduced the
trifluoromethyl group into various aldehydes, cyclic sulfates and imines.
30
Langlois et al.
developed trifluoroacetamides as nucleophilic trifluoromethylating reagents.
31
Umemoto
et al. has synthesized trifluoromethyldibenzothiophenium salts and related analogues as
the first electrophilic trifluoromethylating reagents and successfully transferred “CF
3
+
”to
various N, O, S, C and P nucleophiles using these power-variable electrophilic
trifluoromethylating reagents.
32
In 2007, Togni et al. has also reported the use of
hypervalent iodine, I(III)-CF
3,
for the electrophilic trifluoromethylation of various C and
S nucleophiles.
33

Difluoromethyl compounds carry significant importance in pharmaceutical
chemistry, as “CF
2
H” is a lipophilic isostere of the carbinol group. Its ability to act as a
hydrogen donor, potentially allowing interaction with biological molecules, makes this
moiety biologically important. Until 2005, 39 difluoromethyl derivatives have been
registered to be in different developmental phases of the drug discovery process. Due to
the low polarizability of the Si-CF
2
H bond in TMS-CF
2
H, the cleavage of these bonds
need more rigorous conditions and yields are found to be moderate.
34
Therefore the
development of new reagents to transfer the difluoromethyl group is both challenging and
important. Fuchikami and co-workers have reported the difluoromethylation of carbonyl
compounds using difluoromethylsilane derivatives in poor yields under rigorous reaction
conditions.
35
Prakash et al. synthesized (CH
3
)
3
SiCF
2
Si(CH
3
)
3
and successfully transferred
10
the difluoromethyl group to aldehydes.
36
Burton and co-workers have reported the
difluoromethylation of activated organic halides using difluoromethyl cadmium.
37
During
the past few years, Prakash et al. developed new synthons based on fluorinated
organosulfur compounds to transfer the difluromethyl group selectively into aldehydes,
ketones, organo halides, imines and sulfur-based electrophiles.
38,39,40
This reagent can
also be used to synthesize 1,1-difluoroalkenes from organohalides.
41
The activity of
difluoroalkenes as new types of enzyme inhibitors has attracted much attraction.
Enzyme–trapping agents have been designed utilizing the high reactivity of fluoroalkenes
with nucleophiles such as amines.
Compounds with monflouromethyl group carry significant importance in
biological systems. Monofluoroacetic acid is a lethal inhibitor for Kreb’s cycle.
Sevoflurane, a new generation of monofluromethyl anesthetics has been found to have
fast uptake and elimination properties. Hu and co-workers have reported the
monofluoromethylation of activated imines using monofluoromethyl-phenylsulfone.
42

Both Hu and Shibata have independently reported the synthesis of
fluorobis(phenylsulfonyl)methane (FBPM) from bis(phenylsulfonyl)methane and
Selectfluor
®
and have used FBPM to transfer the monofluoromethyl group to epoxides
and allylic acetates.
43,44

1.2 Chapter 1: Aim and Scope of Present Work

The importance of fluorinated molecules and fluorinated analogues of natural
compounds is of growing interest to the scientific community because of the increased
11
understanding of the influence of fluorine in pharmacological properties. It has triggered
the need for developing new synthetic methodologies for the introduction of fluorine and
fluoroalkyl groups into various organic molecules, which will enable the scientific world
to explore new fluoroorganics. Even though some methods for introducing mono- and
difluoromethyl groups into various organic molecules, have been reported in the
literature, better methodologies and reagents are required in order to satisfy the increased
demand for more potent, fluorinated pharmaceuticals. While reagents for electrophilic
trifluoromethylation have been synthesized and studied extensively, there have been no
reports on electrophilic difluoromethylation and monofluoromethylation. Attempt to
synthesize and characterize novel electrophilic reagents for difluoromethylation and its
use to generate a library of new difluoromethyl substituted compounds, was one of the
major goals of the research undertaken in this t hesis. Considerable amount of research is
also directed by scientific community toward developing solid-phase reagents for the
transfer/ transformation of various groups in an effective, enviormentally friendly way. A
major aim of this work was to extend the chemistry of electrophilic difluoromethylation
to develop polymer-bound solid-supported electrophilic difluoromethylating reagent and
their characterization and implementation, in different organic transformations.
The third major objective of this research was to extend the chemistry of
monofluoromethylation to different substrates by developing novel methodologies. This
study also intended to expand these methodologies to synthesize of biologically
important molecules that have significant influence in therapeutic applications, as well as
understanding the biochemical pathways of various biological processes.
12
1.3 Chapter 1: References

1. Christe, K. O. Inorg. Chem. 1986, 25, 3721.
2. Kirsch, P. Modern Fluoroorganic Chemistry, Wiley-VCH, Weinheim, Germany,
2004.
3. Bohm Hans-Joachim; Banner, D.; Bendels, S.; Kansy, M.; Kuhn, B.; Müller, K.;
Obst-Sander, U.; Stahl, M. Chem. Biochem. 2004, 5, 637.
4. Muller, K; Faeh, C; Diederich, F. Science 2007, 317, 1881.
5. Selig, H.; Holloway, J. H.; Topics in Current Chemistry, Boschke, Springer-Verlag:
Berlin, 1984, Vol 124, pp 30-99.
6. Le Bars, D. J. Fluorine Chem. 2006, 127, 1488.
7. Patani, G. A.; Lavoie, E. J. Chem. Rev. 1996, 96, 3147.
8. Zhao, K; Lim, D, S; Funaki, T, J; Welch, J, T. Bioorg. Med. Chem. Lett. 2003, 11,
207.
9. Banks, R, E; Smart, B, E; Tatlow, J, C. Organofluorine Chemistry, Plenum, New
York, 2004.
10. Rozen, S.; Brand, M. J. Org. Chem. 1986, 51, 3607.
11. Barton, D. H. R.; Lister-James, J.; Hesse, R. H.; Pechet, M. M.; Rozen, S. J. Chem.
Soc., Perkin Trans. 1, 1982,1105.
12. Rozen, S.; Ben-Shushen, G. J. Org. Chem. 1986, 51, 3522.
13. Barton, D. H. R.; Godinh, L. S.; Hesse, R. H.; Pechet, M. M. Chem. Commun. 1968,
806.
14. Nyffeler, P. T.; Duron, S. G.; Burkart, M. D.; Vincent, S. P.; Wong, C. Angew. Chem.
Int. Ed. 2005, 44, 192.
15. Singh, R. P.; Shreeve, J. M. Acc. Chem. Res. 2004, 37, 31.
16. Umemoto, T.; Fukami, S.; Tomizawa, G.; Harasawa, K.; Kawada, K.; Tomita, K. J.
Am. Chem. Soc. 1990, 112, 8563.
13

17. Umemoto, T.; Kawada, K.; Tomita, K. Tetrahedron Lett. 1986, 27, 4465.
18. Resnati, G.; DesMarteau, D. D. J. Org. Chem. 1991, 56, 4925.
19. DesMarteau, D. D.; Xu, Z. –Q.; Witz, M. J. Org. Chem. 1992, 112, 8563.
20. Olah, G. A.; Nojima, M.; Kerekes, I. Synthesis. 1973, 779.
21. Olah, G. A.; Nojima, M.; Kerekes, I. Synthesis. 1973, 780.
22. Olah, G. A.; Vankar, Y. D.; Nojima, M.; Kerekes, I.; Olah, J. A. J. Org. Chem. 1979,
44, 3872.
23. Burton, D. J.; Yang, Z. –Y. Tetrahedron 1992, 48, 189.
24. Prakash, G. K. S.; Krishnamurthy, R.; Olah, G. A. J. Am. Chem. Soc. 1989, 111, 393.
25. Prakash, G. K. S.; Yudin, A. K. Chem. Rev. 1997, 97, 757.
26. Planter-Royon, R.; Portella, C. Carbohydr. Res. 2000, 327, 119.
27. Begue, Jean-Pierre; Bonnet-Delphon, D. J. Fluorine. Chem. 2006, 127, 992.
28. Prakash, G. K. S.; Mandal, M.; Olah, G. A. Org. Lett. 2001, 3, 2847.
29. Prakash, G. K. S.; Mandal, M. J. Am. Chem. Soc. 2002, 124, 6538
30. Xu, W.; Dolbier, W. R. J. Org. Chem. 2005, 70, 4741.
31. Joubert, J.; Rouseel, S.; Christophe, C.; Billard, T.; Langlois, B. R.; Vidal, T. Angew.
Chem. Int. Ed. 2003, 42, 3133.
32. Umemoto, T. Chem. Rev. 1996, 96, 1757.
33. Kieltsch, I.; Eisenberger, P.; Togni, A. Angew. Chem. Int. Ed. 2007, 46, 754.
34. Prakash, G, K, S; Hu, J. Acc. Chem. Res. 2007, 40, 921.
35. Hagiwara, T.; Fuchikami, T. Synlett. 1995, 717.
36. Yudin, A. K.; Prakash, G. K. S.; Deffieux, D.; Bradley, M.; Bau, R.; Olah, G. A. J.
Am. Chem. Soc. 1997, 119, 1572.
37. Hartgraves, G. A.; Burton, D. J. J. Fluorine Chem. 1998, 39, 425.
14

38. Prakash, G. K. S.; Hu, J.; Mathew, T.; Olah, G. A. Angew. Chem. Int. Ed. 2003, 42,
5216.
39. Prakash, G. K. S.; Hu, J.; Wang,Y.; Olah, G. A. Org. Lett. 2004, 6, 4315.
40. Prakash, G, K, S; Hu, J; Wang,Y; Olah, G, A. Eur. J. Org. Chem. 2005, 2218.
41. Prakash, G. K. S.; Hu, J.; Wang,Y.; Olah, G. A. Angew. Chem. Int. Ed. 2004, 43,
5203.
42. Li, Y.; Ni, C.; Liu, J.; Zhang, L.; Zheng, J.; Zhu, L.; Hu, J. Org. Lett. 2006, 8,1693.
43. Ni, C.; Li, Y.; Hu, J. J. Org. Chem. 2006, 71, 6829.
44. Fukuzumi, T.; Shibata, N.; Sugiura, M.; Yasui, H.; Nakamura, S.; Toru, T. Angew.
Chem. Int. Ed. 2006, 45, 4973.

15
2 Chapter 2: Stereoselective Monofluoromethylation of
Primary and Secondary Alcohols Using a Fluorocarbon
Nucleophile in Mitsunobu Reactions
2.1 Chapter 2: Introduction

Stereoselective monofluoromethylation is one of the major areas of interest to life
scientists since fluoromethyl substituted compounds carry great importance in biological
systems, medical treatments and in healthcare.
1,2,3,4,5
Sevoflurane, a new generation of
fluoromethylated anaesthetics is found to have fast uptake and elimination properties.
6

The selective peripheral activity of α-monofluoromethyl-dopa is attributed to the
presence of monofluoromethyl group at the α-carbon.
7
Fluoromethylglutamic acid is
found to inhibit glutamic acid decarboxylase, and 4-amino-5-fluoropentanoic acid is
found to be effective in blocking γ-aminobutyric acid (GABA) transaminase and is
recognized as potential anticonvulsant.
8,9,10,11
The biomedical toxic defensive mechanism
of the shrub Dichapetalum Cymosum towards mammals is due to the presence of
fluoroacetate.
12
Monofluoroacetic acid has been found to be an inhibitor for Krebs
cycle.
13
An effective method for the diastereoselective monofluoromethylation of imines
using fluoromethyl phenyl sulfone has been reported recently by Hu et. al.
14
Palladium
catalysed stereoselective monofluoralkylation reported by Shibata et al. requires the
generation of the long lived fluoroalkyl anion, longer reaction times, low temperature and
is only applicable for the fluoroalkylation of allylic acetates.
15
On the otherhand,
Mitsunobu reaction
16,17,18,19
is widely used in organic synthesis due to its mild reaction
16
conditions, stereospecificity, and versatility. There has been significant progress made in
recent years in the reagent modification and in the application of Mitsunobu
reaction.
20,21,22,23
Mitsunobu reaction has been studied using a variety of substrates, under
different reaction conditions and it provides an efficient protocol towards the formation
of C-O, C-N, C-S, C-X or C-C bond, synthesis of aryl ethers, etc. The most prominent
feature, we noticed during our study, is the inversion of configuration in the case of
secondary alcohols. To our best knowledge, there has been no report on Mitsunobu
reaction using fluorocarbon nucleophiles. In spite of all the improvements in the redox
system, the selection of the acidic component is limited by the pKa of the pronucleophile
for satisfactory results.
24
Falck and co-workers have fine-tuned the acidity of α-hydrogen
in carbon nucleophiles with various electron withdrawing groups to satisfy the
requirement for this reaction.
25,26,27,28
Failed attempts of alkylation of monofluoromethyl
derivatives of similar systems by alkyl halides is reported by Takeuchi.
29
Nucleophilic
fluoroalkylation has been one of the major interests in our group for a decade and
significant progress has been made in this arena.
30,31,32,33
During our study on
stereoselective nucleophilic fluoromethylation, we found that bis(phenylsulfonyl)
substituted fluorocarbon nucleophiles facilitate the reaction even at room temperature.

+
ROH R
F
PPh
3
, DIAD
C
6
H
6
, rt
Reductive
Desulfonation
1
H
H
S
O
O
Ph
S
O
O
Ph
F
H
S
O
O
Ph
S
O
O
Ph
F
R

Scheme 2.1 Mitsunobu Reaction of alcholos using 1-Fluoro-bis(phenyl sulfonyl)methane
17

1-Fluoro-bis(phenyl-sulfonyl)methane (1) for Mitsunobu reaction was used as the
pronucleophile which is the synthetic equivalent of monofluoromethide species. The
reactions were carried out using triphenylphosphine (PPh
3
) and diisopropyl
azodicarboxylate (DIAD) as the redox couple in benzene at room temperature under
neutral conditions to give products in good yields. The presence of phenylsulfonyl group
was very effective in stabilizing the carbanion as well as in counteracting the so called
negative “fluorine effect”.
34
The methodology works efficiently for a wide variety of
alcohols including primary, secondary, allylic, alicyclic and benzylic alcohols. The
reaction proceeds through a typical S
N
2
type pathway leading to stereochemical inversion
(Walden inversion). With chiral alcohols, the inverted adducts were obtained with high
enantiomeric excess up to 98%. Mitsunobu reaction followed by reductive
desulfonylation has been applied for the synthesis of monofluoromethylated Vitamin D3.
Monofluro-bis(phenylsulfonyl) derivative of 1,2,3,4-tetra-O-acetyl- β-D-glucopyranose
was also synthesized by following this protocol.
2.2 Chapter 2: Results and Discussion

The reactions of 1-fluoro-bis(phenylsulfonyl)methane with primary, secondary,
allylic, benzylic and alicyclic alcohols were found to produce the corresponding 1-fluoro-
bis(phenylsulfonyl) derivatives under suitable reaction conditions. The reaction was
carried out under an inert atmosphere, by adding DIAD slowly to the reaction flask
containing a mixture of alcohol, 1-fluoro-bis(phenylsulfonyl)methane and PPh
3
. The
18
progress of the reaction was monitored by
19
F NMR and found to be complete in 1 hour.
Highest yields were obtained when 1 equivalent of 1-fluoro-bis(phenylsulfonyl)methane
was treated with 1.1 equivalent of alcohol and 1.5 equivalents of the redox couple at
room temperature in benzene as a solvent. Primary and benzylic systems were found to
react faster and give the products in excellent yields while the reaction with secondary
alcohols and crowded systems were slightly sluggish.
Table 2.1 Mitsunobu reaction of various alcohols with 1-fluoro-
bis(phenylsulfonyl)methane

PPh
3
,DIAD
C
6
H
6
,rt
Entry
[a]
Yield (%)
[b]
1
2
3
Ph 4
5
90
Ph
2
CHCH
2
6
Ph
7
CH
3
(CH
2
)
5
8
(CH
2
)
5
9
10
R
2
R
3
H
H
H
CH
3
CH
2
Ph
CH
3
2-naphthyl CH
3
Ph-CH=CH
H
H
81
75
60
80
73
73
67
60
75
p -Tolyl
R
2
R
3
HO
+
R
2
R
3
CF(SO
2
Ph)
2
1
[a]
In all cases, DIAD (1.5 equiv) in dry benzene was added to a
mixture of 1 (1equiv), PPh
3
(1.5 equiv), alcohol (1.1 equiv) in benzene
at room temperature.
[b]
isolated yield
5
5
a
b
c
d
e
f
g
h
i
j
CH
3
(CH2)
7
(CH
3
)
2
C=CH

19

Mitsunobu reaction proceeds through activation of the alcohol by the redox couple to
form the oxophosphonium intermediate and displacement of the activated hydroxyl group
by the nucleophile. It has been reported that the enantiospecificity of Mitsunobu reaction
by Walden inversion of secondary chiral alcohols varies up to 99% ee. The yield of the
inverted product depends on the pKa of the pronucleophile and the steric environment of
the reacting alcohols.
35, 36

CH
3
OH
+
PPh
3
, DIAD
C
6
H
6
, rt
CH
3
CF(SO
2
Ph)
2
1

Figure 2.1 Crystal structure of monofluoromethyl adduct of (S)-(-)- α-methyl-2-
naphthalenemethanol

20
To estimate the enantiospecificity of the reaction in benzene at room temperature,
we have chosen three different chiral alcohols as representative examples and found that
the reaction proceeds through a stereochemical inversion of configuration, which gave
enantiomeric excess (ee) up to 98% (Table 2.2), as determined by chiral HPLC analysis.
The inversion of the chiral center has been confirmed by X-ray crystallographic analysis
of the product obtained from the Mitsunobu reaction of (S)-(-)- α-Methyl-2-
naphthalenemethanol with 1-fluoro-bis(phenylsulfonyl)methane . The product is found to
have R absolute configuration as evident from the crystal structure (Figure 2.1).
Inspired by the excellent stereospecificity of this reaction, we continued our study
by subjecting the products to reductive desulfonylation reaction. It is found that the use of
activated magnesium in methanol at 0
o
C
37
produces selectively the desulfonylated
monofluoromethyl derivatives and the methodology works well for primary, secondary,
and even allylic systems (Table 2.3).

Table 2.2 Walden inversion of chiral alcohols using Mitsunobu reaction

Entry R-OH % ee
[a]
1
2
3
S-2-octanol
R-2-octanol
96
96
98
[a]
Determined by HPLC analysis using CHIRALPAK AD-H Column using hexane and
isopropanol in 80:20 ratio
S-PhCH(OH)CH
3
R-CF(SO
2
Ph)
2
CH
3
(CH
2
)
5
CH(CH
3
)CF(SO
2
Ph)
2
CH
3
(CH
2
)
5
CH(CH
3
)CF(SO
2
Ph)
2
PhCH(CH
3
)CF(SO
2
Ph)
2

21
Table 2.3 Reductive desulfonylation using activated magnesium and methanol
Entry
[a]
Yield [%]
[b]
1
PhCH(CFH
2
)CH
2
Ph 76 2
3 PhCH=CH-CH
2
CFH
2
74
PhCH{CF(SO
2
Ph)
2
}CH
2
Ph
Ph
2
CH(CH
2
)
2
CFH
2
81
[a]
In all cases, the reaction was carried out in methanol using activated
magnesium at 0
o
C.
[b]
isolated yield.
R-CF(SO
2
Ph)
2
R-CFH
2
PhCH=CH-CH
2
CF(SO
2
Ph)
2
Ph
2
CH(CH
2
)
2
CF(SO
2
Ph)
2

After establishing an easy route to generate chiral monofluoromethyl derivatives,
we applied this methodology for the synthesis of biologically important molecules, sugars
etc. Vitamin D
3
and its fluoroderivatives are used as molecular probes for vitamin D
metabolites and their target molecules. Various synthetic vitamin D analogues
(deltanoids) are being recognized for their potent antiproliferative, prodifferentiative, and
immuno-modulatory activities.
38, 39, 40
Using our methodology we were successful in the
stereoselective synthesis of monofluoromethylated vitamin D
3
, under very mild
conditions (Scheme 2.2).

22
Scheme 2.2 Monofluoromethylation of Vitamin D
3

H
3
C
CH
3
CH
2
H
H
3
C
CH
3
CH
2
H
F
PhO
2
S
SO
2
Ph
H
3
C
CH
3
CH
2
H
H
H
HO
1, PPh
3
, DIAD
C
6
H
6
, rt
58 %
Mg/MeOH
0
0
C
67 %
F

Fluorinated carbohydrates are found to be very important in enzyme-carbohydrate
interaction studies due to their intrinsic biological activities.
41, 42, 43
The bioisosteric
properties of C-F bond with C-OH bond and its ability to participate in hydrogen bonding
make some of the fluorinated sugars as glycosylation inhibitors. This methodology has
been used for the synthesis of monofluoro-bis(phenylsulfonyl)-1,2,3,4-tetra-O-acetyl-β-
D-glucopyranose. The parent compound is found to be important in the study of
substrates for inositol synthase and also in the preparation of anionic surfactants.
44, 45
Scheme 2.3 Mitsunobu reaction of 1,2,3,4-tetra-O-acetyl- β-D-gluco pyranose

O
OAc AcO
AcO
OAc
PPh
3
, DIAD
C
6
H
6
, rt
1
CF(SO
2
Ph)
2
+
O
OAc AcO
AcO
OAc
OH

This reaction is found to be applicable to other monofluoro systems with the
appropriate pKa. We have synthesized monofluorophenylsulfonyl nitromethane (6) from
phenylsulfonyl nitromethane by the electrophilic fluorination using Selectfluor.
46
It
23
smoothly underwent Mitsunobu reaction under the reaction conditions giving the adduct
(7) in high yields. This expands the versatility and scope of this reaction to produce a
range of synthetically important monofluoroorganics.
Scheme 2.4 Monofluoronitromethylation of alcohols using Mitsunobu reaction

S NO
2
F
S NO
2
KOH, CH
3
CN
Selectflour
PPh
3
, DIAD
(90 %)
6
7
H H
H
O
O
Ph
Ph
O O
CH
2
OH
CH
3
H
2
C
CH
3
S
Ph
O
O
O
2
N
F
+
C
6
H
6
, rt
6

2.3 Chapter 2: Conclusion

In conclusion, we have reported a new, efficient Mitsunobu reaction using
fluorinated carbon pronucleophile for the facile synthesis of monofluoromethyl
derivatives of alcohols. This reaction can be performed under mild conditions and is
highly feasible for primary, secondary, allylic, benzylic and alicyclic alcohols. Excellent
enantioselectivity is observed for chiral alcohols. The versatile synthetic utility of this
method has been manifested by the synthesis of monofluoromethylated vitamin D
3
and
24
monofluoromethyl adduct of glucopyranose. Therefore, this methodology provides a
convenient synthetic protocol for the preparation of many organofluorine compounds.
2.4 Chapter 2: Experimental

Unless otherwise mentioned, all the chemicals were purchased from commercial
sources. Sodium hydride (95%, Aldrich) was used as received. Benzene was distilled
over sodium and benzophenone. 1-Fluorobis(phenylsulfonyl)methane was prepared
following literature procedures. Purification of the products was performed by column
chromatography using silica gel (60-200 mesh, with a mixture of hexane and
dichloromethane as eluant).
1
H,
13
C, and
19
F spectra were recorded on 400 MHz Varian
NMR spectrometer.
1
H NMR chemical shifts were determined relative to the signal of
tetramethylsilane as the internal standard ( δ 0.00 ppm).
13
C NMR shifts were determined
relative to the signal of internal TMS at δ 0.00 ppm or to the signal of solvent CDCl
3
at

δ
77.0 ppm.
19
F NMR chemical shifts were determined relative to internal standard CFCl
3

at δ 0.00 ppm. MS analyses were performed on Thermo Femigan TRACE GC/DSQ
spectrometer (at Loker Hydrocarbon Research Institute) and high resolution Micromass
GCT (GC-MS OTF) spectrometer at Dept. of Chemistry, University of Arizona) in EI or
ESI mode. Enantiomeric excess data were determined in LC-8A Shimadzu HPLC with
SPD-10A UV-Vis detector at 254 nm and CHIRALPAK- ADH column. Using 80 : 20
mixture of hexane and isopropanol as eluent at a flow rate of 1.5 mL/min.
25
2.4.1 Typical procedure for Mitsunobu reactions of
fluorobis(phenylsulfonyl)methane with alcohols.

Under an argon atmosphere, into a Schlenk flak containing a mixture of 1-
fluorobis(phenylsulfonyl)methane(314 mg, 1mmol), p-methylbenzyl alcohol (134 mg,
1.1 mmol) and triphenyl phosphine (393 mg, 1.5 mmol) in 5 mL dry benzene was added
via a syringe diisopropyl azodicarboxylate (DIAD) (0.290 mL, 1.5 mmol) in benzene.
The reaction mixture was stirred at room temperature and the completion of the reaction
was monitored by
19
F NMR. After completion, the reaction mixture was quenched by
adding water followed by extraction using dichloromethane (15 mL x 3).The combined
organic phase was dried over MgSO
4
, filtered, and solvent was removed by vacuum
evaporation. The residue was purified by column chromatography (x:y mixture of
hexane-dichloromethane) to give 1, 1-bis(phenylsulfonyl)-1-fluoro- 2-(4-tolyl)ethane 5a
(379 mg, 90 %) as white powder.
1
H NMR (400 MHz, CDCl
3
) : δ 2.27 (s, 3H), 3.80 (d, J = 22 Hz, 2H), 6.91 (s, 4H), 7.44
(m, 4H), 7.64 (m, 2H), 7.75 (m, 4H);
13
C NMR (100 MHz, CDCl
3
) : δ 21.0, 34.6 (d,
2
J
C-F

= 17 Hz), 115.7(d,
1
J
C-F
= 270 Hz), 126.8, 128.7, 128.9, 130.6, 130.9, 134.8, 135.4,
137.4;
19
F NMR (376 MHz, CDCl
3
): δ -142.3 (t, J = 22 Hz); HRMS (FAB): m/z calcd.
for C
21
H
20
FO
4
S
2
[(M+H)
+
] 419.0787, found 419.0805.
1,1-Bis(phenylsulfonyl)-1-fluorodecane (5b)

F
SO
2
Ph
SO
2
Ph

26
1
H NMR (400 MHz, CDCl
3
): δ 0.81 (t, J = 7 Hz, 3H), 1.21-1.52 (m, 14H), 2.22 (m, 2H),
7.55 (m, 4H), 7.71 (m, 2H), 7.83 (m, 4H);
13
C NMR (100 MHz, CDCl
3
) : δ 14.1, 22.3 (d,
3
J
C-F
= 6 Hz), 22.6, 28.9, 29.2, 29.3, 29.7, 30.3 (d,
2
J
C-F
= 18 Hz), 31.8, 115.8 (d,
1
J
C-F
=
266 Hz), 128.9, 130.7, 135.1, 135.4;
19
F NMR (376 MHz, CDCl
3
) δ -142.9 (t, J = 16
Hz); HRMS (FAB): m/z calcd. for C
22
H
30
FO
4
S
2
[(M+H)
+
] 441.1570 , found 441.1568.

1,1-Bis(phenylsulfonyl)- 4,4-diphenyl-1-fluorobutane (5c)

F
SO
2
Ph
SO
2
Ph
Ph
Ph

1
H NMR (400 MHz, CDCl
3
): δ 2.26 (m, 2H), 2.50 (m, 2H), 3.77 (t, J = 7 Hz, 1H), 7.16
(m, 6H), 7.25 (m, 4H), 7.47 (m, 4H), 7.67 (m, 2H), 7.79 (m, 4H);
13
C NMR (100 MHz,
CDCl
3
): δ 28.1 (d,
3
J
C-F
= 6 Hz), 29.6 (d,
2
J
C-F
= 19 Hz), 51.1, 115.3 (d,
1
J
C-F
= 266 Hz),
126.4, 127.7, 128.6, 128.9, 130.7, 134.9, 135.1, 143.4;
19
F NMR (376 MHz, CDCl
3
): δ -
141.7 (t, J = 16 Hz); HRMS (FAB): m/z calcd. for C
28
H
26
FO
4
S
2
[(M+H)
+
] 509.1257,
found 509.1281.

1,1-Bis(phenylsulfonyl)-1-fluoro-2-phenylpropane (5d)

Ph
H
3
C
F
SO
2
Ph
SO
2
Ph

27
1
H NMR (400 MHz, CDCl
3
): δ 2.00 (d, J = 8 Hz, 3H), 4.00(m, 1H), 7.09-7.40 (m, 13H),
7.63 (m, 1H), 7.83 (m, 2H).
13
C NMR (100 MHz, CDCl
3
) δ 14.6 (d,
3
J
C-F
= 5 Hz) , 42.4
(d,
2
J
C-F
= 16 Hz), 116.5 (d,
1
J
C-F
= 267 Hz), 127.7, 127.8, 128.2, 128.7, 130.3, 130.9,
131.0, 134.3, 134.9, 135.2, 135.7, 136.7;
19
F NMR (376 MHz, CDCl
3
): δ -127.4 (d, J = 9
Hz). HRMS (FAB): m/z calcd for C
21
H
20
FO
4
S
2
[(M+H)
+
] 419.0787 , found 419.0799.

1,1-Bis(phenylsulfonyl)- 2,3-diphenyl-1-fluoropropane (5e)

Ph
Ph
PhO
2
S
SO
2
Ph
F

1
H NMR (400 MHz, CDCl
3
): δ 3.80 (m, 1H), 4.09 (m, 1H), 4.14 (m, 1H), 7.07-7.14 (m,
10H), 7.41 (m, 2H), 7.49 (m, 2H), 7.61(m, 1H), 7.68 (m, 1H), 7.75 (m, 2H), 7.81 (m,
2H);
13
C NMR (100 MHz, CDCl
3
): δ 34.2 (d,
3
J
C-F
= 3Hz), 51.6 (d,
2
J
C-F
= 17 Hz), 115.9
(d,
1
J
C-F
=269 Hz), 126.2, 127.8,128.2, 128.4, 128.9, 129.0, 130.8, 130.9, 131.2, 132.8,
132.9, 134.6, 134.7, 135.1, 136.8, 139.1,;
19
F NMR (376 MHz, CDCl
3
): δ -127.3(d, J = 5
Hz). HRMS (FAB): m/z calcd. for C
27
H
24
FO
4
S
2
[(M+H)
+
] 495.1100 , found 495.1093.

1,1-Bis(phenylsulfonyl)-1-fluoro-2-methyloctane (5e)

CF(SO
2
Ph)
2

28
1
H NMR (400 MHz, CDCl
3
): δ 0.85 (t, J = 6 Hz, 3H), 1.21-1.41 (m, 11H), 1.61 (m, 1H),
2.04 (m, 1H), 2.45 (m, 1H), 7.48 (m, 4H), 7.64 (m, 2H), 7.83 (m, 4H);
13
C NMR (100
MHz, CDCl
3
): δ 13.6, 13.9, 22.5, 28.1, 28.8, 29.9, 31.6, 38.4 (d,
2
J
C-F
= 16 Hz), 117.5 (d,
1
J
C-F
= 265 Hz), 128.7, 128.8, 130.7, 130.8, 134.8, 134.9, 136.1, 136.3;
19
F NMR (376
MHz, CDCl
3
) δ -132.8; HRMS (FAB): m/z calcd. for C
21
H
28
FO
4
S
2
[(M+H)
+
] 427.1413 ,
found 427.1413.

1,1-Bis(phenylsulfonyl)-1-fluoro-2-(2-naphthyl)propane (5g)

F
SO
2
Ph
SO
2
Ph

1
H NMR (400 MHz, CDCl
3
): δ 2.07(d, J = 7 Hz, 3H), 4.17 (m, 1H), 6.96 (t, J = 8 Hz,
2H), 7.14 (m, 1H), 7.23 (m, 1H), 7.30-7.62 (m, 11H), 7.82 (d, J = 8 Hz, 2H);
13
C NMR
(100 MHz, CDCl
3
): δ 14.7, 42.3 (d,
2
J
C-F
= 17 Hz), 116.8 (d,
1
J
C-F
= 267 Hz), 125.9,
126.2, 127.1, 127.2, 127.8, 127.9, 128.6, 129.5, 130.1, 131.0, 132.6, 132.7, 133.1, 134.0,
134.8, 135.6, 136.6;
19
F NMR (376 MHz, CDCl
3
): δ -128.12 (d, J = 11 Hz). HRMS
(FAB): m/z calcd. for C
25
H
22
O
4
FS
2
[(M+H)
+
] 469.0944 , found 469.0938.

29
1,1-Bis(phenylsulfonyl)-1-fluoro-4-phenylbut-3-ene (5h)

F
SO
2
Ph
SO
2
Ph

1
H NMR (400 MHz, CDCl
3
): δ 3.26 (dd, J = 18 Hz, 7 Hz, 2H), 5.88 (m, 1H), 6.26 (d, J =
16 Hz, 1H), 7.16 (m, 5H), 7.44 (m, 4H), 7.60 (m, 2H), 7.86 (m, 4H);
13
C NMR (100
MHz, CDCl
3
): δ 33.8 (d,
2
J
C-F
=16 Hz), 114.6 (d,
1
J
C-F
= 265 Hz), 117.7 (
3
J
C-F
, J = 7 Hz),
126.4, 127.9, 128.5, 128.9, 130.9, 135.2, 135.3, 136.1, 136.2;
19
F NMR (376 MHz,
CDCl
3
): δ -142.93 (t, J = 18 Hz). MS(ESI) (m/z) [(M+H)
+
] 430.9.

1,1-Bis(phenylsulfonyl)-1-fluoro-4-methylpent-3-ene (5i)

SO
2
Ph
SO
2
Ph
F

1
H NMR (400 MHz, CDCl
3
): δ 1.37 (s, 3H), 1.51 (s, 3H), 3.05 (dd, J =16 Hz, 9 Hz, 2H),
4.89 (t, J = 7Hz , 1H), 7.48 (m, 4H), 7.63 (m, 2H), 7.85 (m, 4H);
13
C NMR (100 MHz,
CDCl
3
): δ 17.8, 25.8, 29.0 (d,
2
J
C-F
= 20 Hz), 112.1 (d,
3
J
C-F
= 6 Hz), 115.3 (d,
1
J
C-F
= 267
Hz), 128.9, 130.8, 135.1, 135.6, 138.2;
19
F NMR (376 MHz, CDCl
3
): δ -143.7 (t, J = 18
Hz); HRMS (FAB): m/z calcd. for C
18
H
20
FO
4
S
2
[(M+H)
+
] 383.0787, found 383.0804.
30
1,1-Bis(phenylsulfonyl)-1-cyclohexyl-1-fluoromethane (5j)

PhO
2
S
SO
2
Ph
F

1
H NMR (400 MHz, CDCl
3
): δ 1.04-1.22 (m, 4H), 1.65-1.80 (m, 4H), 2.13 (m, 2H), 2.30
(m, 1H), 7.51 (m, 4H), 7.68 (m, 2H), 7.86 (m, 4H).
13
C NMR (100 MHz, CDCl
3
) δ 25.7,
26.4 (d,
3
J
C-F
=6 Hz), 26.7, 43.8 (d,
2
J
C-F
= 17 Hz), 116.8 (d,
1
J
C-F
=266 Hz); 128.8, 130.7,
134.9, 136.3.
19
F NMR (376 MHz, CDCl
3
) δ –135.9. HRMS (FAB): m/z calcd. for
C
19
H
22
FO
4
S
2
[(M+H)
+
] 397.0944, found 397.0944.
2.4.2 Crystal Structure of C
25
H
21
O
4
S
2
F

Diffraction data were collected at 150 K on a SMART APEX CCD diffractometer with
graphite fine-focused monochromatic Mo-K
α
radiation ( λ = 0.71073 Ǻ). The cell
parameters for (C
25
H
21
O
4
S
2
F) were obtained from the least-squares refinement of the
spots (from 60 collected frames) using the SMART program of a colorless crystal sample
measuring 1.0 x 0.22 x 0.05 mm
3
in size. A hemisphere of data were collected up to a
resolution of 0.75 Ǻ, the intensity data were processed using the Saint Plus program. All
calculations for the structure determination were carried out using the SHELXTL
package (version 6.14).
47
Initial atomic position were located by direct methods using
XS, and the structure was refined by the least square methods using SHELX with 3478
independent reflections and within the range of theta 2.27 to 27.45
o
(completeness
31
94.2%). Absorption corrections were applied by SADABS.
48
Calculated hydrogen
position were input and refined in a riding manner along with the corresponding carbons.
A summary of the refinement details and the resulting factors are given in Table
(C
25
H
21
O
4
S
2
F).
Table 2.4 Crystal data and structure refinement for C
25
H
21
O
4
S
2
F

Identification code x2so2phm
Empirical formula C25 H21 F O4 S2
Formula weight 468.54
Temperature 423(2) K
Wavelength 0.71073 Å
Crystal system Triclinic
Space group P1
Unit cell dimensions a = 8.037(2) Å ∝ = 92.665(4)°.
b = 8.092(2) Å β = 105.050(4)°.
c = 9.342(2) Å γ = 105.115(4)°.
Volume 562.2(3) Å
3

Z 1
Density (calculated) 1.384 Mg/m
3

Absorption coefficient 0.275 mm
-1

F(000) 244
Crystal size 1.0. x 0.22 x 0.05 mm
3

32
Theta range for data collection 2.27 to 27.45°.
Index ranges -9<=h<=10, 10<=k<=9, -12<=l<=8
Reflections collected 3478
Independent reflections 2877 [R(int) = 0.0378]
Completeness to theta = 27.45° 94.2 %
Absorption correction None
Refinement method Full-matrix least-squares on F
2

Data / restraints / parameters 2877 / 3 / 291
Goodness-of-fit on F
2
1.057
Final R indices [I>2sigma(I)] R1 = 0.0546, wR2 = 0.1426
R indices (all data) R1 = 0.0568, wR2 = 0.1451
Absolute structure parameter 0.07(11)
Extinction coefficient 0.000(7)
Largest diff. peak and hole 0.785 and -0.293 e.Å
-3
2.4.3 Typical procedure for reductive desulfonylation of fluorobis(phenylsulfonyl)
derivatives

Under argon atmosphere, excess activated Mg turnings were added into a Schlenk
flask containing 1,1-bis(phenylsulfonyl)-1-fluoro-4-phenyl but-3-ene 5h (0.215g, 0.5
mmol) in 5 mL anhydrous methanol at 0
o
C. The reaction mixture was stirred at 0
o
C and
the completion of the reaction was monitored by
19
F NMR. Fresh Mg turnings were
added after 2 hours to ensure the complete conversion. The reaction mixture was filtered,
33
washed with dilute HCl and water followed by extraction with dichloromethane (3 x 15
mL). The combined organic layers were collected and the solvent was removed under
reduced pressure. The crude product was purified by flash chromatography, to provide
the pure product 6h (110 mg, 74%).
1-Fluoro-4-phenylbut-2-ene.

F

1
H NMR (400 MHz, CDCl
3
): δ 2.50 (m, 2H), 4.40 (t, J = 6 Hz, 1H), 4.52 (t, J = 6 Hz,
1H), 6.13 (m, 1H), 6.42 (d, J = 16 Hz, 1H), 7.12-7.29 (m, 5H);
13
C NMR (100 MHz,
CDCl
3
): δ 53.3, 83.1 (d,
1
J
C-F
= 166 Hz), 124.5, 126.0, 127.2, 128.2, 128.4, 132.7, 137.1;

19
F NMR (376 MHz, CDCl
3
): δ -217.8 (m). HRMS (EI): m/z calcd. for C
10
H
11
F [M
+
]
150.0845 , found 150.0832.

2,3-Diphenyl-1-fluoropropane.

F

1
H NMR (400 MHz, CDCl
3
): δ 2.86 (m, 1H), 3.04-3.14 (m, 2H), 4.41 (m, 1H), 4.53 (m,
1H), 6.99-7.21 (m, 10H);
13
C NMR (100 MHz, CDCl
3
): δ 37.9 (d,
3
J
C-F
= 5 Hz), 43.2 (
2
J
C-
34
F
= 19 Hz), 85.7 (d,
1
J
C-F
= 172 Hz), 126.1, 126.8, 127.9, 128.2, 128.4, 129.0, 139.0,
140.7;
19
F NMR (376 MHz, CDCl
3
): δ -221.90 (m). HRMS (EI): m/z calcd. for C
15
H
15
F
[(M
+
] 214.1158 , found 214.1166.

4,4-Diphenyl-1-fluorobutane

F

1
H NMR (400 MHz, CDCl
3
): δ 1.67(m, 2H), 2.17 (m, 2H), 3.92 (t, J = 8 Hz, 1H), 4.43
(td, J = 47 Hz, 6 Hz, 2H), 7.15-7.30 (m, 10H);
13
C NMR (100 MHz, CDCl
3
): δ 31.2, 31.3,
50.8, 83.7 (d,
1
J
C-F
=164 Hz), 126.2, 127.7, 128.4, 144.5;
19
F NMR (376 MHz, CDCl
3
): δ-
219.06 (m).
2.4.4 Synthesis of monoflouromethyl vitamin D
3
.

Monofluoromethyl vitamin D3 was synthesized from vitamin D
3
, following the same
procedures as mentioned above.
35
H
3
C
CH
3
CH
2
H
F
PhO
2
S
SO
2
Ph

1
H NMR (400 MHz, CDCl
3
): δ 0.54-2.84 (m, 39H), 4.85 (m, 1H), 5.04 (m, 1H), 6.01 (d,
J=10Hz, 1H), 6.16 (d, J = 10Hz, 1H), 7.51 (m, 4H), 7.68 (m, 2H), 7.86 (m, 4H);
13
C
NMR (100 MHz, CDCl
3
): δ 11.8, 18.8, 22.3, 22.5, 22.7, 23.6, 23.7, 27.3, 27.5, 27.9, 29.0,
35.5, 36.0, 37.2, 39.4, 40.4, 43.6, 43.8, 45.9, 56.3, 56.6, 113.1, 116.2 (d, J = 272 Hz),
117.3, 121.5, 128.8, 128.9, 130.7, 130.8, 130.8, 130.9, 134.9, 136.0, 136.1, 142.7, 144.1;

19
F NMR (376 MHz, CDCl
3
): δ -136.02. HRMS (FAB): m/z calcd for C
40
H
54
FO
4
S
2
[(M+H)
+
] 681.3447, found 681.3496.

1-fluoro-1,1-bis(phenylsulfonyl)-1-fluoromethyl substituted 1,2,3,4-tetra-O-acetyl- β-
D-glucopyranose (3)
O
OAc AcO
AcO
OAc 3
CF(SO
2
Ph)
2

36
1
H NMR (400 MHz, CDCl
3
): δ 1.98-2.12 (m, 12H ), 2.45 (m, 1H ), 2.87 (m, 1H ), 4.15 (t,
J = 9 Hz, 1H), 4.82 (t, J = 10 Hz, 1H), 4.96 (t, J = 9Hz, 1H), 5.19 (t, J = 10 Hz, 1H), 5.55
(d, J = 8 Hz, 1H), 7.51-7.98 (m, 10H);
13
C NMR (100 MHz, CDCl
3
): δ 20.5, 20.6, 20.7,
31.8, 31.9, 69.6, 69.7, 70.1, 70.7, 72.4, 91. 0, 113.1 (d, J = 271 Hz), 128.9, 130.8, 131.1,
133.9, 134.8, 135.1, 135.4, 168.2, 169.3, 169.8, 170.1;
19
F NMR (376 MHz, CDCl
3
): δ -
147.7 (dd, J = 23 Hz, 9 Hz); HRMS (ESI): m/z calcd. for C
27
H
29
FO
13
S
2
Na [(MNa)
+
]
667.0931, found 667.0924.

1-Fluoro--1-nitro 1-phenylsulfonyl -2-(4-tolyl)ethane

SO
2
Ph
F
NO
2

1
H NMR (400 MHz, CDCl
3
): δ 2.22, 3.68 (m), 4.02(m), 6.99(m), 7.55(m), 7.74(m),
7.85(m).
13
C NMR (100MHz, CDCl
3
): δ 18.74, 33.3(d, J=18 Hz), 120.9(d, J=281 Hz),
122.3, 127.3, 127.4, 127.8, 128.4, 128.8, 133.9, 136.3.
19
F NMR (376 MHz, CDCl
3
) δ -
125.6 (dd, J=35Hz, 9 Hz). HRMS (EI): m/z calcd for C
15
H
14
NF0
4
S [M
+
] 323.0628, found
323.0630.

37
2.5 Chapter 2: Representative Spectra

19
F NMR Spectrum of 5a

38
1
H NMR Spectrum of 5a

39
13
C Spectrum of 5a

40
19
F NMR Spectrum of 1-Fluoro-4-phenylbut-2-ene

41
1
H NMR Spectrum of 1-Fluoro-4-phenylbut-2-ene (6h)

42
13
C NMR Spectrum of 1-Fluoro-4-phenylbut-2-ene (6h)

43
2.6 Chapter 2 References

1. Smart, B. E. J. Fluorine Chem. 2001, 109, 3.
2. Kirsh, P. Modern Flouroorganic Chemistry, Wiley-VCH, Weinheim, 2004.
3. Banks, R. E.; Smart, B. E.; Tatlow, J. C. Organofluorine Chemistry: Principles and
Commercial Applications, Plenum, New York, 1994.
4. Kirk, K. L. J. Fluorine Chem. 2006, 127, 1013.
5. Begue, J.; Bonnet-Delpon, D. J. Fluorine Chem, 2006, 127, 992.
6. Hiyama, T. Organofluorine Compunds Springer, Berlin, 2000.
7. Welch, J. T. Tetrahedron 1987, 43, 3123.
8. Kuo, D.; Rando, R. R. Biochemistry 1981, 20, 506.
9. Silverman, R. B., Levy, M. A. J. Org. Chem. 1980, 45, 815.
10. Silverman, R. B.; Levy, M. A. Biochemistry 1980, 20, 1197.
11. Silverman, R. B.; Levy, M. A. Biochem. Biophys. Res. Commun. 1980, 95, 250.
12. Harper, D. B.; O’Hagan, D. Nat. Prod. Rep. 1994, 11, 123.
13 Gribble, G. W. J. Chem. Edu. 1973, 50, 460.
14. Li, Y.; Ni, C.; Liu, J.; Zhang, L.; Zhang, J.; Zhu, L.; Hu, J. Org. Lett. 2006, 8, 1693.
15. Fukuzumi, T.; Shibata, N.; Sugiura, M.; Yasui, H.; Nakamura, S.; Toru, T. Angew.
Chem. Int. Ed. 2006, 45, 4973.
16. Mitsunobu, O. Synthesis 1981, 1.
17. Hughes, D. L. Organic Reactions, Wiley, New York 1992, 42, 335.
18. Mitsunobu, O.; Eguchi, M. Bull. Chem. Soc. Jpn. 1971, 44, 3427.
19. Hughes, D. L. Org. Prep. Proced. Int. 1996, 28, 127.
20. Dembinsky, R. Eur. J. Org. Chem. 2004, 13, 2763.
44

21. Ito, S.; Tsunoda, T. Pure Appl. Chem. 1999, 71, 1053.
22. Dandapani, S.; Curran, D. P. Chem. Eur. J. 2004, 10, 3130.
23. But, T. Y. S.; Toy, P. T. J. Am. Chem. Soc. 2006, 128, 9636.
24. Tsunoda, T.; Nagaku, M.; Nagino, C.; Kawamura, Y.; Ozaki, F.; Hioki, H.; Ito, S.
Tetrahedron Lett. 1995, 36, 2531.
25. Yu, J.; Cho, H.; Falck, J. R. J. Org. Chem. 1993, 58, 5892.
26. Li, J.; Yu, J.; Hawkins, R. D.; Falck, J. R. Tetrahedron Lett . 1995, 36, 5691.
27. Yu, J.; Cho, H.; Falck, J. R. Tetrahedron Lett. 1995, 36, 8577.
28. Yu, J.; Falck, J. R. J. Org. Chem. 1992, 57, 3757.
29. Takeuchi, Y.; Nagata, K.; Koizumi, T. J. Org. Chem. 1989, 54, 5453.
30. Prakash, G. K. S.; Yudin, A. K. Chem. Rev. 1997, 97, 757.
31. Prakash, G. K. S.; Hu, J.; Olah, G. A. J. Org. Chem. 2003, 68, 4457.
32. Prakash, G. K. S.; Mandal, M. J. Am. Chem. Soc. 2002, 124, 6538.
33. Prakash, G. K. S.; Hu, J. ACS Symposium Series 2005, 911, 16.
34. Ni, C.; Li, C.; Hu, J. J. Org. Chem. 2006, 71, 6829.
35. Martin, S. F.; Dodge, J. A. Tetrahedron Lett. 1991, 32, 3017.
36. Saiah, M.; Bessodes, M.; Antonkias, K. Tetrahedron Lett. 1992, 33, 4317.
37. Brown, A. C.; Caprino, L. A. J. Org. Chem, 1985, 50, 1749.
38. Nagpal, S.; Na, S.; Rathnachalam, R. Endocr. Rev. 2005, 26, 662.
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40. Giuffredi, G.; Bobbio, C.;Gouverneur, V.J. Org. Chem. 2006, 71, 5361.
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2000, 11, 607.
45

42. Schaffrath, C.; Cobb, S. L.; O’Hagan, D.Angew. Chem. Int. Ed. 2002, 41, 3913.
43. Card, P. J. J. Org. Chem. 1983, 48, 393.
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46
3 Chapter 3: New Electrophilic Difluoromethylating Reagent

3.1 Chapter 3: Introduction

Difluoromethyl group is known to be isosteric and isopolar to a carbinol (CH
2
OH)
unit and can act as a hydrogen donor through hydrogen bonding.
1,2
These properties make
it a very attractive building block in medicinal chemistry and drug discovery. Due to
unique lipophilic and CH
2
OH like substituent character, methods for the introduction of
CF
2
H building block are becoming increasingly important. In contrast to
trifluoromethylation procedures, new methods for the direct introduction of a
difluoromethyl group to organic molecules are still relatively sparse. While several new
methods for the coupling of difluoromethyl moiety to electrophilic carbon have been
reported recently, there are few methods for the synthesis O- and S- difluoromethyl
ethers, esters, CF
2
H-phosphonium salts, and N-difluoromethylated heterocyclic
compounds. Chlorodifluoromethane,
3,4
fluorosulfonyldifluoroacetic acid,
5
and difluoro
diazirine
6
have been indicated as the most commonly used reagents for the introduction
of difluoromethyl group to oxygen, sulfur, phosphorus and nitrogen nucleophiles. It is
worth mentioning that the difluoromethylation efficiency of fluorosulfonyldifluoroacetic
acid, difluorodiaziridine, chlorodifluoromethane and 2-chloro-2,2-difluoro-acetophenone
is due to singlet difluorocarbene generated in situ by their decomposition.
7
To the best of
our knowledge, an electrophilic reagent for the direct introduction of ‘CF
2
H
+’
is yet to be
reported. This might be due to the acidity of the proton in CF
2
H group, which can lead to
47
the protonation (deactivation) of the nucleophilic substrate and to the decomposition of
the reagent. This phenomenon makes it more difficult to find an appropriate
difluoromethylating reagent compared to the trifluoromethylating agents. S-
(trifluoromethyl)dibenzo-thiophenium (1) and S-(trifluoromethyl)diphenyl-sulfonium
salts (2) constitute an important subset of these reagents (Figure 3.1). They are known to
be powerful electrophilic trifluoromethylation agents, which are successfully used for the
trifluoromethylation of a wide range of substrates differing in reactivity
8,9,10,11,12, 13,14
However, either S-(difluoromethyl)ibenzothiophenium nor S-
difluoromethyl)diphenylsulfonium salts have been previously reported. Our aim was to
synthesize and explore the chemistry of these compounds to ascertain their use as
electrophilic difluoromethylating reagents. In this chapter, we wish to report the results of
our studies toward the synthesis of S-(difluoromethyl)dibenzothiophenium triflate and S-
(difluoromethyl)diphenylsulfonium tetrafluoroborate and demonstrate the effectiveness
of these reagents in electrophilic difluoromethylation reactions.

S
CF
3 X
S
CF
3 X
X = TfO, BF
4
R
2
R
1
R
3
R
4
R
5
R
1
= H, NO
2
R
2
= H, NO
2
R
3
= H, F
R
4
= H, NO
2
R
5
= H, F
1 2
+
-
-
+
-

Figure 3.1 Electrophilic Trifluoromethylating Agents

48

3.2 Chapter 3: Results and Discussion

Our first target was the preparation of S-(difluoromethyl)dibenzothiophenonium
triflate (8) (Scheme 3.1). 2-[(Difluoromethyl)sulfanyl]biphenyl (5) was prepared by
reacting 2-bromothiophenol (3) with difluorochloromethane followed by Suzuki coupling
of the resulting sulfide
15
(4) with phenylboronic acid. 2-
[Difluoromethyl(sulfinyl)]biphenyl (7) was obtained from the oxidation of the sulfide
with m-chloroperbenzoic acid. An alternative reaction pathway consisting of oxidation of
2-(difluoromethylsulfanyl)bromobenzene (4) followed by Suzuki reaction also proved to
be successful. However, in the latter case the overall yield was lower. Cyclization of the
sulfoxide (7) was carried out by addition of triflic anhydride to the solution in
dichloromethane at 0 ºC. The reaction mixture was warmed up to room temperature and
stirred for 2 hours.
19
F NMR analysis of the reaction mixture showed only a trace amount
of sulfoxide (7). However, the major product was identified as difluoromethyl
trifluoromethanesulfonate (10) instead of the expected sulfonium compound (8).
Formation of the difluoromethyl ester of triflic acid can be explained by the in situ
difluoromethylation of the trifluoromethylsulfonyl anion by the S-
(difluoromethyl)dibenzothiophenonium cation. This is supported by the fact that after the
removal of the solvent quantitative amount of dibenzothiophene (9) was recovered. To
support the formation of the S-(difluorormethyl)dibenzothiophenonium cation, the
cyclization reaction was repeated at -80 ˚C and the reaction mixture was monitored by
49
low temperature
19
F NMR. Under these circumstances no trace of difluoromethyl
trifluoromethanesulfonate was detected. However, a doublet observed at -101.7 ppm in
the
19
F NMR having J = 56.8 Hz coupling constant indicates the formation of S-
(difluoromethyl)dibenzothiophenonium cation. In two hours at – 80 °C, the conversion
was 15% relative to the sulfoxide. Apart from the doublet and the starting materials
signals, no other signals were observed in the
19
F NMR spectrum.

SH
S
CF
2
H
S
CF
2
H O
Br
Br
Br
S
CF
2
H
S
CF
2
H
O
S
S
HF
2
C
CF
3
S
O
O
O HF
2
C
3 4
5
6
7
8
9
10
CF
2
HCl
PhB(OH)
2
m-CPBA
m-CPBA
PhB(OH)
2 78%
64%
92%
72%
56%
Tf
2
O
87%
+
CF
3
S
O
O
O
-

Scheme 3.1 Preparation of S-(Difluoromethyl)dibenzotiophenonium
trifluoromethanesulfonate.

50
In order to compare the reactivity of the S-difluoromethyl-
(dibenzothiophenonium) cation to that of S-trifluoromethyl(dibenzothiophenonium)
cation, a detailed literature search on the possible reaction of the latter with triflate anion
was conducted. It was found that in the case of S-(trifluoromethyl)dibenzothiophenonium
triflate, transfer of the trifluoromethyl group to the triflate anion occurs at a high
temperature of 200 °C. Due to the instability of S-(difluoromethyl)dibenzothiophenonium
triflate at room temperature (the cation is too reactive towards the anion), a different
approach was pursued. Since the reactivity of the S-
(trifluoromethyl)diphenylthiophenium salts (2) is not in the expected fashion, we decided
to prepare an S-(difluoromethyl)-diphenylsulfonium derivative (13).

S
O
CF
2
H
S
CF
2
H
1. Tf
2
O / Et
2
O
- TfOH
2. NaBF
4
/H
2
O/ CH
2
Cl
2
11 12 13
BF
4
Yield: 51%
+
-

Scheme 3.2 Preparation of S-Difluoromethyl-S-phenyl-2,3,4,5
tetramethylphenylsulfonium tetrafluoroborate

In a separate experiment, 2-[(Difluoromethyl)sulfinyl]bromobenzene (6) was
reacted in benzene with triflic anhydride at 0-5 ºC. Apart (or along with) from the
unreacted sulfoxide, a significant amount of difluoromethyl trifluoromethanesulfonate
was identified by
19
F NMR, after two hours of stirring of the reaction mixture. A new
51
signal at –98 ppm having a pattern matching with that of the expected
(difluoromethyl)sulfonium cation was also observed. We concluded that similar to the
dibenzothiophene derivative, the cation reacts with the triflate anion under these
conditions. To increase the stability of the desired (difluoromethyl)diphenyl-sulfonium
cation, introduction of electron donating substituents onto the phenyl ring seemed to be a
reasonable approach.
Difluoromethyl phenyl sulfoxide
16
(11) was prepared from difluoromethyl phenyl
sulfide
17
by oxidation with m-CPBA. The Friedel- Craft type reaction of the sulfoxide
(11) with 1,2,3,4-tetramethylbenzene in the presence of triflic anhydride was found to be
complete in 2 hours by
19
F NMR analysis (Scheme 3.2). As in the previous cases,
difluoromethyl trifluoromethanesulfonate was also detected in the reaction mixture. To
avoid further decomposition of the product, the triflate anion was replaced by less
nucleophilic tetrafluoroborate anion. S-(Difluoromethyl)diphenylsulfonium
tetrafluoroborate (13) obtained by anion exchange was found to be stable for several
weeks at room temperature or several months in the refrigerator. Only 13%
decomposition was observed after 3 months storage at -20 ºC.
During the course of testing the stability of the new reagent in different dry
solvents it was found that it decomposes within several hours in THF, alcohols and DMF.
However, it showed higher stability in acetonitrile and dichloromethane. In acetonitrile,
only 2% decomposition was observed in three days at room temperature. Phenyl 2,3,4,5-
tetramethylphenyl sulfide (15) was identified as the decomposition product in all case.
The first result regarding the CF
2
H transfer ability of the reagent was the formation of the
52
expected CD
3
OCF
2
H in a CD
3
OD solution. After 40 minutes 100% conversion was
observed based on
1
H and
19
F NMR analyses.
The reactivity of the reagent was tested in acetonitrile in a wide variety of
nucleophiles: alcohols, phenols, thiophenols, carboxylic acids, sulfonic acids, 1-
(trimethylsilyloxy)cyclohexene, aniline, imidazole, pyridine, potassium cyanide and
lithium phenylacetylene. In the case of nucleophiles bearing acidic hydrogen the
reactions were attempted both in the presence and absence of alkali carbonates or alkali
bicarbonates. Alkali sulfonates, carboxylates and imidazole were found to be the most
suitable substrates among the nucleophiles studied. The yields were very low in the case
of alcohols and no desired products were detected for phenols, thiophenols and other
carbon nucleophilies. Since O-nucleophiles having less basic character worked well, we
expected that phenols and alcohols with stronger acidic character would also react.
However, substrates such as pentafluorophenol, 2,4,6-trinitrophenol and
hexafluoroisopropanol did not react even under a variety of reaction conditions.
Since sulfonic acids were considered to be one of the most promising substrates in
this methodology, their reactions were studied more thoroughly. Li, Na and K salt of
benzenesulfonic acid were reacted under similar conditions. The highest reactivity was
found in the case of K salt, so was the concomitant decomposition. When these two
factors and the solubility of the sulfonic acid salts were taken into account, sodium salts
were found to be the best choice of substrates.

53

Table 3.1 Reaction of 13 with Sulfonate salts

RS
O
O
O +
S
CF
2
H
BF
4
RS
O
O
O CF
2
H
M
CH
3
CN
-Ph-S-C
6
HMe
4
-MBF
4
+
-
+
-
13 14
15
16

SO
3
Na
SO
3
Na
HO SO
3
Na
SO
3
Na
SO
3
K
SO
3
K
SO
3
Na
O
2
N
SO
3
Na
O
NaO
3
S
SO
3
CF
2
H
SO
3
CF
2
H
HO SO
3
CF
2
H
SO
3
CF
2
H
SO
3
CF
2
H
SO
3
CF
2
H
SO
3
CF
2
H
O
2
N
SO
3
CF
2
H
O
HF
2
CO
3
S
entry starting material (14) product (16)
1
2
3
4
5
6
7
8
condn
60
o
C/12 hr
45
o
C/3 days
rt/6 days
60
o
C/1 day
60
o
C/1 day
60
o
C/3 days
60
o
C/1 day
60
o
C/12 hrs
convn
100
82
100
88
100
92
73
100
yield(%)
b
(%)
a
77
c
67
84
78
89
74
c
54
86
c
a
The conversions were determined by
19
F NMR based on internal standard. The conversions refer to the
substrates.
b
Isolated yields. Reagent / -SO2OM group in substrate (molar ratio) = 2.5 / 1.0.
c
Known
compounds.
a
b
c
d
e
f
g
h
a
b
c
d
e
f
g
h

54
We obtained high conversions using aromatic sulfonic acids having both electron
withdrawing and electron donating substituents. The reaction also was found to be
selective in the case of phenolic as well as vinyl phenylsulfonic acid derivatives. Among
aliphatic sulfonic acids, 10-camphorsulfonic acid afforded the desired product in high
yield and purity. Although sodium carboxylates such as sodium benzoate, acetate or
sodium 4-phenylbutyrate afforded the desired difluoromethyl esters based on
19
F NMR
analyses, they were not stable enough for purification by silica gel column
chromatography.
In the course of testing the reactivity of some nitrogen nucleophiles towards this
reaction, we found that the reagent underwent decomposition without transferring CF
2
H
group to the nitrogen atom in the case of primary and secondary amines. However,
tertiary amines and certain nitrogen containing heterocyclic compounds reacted readily
even at room temperature to give difluoromethylammonium salts and N-
difluoromethylated heterocyclics. (Scheme 3. 3). Imidazole derivatives were found to be
one of the most reactive substrates among the studies as evident by their highly
exothermic reaction with 13 and high yield of the product. It should be noted that the
synthesis of N-difluoromethylammonium compounds from tertiary and N-formyl
secondary amines is known.
18,19
The preparation of of N-(difluoromethyl)imidazolium
derivatives (Scheme 3.3) has not yet been reported in the literature. Perfluorinated
imidazolium salts are of interest as hydrophobic ionic liquids.
20

55
Scheme 3.3 Reaction of (13) with Imidazoles, Phosphines and Tertiary amines.

N N
R
3
CF
2
H
N N
S
CF
2
H
+
MeCN, rt, 16 h
BF
4
BF
4
- Ph-S-C
6
HMe
4
cat. DIAD / CH
2
Cl
2
,rt,16 h
- Ph-S-C
6
HMe
4
BF
4
13
20 R
1
=R
2
=H
21 R
1
=Me, R
2
=H
22 R
1
=R
2
=Me
23 R
2
=H, R
3
=CF
2
H
24 R
2
=H, R
3
=Me
25 R
2
=Me, R
3
=Me
(15)
MeCN, rt, 16 h
NCF
2
H
BF
4
R
1
R
2 R
2
- Ph-S-C
6
HMe
4
15
Yield: 60-70%
Yield: 72-83%
Yield: 77-84%
-
+
-
+
-
-
N
R
1
R
2
R
3
R
1
R
2
R
3
17 R
1
=R
2
=R
3
=Et
18 R
1
=R
2
=Me, R
3
=Ph
19 R
1
=R
2
=Me, R
3
=p-Tolyl
R
3
PCF
2
H
+ 26 R=Ph
27 R=4-Fluorophenyl
28 R=Cyclohexyl
+
PR
3
+
+

Isolated yields. (The conversion referred to the substrate was found to be 100% in all cases.) Reagent /
substrate (molar ratio) = 1.05/1.0. In case of not N-alkylated imidazole 2.1 equiv of reagent was used.

To test the reactivity toward phosphorus nucleophiles, reaction of 13 with
phosphines was carried out (Scheme 3.3). We observed only 15% conversion after 1 day
of stirring at room temperature. However, by repeating the experiment in the presence of
at least 15% of diisopropyl azodicarboxylate, 100% conversion was achieved in 16 hours.
Other phosphines worked equally well under similar conditions. Although
difluoromethyltriphenylphosphonium tetrafluoroborate is a new compound, other related
salts were already known: for example the tetrachlorobismuthate salt was synthesized by
reacting triphenylphosphine with Bi(CF
3
)
3.
21

56
3.3 Chapter 3: Conclusion

In conclusion, S-(difluoromethyl)diphenylsulfonium has been synthesized and
used as a convenient electrophilic difluoromethylating reagent for various oxygen,
nitrogen and phosphorus nucleophiles.
3.4 Chapter 3: Experimental

3.4.1 General

Unless otherwise mentioned, all reagents were purchased from commercial
sources. Dichloromethane was distilled under nitrogen over calcium hydride or was used
as received from Aldrich (water content < 50 ppm). Acetonitrile was distilled under
nitrogen over phosphorus pentoxide or dry acetonitrile (water content < 50 ppm) was
used as received from Aldrich. Diethyl ether was distilled under nitrogen over sodium.
1
H,
13
C,
19
F and
31
P NMR spectra were recorded on Varian Mercury-400 MHz NMR
spectrometer.
1
H-NMR chemical shifts were determined relative to internal
tetramethylsilane (TMS) at 0.00 ppm.
13
C NMR chemical shifts were determined relative
to internal TMS at 0.00 ppm. CFCl
3
was used as internal standard for
19
F and H
3
PO
4
for
31
P NMR. High resolution mass spectral data were recorded in the EI mode on a high
resolution micromass spectrometer at Department of Chemistry, University of Arizona.
Abbreviations: TDA: tris[2-(2-methoxyethoxy)ethyl]amine, m-CPBA: m-
Chloroperbenzoic acid, DCM: dichloromethane, DMSO: dimethylsulfoxide, DIAD:
diisopropyl azodicarboxylate.
57
3.4.2 Preparation of 2-(Difluoromethylsulfanyl)bromobenzene

2-Sulfanylbromobenzene (3) (10 g, 53 mmol) was dissolved in hexane (50 mL).
Finely powdered NaOH (5.3 g, 133 mmol, powdered in glove box) and TDA (0.85 g, 2.6
mmol) were added at room temperature under argon. The reaction mixture was warmed
up to 70 ˚C, a balloon containing argon was attached to the reaction vessel and CF
2
HCl
gas was bubbled into the stirred mixture from a cylinder for 16h. The reaction was
monitored by GC-MS. After complete conversion of the starting material, the mixture
was cooled down to room temperature. The reaction mixture was washed with sodium
carbonate solution (10%, 50 mL) and the organic layer was extracted and washed again
with sodium carbonate solution followed by water (50 mL). The hexane phase was dried
over anhydrous MgSO
4
, the drying agent was filtered and the solvent was removed in
vacuum. The crude product was distilled in vacuum (20 Hgmm, 64 ˚C) to give 9.8 g of
the product as a colorless oil. Yield: 78%.
1
H NMR (CDCl
3
): 6.87 (t, 1H, J
H-F
= 57.5 Hz),
7.20-7.26 (m, 1H), 7.28-7.34 (m, 1H), 7.60-7.68 (m, 2H).
19
F NMR (CDCl
3
): -92.65 (d,
J
H-F
= 57.50 Hz).
13
C NMR (CDCl
3
): 120.6 (t, J
C-F
= 277 Hz), 128.50, 128.52, 129.3,
131.2, 134.0, 136.6. GC-MS (EI, m/z): 239 (M
+
).
3.4.3 Preparation of 2-(Difluoromethylsulfanyl)biphenyl

A mixture of 2-(difluoromethylsulfanyl)bromobenzene (4) (1.07 g, 4.47 mmol),
phenylboronic acid (600 mg, 4.92 mmol), sodium carbonate (531 mg, 4.9 mmol) and
tetrakis(triphenylphosphine)palladium (0) (210 mg, 0.19 mmol) in ethanol (5mL) was
stirred at 100°C for 1 hour in a pressure tube in a microwave reactor (Discover, CEM).
58
The solid was filtered off, the solvent was removed in vacuum and the residue was
purified by silica gel column chromatography (eluent: 0.1% ethyl acetate in hexane) to
give 675 mg of the expected compound as a colorless oil. Yield: 64%.
1
H NMR (CDCl
3
):
6.66 (t, J
H-F
= 56.8 Hz, 1H), 7.3-7.5 (m, 8H), 7.72 (d, 1H, J = 7.9 Hz).
19
F NMR (CDCl
3
):
-91.95 (d, J
H-F
= 56.8 Hz).
13
C NMR (CDCl
3
): 121.1 (t, J
C-F
= 275 Hz), 125.5, 127.8,
128.1, 128.3, 129.6, 129.7, 131.2, 135.6, 140.5, 146.6. GC-MS (EI, m/z): 236 (M
+
).
HRMS calculated for C
13
H
10
F
2
S. Expected: 236.0471. Found: 236.0477.
3.4.4 Preparation of 2-(Difluoromethylsulfinyl)bromobenzene

2-(Difluoromethylsulfanyl)bromobenzene (4, 1.05 g, 4.4 mmol) was dissolved in
DCM (8 mL). m-CPBA (1.52 g, 70%, 6 mmol) was added at 0-3 °C in four portions each
dissolved in DCM (4 mL) over a period of 24h. The reaction mixture was diluted with
cold DCM (100 mL) and extracted with sodium carbonate solution (20%, 2 × 50 mL).
The organic layer was separated and dried over anhydrous magnesium sulfate. The
solvent was evaporated in vacuum to give 0.95 g of the crude product as a white solid
(GC-MS purity: 92%). The crude product was recrystallized from n-hexane to yield 806
mg product having 97% GC purity. Yield: 72%. mp = 62-63 °C.
1
H NMR (CDCl
3
): 6.29
(t, 1H, J
H-F
= 54.5 Hz), 7.40-7.50 (m, 1H), 7.55-7.64 (m, 2H), 7.84-7.90 (m, 1H).
19
F
NMR (CDCl
3
): -115.95 (dd, J
H-F
= 54.5 Hz, J
F-F
= 250.2 Hz), -123.00 (dd, J
H-F
= 54.5 Hz,
J
F-F
= 250.2 Hz).
13
C NMR (CDCl
3
): 120.19, 120.25 (t, J
C-F
= 294 Hz), 120.3, 128.0,
128.9, 133.5, 134.0. HRMS calculated for C
7
H
5
BrF
2
S. Expected: 253.9213. Found:
253.9203.
59
3.4.5 Preparation of 2-(Difluoromethylsulfinyl)biphenyl

Method A: To a solution of 2-(Difluoromethylsulfanyl)biphenyl (420 mg, 1.78
mmol) in DCM (7 mL). m-CPBA (440 mg, 70%, 1.80 mmol) dissolved in CH
2
Cl
2
(12ml)
was added at 0-3 °C in four portions over a period of 12h. The reaction mixture was
diluted with cold DCM (50 mL) and extracted with sodium carbonate solution (20%, 2 ×
20 mL). The organic layer was separated and dried over anhydrous magnesium sulfate.
The solvent was evaporated in vacuum to give the expected product as a white solid
(413mg, 92%) mp 69-70 °C.
Method B: A mixture of 2-(difluoromethylsulfinyl)bromobenzene (500 mg, 1.96
mmol, 4), phenylboronic acid (250 mg, 2.05 mmol), sodium carbonate (210 mg, 1.96
mmol) and tetrakis(triphenylphosphine)palladium (0) (100 mg, 0.09 mmol) in ethanol
(5mL) was stirred at 90 °C for 40 min in a pressure tube in a microwave reactor
(Discover, CEM). The solid was filtered off, the solvent was removed from the filtrate in
vacuum and the residue was purified by silica gel column chromatography (eluent: 0.1%
ethyl acetate in hexane) to give the expected compound as a white solid (288mg, 56%)
mp = 68-69 °C.
1
H NMR (CDCl
3
): 5.83 (t, 1H, J
H-F
= 54.90 Hz), 7.20-7.30 (m, 2H), 7.30-7.44 (m, 4H),
7.50-7.64 (m, 2H) 7.96-8.06 (m, 1H).
19
F NMR (CDCl
3
): -116.27 (dd, J
H-F
= 54.9 Hz, J
F-F
= 254.8 Hz), -121.66 (dd, J
H-F
= 54.9 Hz, J
F-F
= 254.8 Hz).
13
C NMR (CDCl
3
): 121.1 (t,
J
C-F
= 290.7 Hz), 125.7, 128.7, 128.9, 129.0, 129.6, 131.1, 132.6, 135.5, 137.2, 142.4.
60
GC-MS (EI, m/z): 252 (M
+
). HRMS calculated for C
13
H
10
F
2
OS. Expected: 252.0420.
Found: 252.0430.
3.4.6 Reaction of 2-(Difluoromethylsulfinyl)biphenyl (7) with
Trifluoromethanesulfonic Anhydride

A: 2-(Difluoromethylsulfinyl)biphenyl (7) (150 mg, 0.6 mmol) was dissolved in
DCM (2mL), the solution was cooled to 0 °C under argon and trifluoromethanesulfonic
anhydride (170 mg, 0.6 mmol) was added drop wise. The reaction mixture was allowed
to warm up to room temperature. The reaction mixture was analyzed by
19
F NMR.
Difluoromethyl trifluoromethanesulfonate (8) was identified as the major fluorine
containing product.
19
F NMR (CH
2
Cl
2
): -74.84 (9) (t, J
F-F
= 3.05 Hz), 82.43 (dq, J
F-H
= 68
Hz, J
F-F
= 3.05 Hz)

The DCM was removed in vacuum. The residue was identified as a
mixture of dibenzothiophene (9) and trifluoromethanesulfonic acid. The mixture was
dissolved in DCM, extracted with water and dried over anhydrous MgSO
4
.The drying
agent was filtered off and the solvent was removed in vacuum to give 9 as a white solid.
Yield: 87%. mp.: 87-90 ˚C
1
H-NMR (CDCl
3
): 7.2-7.4 (m, 4H), 7.7-7.9 (m, 2H), 8.0-8.2
(m, 2H).
13
C-NMR (CDCl
3
): 121.7, 122.9, 124.4, 126.8, 135.6, 139.5. B: Experiment
carried out at -78 ˚C: 7 (50 mg, 0.2 mmol) was dissolved in DCM (1mL) in an NMR
tube. The solution was cooled to -78 °C under argon and trifluoromethanesulfonic
anhydride (54 mg, 0.2 mmol) was added drop wise. The reaction mixture was analyzed
by
19
F NMR at low temperature (-78 °C): -71.4 s, trifluoromethanesulfonic anhydride,
61
starting material, -78.8 s, triflic acid, -101.6 (d, J
H-F
= 56.8 Hz, product 8), -116.8(d, J
F-F
= 268 Hz), -121.7 (d, J
F-F
= 268 Hz, starting material 7).
3.4.7 Reaction of 2-(Difluoromethylsulfinyl)bromobenzene (6) with Benzene in the
Presence of Triflic Anhydride.

To a solution of 6 (53 mg, 0.21 mmol) in benzene (0.5 mL) triflic anhydride (36
µL, 0.21 mmol) was added at 5-10 °C under argon atmosphere. The reaction mixture was
stirred overnight at rt, CD
3
CN was added to dissolve the resulting precipitate and the
solution was analyzed by
19
F-NMR. Trifluoromethanesulfonic acid and
trifluoromethanesulfonic acid difluoromethyl ester (10) were identified as major
products.
19
F NMR (benzene): triflic acid (-78, s), trifluoromethanesulfonic acid
difluoromethyl ester -74.8 (t, J
F-F
= 3Hz, 3H), -82.5 (dq, J
F-F
= 3Hz, J
F-H
= 68 Hz, 2H).
The following compounds were also identified in the reaction mixture based on
19
F-
NMR: triflic anhydride (trace, -74, s), 2-(difluoromethylsulfinyl)brombenzene (m, -116- -
123). The multiplet at (-97 - -98.5) probably belongs to S-(difluoromethyl)-phenyl-2-
bromophenylsulfonium cation.
3.4.8 Preparation of Difluoromethyl Phenyl Sulfide

Thiophenol (42 g, 0.36 mol) was dissolved in hexane (500 mL). Finely powdered
NaOH (40 g, 1.0 mol, powdered in glove box) and TDA (6 g, 0.0185 mmol) were added
at room temperature under argon. The reaction mixture was warmed up to 65 ˚C, a
balloon filled with argon was attached to the reaction vessel and CF
2
HCl gas was bubbled
62
into the stirred mixture from a cylinder for 6h. The reaction was monitored by GC-MS.
When all of the starting material was converted into the product, the mixture was cooled
down to room temperature. The solid was filtered off and dissolved in sodium carbonate
solution in water (10%, 300 mL). The resulting solution was extracted with hexane (2 ×
300 mL). The combined organic layer was extracted with sodium carbonate solution (10
%, 1 × 200 mL), water (1× 200 mL), brine (1× 200 mL) and dried over anhydrous
magnesium sulfate. The drying agent was filtered off and the solvent was removed in
vacuum to give 53.7 g of the crude product (GC purity 93%) as a colorless oil. Vacuum
distillation of the crude product yielded 45.3 g of the expected product. Yield: 79%.
1
H
NMR (CDCl
3
): 6.84 (t, 1H, J
H-F
= 57.04 Hz), 7.36-7.48 (m, 3H), 7.56-7.64 (m, 2H).
19
F
NMR (CDCl
3
): -91.88 (d, 2F, J
H-F
= 56.46 Hz).
13
C NMR (CDCl
3
): 121.2 (t, J
C-F
= 275.0
Hz), 126.3, 129.5, 129.9, 135.5. GC-MS (EI, m/z): 160 (M
+
).
3.4.9 Preparation of Difluoromethyl Phenyl Sulfoxide

Difluoromethyl phenyl sulfide

(44.0 g, 0.275 mol) was dissolved in
dichloromethane (300 mL). m-CPBA (55%, 100 g, 0.32 mol) was added in DCM (600
mL) at 0-3˚C over a period of 5h. The reaction mixture was extracted with sodium
carbonate solution in water (10%, 3 × 300 mL), with water (1 × 300 mL) and with brine
(1 × 300 mL). The organic layer was dried over anhydrous magnesium sulfate and the
drying agent was filtered off. The solvent was removed in vacuum to give 46.4 g of the
crude product as a colorless oil (GC purity 91%). A portion of the crude product (10 g)
63
was purified by gradient silica gel column chromatography (500 g silica gel, A eluent: n-
hexane, B-eluent: ethyl-acetate, B was increased from 1 to 5% at a flow rate of 0.25
ml/(min× cm
-2
)) to give the pure product 8.3g, 80%.
1
H NMR (CDCl
3
): 6.04 (t, 1H, J
H-F
=
55.11 Hz), 7.50-7.62 (m, 3H), 7.65-7.73 (m, 2H).
19
F NMR (CDCl
3
): 119.56 (dd, 1F, J
F-F

= 261.78 Hz, J
H-F
= 55.11 Hz), 120.33 (dd, 1F, J
F-F
= 261.78, J
HF
= 55.11 Hz),
13
C NMR
(CDCl
3
): 120.9 (t, J
C-F
= 289.0 Hz), 125.5, 129.6, 132.9, 136.6. GC-MS (EI, m/z): 176
(M
+
).
3.4.10 Preparation of S-Difluoromethyl-S-phenyl-2,3,4,5-
tetramethylphenylsulfonium Tetrafluoroborate

To a

stirred solution of phenyl difluoromethyl sulfoxide 11 (4.00 g, 25 mmol) and
1,2,3,4-tetramethylbenzene (3.35 g, 25 mmol) in dry diethyl ether (60 mL) at 0 °C under
argon was added trifluoromethanesulfonic acid anhydride (7.0 g, 25 mmol) in small
portions over a period of 2 hours followed by stirring the reaction mixture for 20 minutes
at the same temperature. The oil formed was separated from the diethyl ether phase under
nitrogen. It was purified by washing with diethyl ether (30 mL) four times. The resulting
oil was dissolved in dichloromethane (50 mL), the dichloromethane solution was
extracted with sodium tetrafluoroborate solution in water (c = 1 M, 5 × 100 mL) and it
was dried over anhydrous magnesium sulfate. The drying agent was filtered off and the
dichloromethane was removed in vacuum. The product was obtained as a brown semi-
solid (5.9 g, 51%).
1
H NMR (CDCl
3
): 2.31 (s, 3H), 2.32 (s, 3H), 2.40 (s, 3H), 2.57 (s,
3H), 7.49 (s, 1H), 7.65-7.95 (m, 5H), 8.12 (t, 1H, J
H-F
= 47.4 Hz).
19
F NMR

(CDCl
3
): -
64
99.87 (dd, 1F, J
F-F
= 227.4 Hz, J
H-F
= 53.4 Hz), -100.58 (dd, 1F, J
F-F
= 227.4 Hz, J
H-F
=
53.40 Hz), -152.02 (s, 1F), -152.08 (s, 3F).
13
C NMR (CDCl
3
): 17.0, 17.1, 18.0, 21.1,
113.0, 118.90 (t, J
C-F
= 297.5 Hz), 119.0, 129.0, 131.6, 131.9, 135.5, 138.9, 139.1, 140.0,
145.3. HRMS (FAB) calculated for C
17
H
19
F
2
S. Expected: 293.1170. Found: 293.1170.
3.4.11 Preparation of Phenyl 2,3,4,5-Tetramethylphenyl Sulfide

To a solution of S-difluoromethyl-S-phenyl-2,3,4,5-tetramethylphenylsulfonium
tetrafluoroborate 13, (380 mg, 1 mmol) in acetonitrile (5 mL) was added water (1 mL).
After stirring the reaction mixture for 2 hours at room temperature, it was concentrated in
vacuum. The precipitate was filtered off to give the product 15 as a white solid (220 mg,
91%).
1
H-NMR (CDCl
3
): 2.22 (s, 3H), 2.24 (s, 3H), 2.25 (s, 3H), 2.36 (s, 3H), 7.04-7.14
(m, 3H), 7.16-7.25 (m, 3H).
13
C-NMR (CDCl
3
): 16.5, 17.1, 18.0, 20.8, 125.4, 127.7,
128.8, 129.1, 134.2, 134.8, 136.4, 136.6, 137.4, 138.6. GC-MS (EI, m/z): 242 (M
+
).
HRMS calculated for C
16
H
18
S. Calculated: 242.1129. Found: 242.1133.
3.4.12 General Method for the Difluoromethylation of Aryl and Alkyl Sulfonic
Acids

To the stirred solution of 13 (0.83 mmol) in dry acetonitrile (0.5 mL) was added
the substrate (14 a-h) (0.33 mmol) under N
2
. Detailed conditions are shown in Table 1.
After the time showed in Table 1 known amount if 2,4,6-trifluoromesitylene or
fluorobenzene was added as internal standard and the conversion was determined based
on
19
F-NMR. Dichloromethane (10 mL) was added and the diluted reaction mixture was
extracted with sodium bicarbonate solution (10%, 2×10 mL). The solvent was
65
evaporated in vacuum and the difluoromethyl ester was separated from 15 by gradient
silica gel column chromatography. (Eluent: n-hexane, ethyl acetate).
Difluoromethyl 4-Methylbenzenesulfonate (16a). Yield: 77%. Colorless oil.
1
H NMR
(CDCl
3
): 2.48 (s, 3H), 6.78 (t, 1H, J
H-F
= 70.44 Hz), 7.35-7.45 (m, 2H), 7.81-7.87 (m,
2H).
19
F NMR (CDCl
3
): -85.02 (d, J
H-F
= 70.44 Hz).
13
C NMR (CDCl
3
): 21.9, 114.1 (t,
J
C-F
= 266.5), 128.2, 130.4, 132.8, 146.7. MS (EI, m/z): 186 (M
+
).
Difluoromethyl 4-Vinylbenzenesulfonate (16b). Yield: 67%. Colorless oil.
1
H-NMR
(CDCl
3
): 5.52 (d, 1H, J = 10.99 Hz), 5.95 (dd, 1H,
3
J
H-H
= 17.58,
2
J
H-H
= 0.36 Hz), 6.77
(dd, 1H,
3
J
H-H
= 10.99 Hz,
3
J
H-H
= 17.58 Hz), 6.79 (t, 1H, J
H-F
= 71.15 Hz), 7.56-7.64 (m,
2H), 7.86-7.94 (m, 2H),
19
F-NMR (CDCl
3
): -85.01 (d, J
H-F
= 71.15 Hz).
13
C-NMR
(CDCl
3
): 114.1 (t, J
C-F
= 267.3 Hz), 119.2, 127.3, 128.5, 134.3, 135.0, 144.4. HRMS for
C
9
H
8
F
2
O
3
S. Calculated: 234.0162. Found: 234.0167.
Difluoromethyl 4-Hydroxybenzenesulfonate (16c). Yield: 84%. Off-white semisolid.
1
H-NMR (CDCl
3
): 6.00-6.40 (br s, 1H), 6.74 (t, J
H-F
= 70.44 Hz, 1H), 6.95-7.05 (m, 2H),
7.75-7.90 (m, 2H)
19
F-NMR (CDCl
3
): -85.06 (d, J
H-F
= 70.44 Hz).
13
C-NMR (CDCl
3
):
113.9 (t, J
C-F
= 266.6 Hz), 116.4, 126.8, 130.8, 161.6. HRMS for C
7
H
6
F
2
O
4
S. Calculated:
223.9955. Found: 223.9945.
Difluoromethyl 2,4,6-Trimethylbenzenesulfonate (16d). Yield: 78%. Colorless oil.
1
H-
NMR (CDCl
3
): 2.34 (s, 3H), 2.64 (s, 6H), 6.70 (t, 1H, J
H-F
= 70.96), 6.99 (s, 1H).
19
F-
NMR -(CDCl
3
): -85.38 (d, J
H-F
= 70.56 Hz).
13
C-NMR (CDCl
3
): 21.3, 22.7, 113.9 (t, J
C-F
= 265.9 Hz), 130.9, 132.2, 140.3, 145.0. HRMS for C
10
H
12
F
2
O
3
S. Calculated: 250.0475.
Found: 252.0476.
66
Bis(difluoromethyl) o-benzenedisulfonate (16e) Yield: 89%. Colorless oil.
1
H-NMR
(CDCl
3
): 6.97 (t, 2H, J
H-F
= 70.04 Hz), 7.90-8.10 (m, 2H), 8.30-8.50 (m, 2H).
19
F-NMR
(CDCl
3
): -84.66 (d, J
H-F
= 70.04 Hz).
13
C-NMR (CDCl
3
): 114.4 (t, J
C-F
= 270.8 Hz),
133.5, 134.8, 135.7. HRMS for C
8
H
6
F
4
O
6
S
2
. Calculated: 337.9542. Found: 337.9544.
Difluoromethyl 3-nitrobenzenesulfonate (16f) Yield: 74%. Yellow oil.
1
H-NMR
(CDCl
3
): 6.84 (t, 1H, J
H-F
= 70.18 Hz), 7.85 (t, 1H, J = 8.07 Hz), 8.24-8.30 (m, 1H), 8.54-
8.60 (m, 1H), 8.74-8.80 (m, 1H). ).
19
F-NMR (CDCl
3
): -84.68 (d, J
H-F
= 70.18 Hz).
13
C-
NMR (CDCl
3
): 114.1 (t, J
C-F
= 270.1 Hz), 123.4, 129.5, 131.3, 133.4, 137.8, 148.4. MS
(EI, m/z): 217 (M
+
).
Difluoromethyl 2-naphthalenesulfonate (16g). Yield: 54%. Colorless oil.
1
H-NMR
(CDCl
3
): 6.85 (t, 1H, J
H-F
= 70.50 Hz), 7.60-7.80 (m, 2H), 7.8-8.2 (m, 4H), 8.55 (s, 1H).
19
F-NMR (CDCl
3
): -84.78 (d, J
H-F
= 70.19 Hz).
13
C-NMR (CDCl
3
):114.2 (t, J
C-F
= 267.4),
122.2, 128.3, 128.4, 129.8, 130.3, 130.4, 130.5, 132.0, 132.6, 136.0. HRMS for
C
11
H
8
F
2
O
3
S. Calculated: 258.0162. Found: 258.0167.
Difluoromethyl 10-camphorsulfonate (16h). Yield: 86%. Colorless oil.
1
H-NMR
(CDCl
3
): 0.88 (s, 3H), 1.09 (s, 3H), 1.40-1.50 (m, 1H), 1.67-1.78 (m, 1H), 1.96 (d, 1H, J
= 19 Hz), 2.00-2.18 (m, 2H), 2.30-2.45 (m, 2H), 3.23 (d, 1H, J = 15 Hz), 3.75 (d, 1H, J =
15 Hz), 6.81 (t, 1H, J
F-H
= 70.53 Hz).
19
F-NMR (CDCl
3
): -84.78 (dd, J
F-F
= 225.83 Hz, J
F-
H
= 70.53 Hz), -85.23 (dd, J
F-F
= 225.83 Hz, J
F-H
= 70.53 Hz).
13
C-NMR (CDCl
3
): 19.8,
19.9, 25.4, 27.0, 42.5, 43.0, 48.3, 51.2, 58.4, 114.2 (t, J
C-F
= 267.4 Hz), 213.5. HRMS for
C
11
H
16
F
2
O
4
S. Calculated: 282.0737. Found: 282.0735.
67
N-(Difluoromethyl)triethylammonium Tetrafluoroborate (17). To a solution of
triethyl amine (101 mg, 1 mmol) in acetonitrile (1 mL) S-(difluoromethyl)-S-phenyl-
2,3,4,5-tetramethylphenylsulfonium tetrafluoroborate 13 (400 mg, 1.05 mmol) in
acetonitrile (1mL) was added. The mixture was stirred overnight, followed by
evaporation of the solvent in vacuum. The resulting solid was seperately washed (3
times) with diethyl ether (5mL) to give 167 mg (70 %) of the crude product as a
yellowish solid. The product was dissolved in DCM, morpholinomethyl polystyrene (700
mg, loading: 4.2 mmol/g) was added and the mixture was stirred for 30 min. The resin
was filtered off and washed with DCM. The DCM was evaporated in vacuum to give 143
mg of the pure product as a yellowish semi solid. mp = 239-242 °C (dec.).
1
H-NMR
(DMSO-d
6
): 1.25 (q, J = 7.32 Hz, 9H), 3.55 (t, J = 7.29 Hz, 6H), 7.32 (t, J
H-F
= 57.65 Hz,
1H).
19
F-NMR (DMSO-d
6
): -112.00 (d, J
H-F
= 57.65 Hz, 2F), -147.64 (s, 1F), -147.70 (s,
3F).
13
C-NMR (DMSO-d
6
): 7.8, 51.5, 115.0 (t, J
C-F
= 273.1 Hz). HRMS for C
7
H
16
F
2
N.
Calculated: 152.1251. Found: 152.1248.
N-(Difluoromethyl)-N, N-dimethylanilinium Tetrafluoroborate (18)
Yield = 63%.
1
H NMR (CDCl
3
/DMSO-d
6
): 3.82 (s, 6H), 7.60 (t, J
H-F
= 58.6 Hz, 1H),
7.73 (m, 3H ), 8.02 (m, 2H).
19
F NMR (CDCl
3
/DMSO-d
6
): -110.7 (d, J
H-F
= 58.6 Hz,
2F),-147.63 (s, 1F), -147.69 (s, 3F).
13
C NMR (DMSO-d
6
): 47.9, 114.7(t, J
C-F
= 276.9
Hz), 122.6, 130.2, 131.3, 139.3.
N-(Difluoromethyl)-N, N-dimethyl, 4-methylanilinium Tetrafluoroborate (19)
Yield = 64%.
1
H NMR (CDCl
3
/DMSO-d
6
): 2.43(s, 3H). 3.78(s, 6H), 7.37(t, J
H-F
= 59.2
Hz, 1H), 7.44(m, 2H), 7.68(m, 2H).
19
F NMR (CDCl
3
/DMSO-d
6
): -111.44 (d, J
H-F
= 59.2
68
Hz, 2H), -151.01(s, 1H), -151.07 (s, 1H).
13
C NMR (CDCl
3
/DMSO-d
6
): 20.6, 48.6, 115.
02 (t, J
C-F
= 279.5 Hz), 121.3, 131.2, 136.6, 142.4.
N, N’-Bis(difluoromethyl)imidazolium Tetrafluoroborate Hemihydrate (23). To a
solution of imidazole (34 mg, 0.5 mmol) in a mixture of acetonitrile (2 mL) and CH
2
Cl
2

(2 mL) a solution of S-difluoromethyl–S-phenyl-2,3,4,5-tetramethylphenylsulfonium
tetrafluoroborate 13 (400 mg, 1.05 mmol) in acetonitrile (1.0 mL) was added under argon
atmosphere at room temperature. After stirring for one hour, K
2
CO
3
(80 mg, 0.58 mmol)
was added and continued stirring for overnight. The precipitate was filtered off and dried
in vacuum and the remaining semi solid was stirred with diethyl ether. The solution was
decanted, the remaining semi solid was washed with diethyl ether and the solvent was
decanted again. The remaining semisolid was dried in vacuum to give the expected
product. (108 mg, 84%).
1
H NMR (DMSO-d
6
): 3.37 (br s, H
2
O,
1
H), 8.07 (t, J
H-F
= 58.87
Hz, 2H), 8.51 (s, 2H), 10.34 (s, 1H).
19
F NMR (DMSO-d
6
): -96.15 (d, 4F, J
H-F
= 58.87
Hz), -147.69 (s, 1F), -147.73 (s, 3F).
13
C NMR (DMSO-d
6
): 108.9 (t, J
C-F
= 259.0 Hz),
120.0, 138.0. HRMS for C
5
H
5
F
2
N
4
. Calculated: 169.0389. Found: 169.0383.
N-Difluoromethyl-N’-methylimidazole Tetrafluoroborate (24). To a solution of N-
methylimidazole (20) (41 mg, 0.5 mmol) in acetonitrile (1 mL) a solution of S-
difluoromethyl-S-phenyl-2,3,4,5-tetramethylphenylsulfonium tetrafluoroborate (200 mg,
0.54 mmol) in acetonitrile (2mL) was added dropwise under argon atmosphere at room
temperature. The reaction mixture was stirred for 6 hours, followed by evaporation of the
solvent in vacuum. The remaining semi solid was stirred with diethyl ether and the ether
was decanted. The stirring and decantation were repeated three times to give 71 mg (77
69
%) of the expected product as a yellowish semi solid.
1
H-NMR (DMSO-d
6
): 3.90 (s, 3H),
7.90 (s, 1H), 7.98 (t, J
H-F
= 59.0 Hz, 1H), 8.20 (s, 1H), 9.66 (s, 1H).
19
F-NMR (DMSO-
d
6
): -94.84 (d, J
H-F
= 59.0, 2F), -147.63 (s, 1F), -147.70 (s, 3F).
13
C-NMR (DMSO-d
6
):
36.6, 108.7 (t, J
C-F
= 256.0 Hz), 118.6, 125.2, 136.9. HRMS for C
5
H
7
F
2
N
2
. Calculated:
133.0577. Found: 133.0574.
1-Difluoromethyl-2,3-dimethylimidazolium Tetrafluoroborate (25). To a solution of
1,2-dimethylimidazole (21) (77 mg, 0.79 mmol) in acetonitrile (1 mL) a solution of S-
difluoromethyl-S-phenyl-2,3,4,5-tetramethylphenylsulfonium tetrafluoroborate 13 (310
mg, 0.82 mmol) in acetonitrile was added drop wise under argon atmosphere at room
temperature. The reaction mixture was stirred overnight followed by evaporation of the
solvent in vacuum. The remaining solid was repeatedly stirred with diethyl ether to give
126 mg (81%) of the expected product as a white solid. mp = 248-250 °C (dec.).
1
H-
NMR (DMSO-d
6
): 2.75 (s, 3H), 3.81 (s, 3H), 7.83 (d, J
H-F
= 2.29 Hz,1H), 8.07 (t, J
H-F
=
56.93 Hz, 1H), 8.09 (d, J = 2.29 Hz, 1H).
19
F-NMR (DMSO-d
6
): -95.95 (d, J
H-F
= 58.65
Hz, 2F), -147.65 (s, 1F), -147.71 (s, 3F).
13
C-NMR (DMSO-d
6
): 10.2, 35.0, 108.5 (t, J
C-F

= 254.1 Hz), 116.9, 124.1, 146.3. HRMS for C
6
H
9
F
2
N
2
. Calculated: 147.0734. Found:
147.0741.
P-(Difluoromethyl)triphenylphosphonium Tetrafluoroborate (26). A mixture of
triphenylphosphine (131 mg, 0.5 mmol), S-difluoromethyl-S-phenyl-2,3,4,5-
tetramethylphenylsulfonium tetrafluoroborate (200 mg, 0.53 mmol) and DIAD (15 mg,
0.074 mmol) in dichloromethane (1mL) was stirred at rt overnight. Diethyl ether was
added to the reaction mixture. The resulting precipitate was filtered off followed by
70
stirring with diethyl ether again. The solid was filtered off to give 166 mg of the expected
product as a white crystal. Yield: 83%. mp: 130-132 °C (dec.).
1
H-NMR (DMSO-d
6
):
7.80-7.95 (m, 12H), 8.02-8.14 (m, 3H), 8.41 (dt, 1H, J
H-F
= 47.10 Hz, J
H-P
= 29.30 Hz).
31
P (DMSO-d
6
): 19.88 (t, J
F-P
= 77.28 Hz),
19
F-NMR (DMSO-d
6
): -125.74 (dd, J
F-P
=
77.28 Hz, J
H-F
= 47.10 Hz, 2F), -147.65 (s, 1F), -147.70 (s, 3F);
13
C-NMR (DMSO-d
6
):
111.9 (t, J
C-P
= 84.7 Hz); 114.3 (dt, J
C-F
= 268.6 Hz, J
C-P
= 83.9 Hz), 131.0 (d, J
C-P
= 13.0
Hz), 134.8 (d, J
C-P
= 10.7 Hz), 136.8 (d, J
C-P
= 3.0 Hz). HRMS calculated for C
19
H
16
F
2
P.
Expected: 313.0958. Found: 313.0958.
P- (Difluoromethyl)tri(4-flurophenyl)phosphonium Tetrafluoroborate (27)
Yield = 75%.
1
H NMR (CDCl
3
/DMSO-d
6
): 7.48 (m, 6H), 7.82(m, 6H), 7.91(dt, J
H-F
=
47.5 Hz, J
H-P
= 31.4 Hz, 1H).
19
F NMR (CDCl
3
/DMSO-d
6
): -96.4 (s, 3F),
-126.28 (dd, J
F-P
= 80.6 Hz, J
H-F
= 47.6 Hz, 2F), -152.01 (s, 1F), -152.06 (s, 3F).
13
C NMR
(CDCl
3
/DMSO-d
6
): 107.4(d, J= 90.1 Hz), 113.7 (dt, J
C-F
= 269.6 Hz, J
C-p
= 88.2 Hz),
119.1(m), 137.5 (m), 167.8(d, J
C-F
=263.7 Hz).
31
P NMR (CDCl
3
/DMSO-d
6
): 19.03 (t,
2
J
P-F
= 80.8 Hz).
P- (Difluoromethyl)tricyclohexylphosphonium Tetrafluoroborate (28)
Yield = 73%.
1
H NMR (CDCl
3
/DMSO-d
6
): 1.31-2.13 (m, 30H), 2.80 (m, 3H), 7.28 (dt,
J
H-F
= 46.8 Hz, J
H-P
= 26.3 Hz, 1H).
19
F NMR (CDCl
3
/DMSO-d
6
): -123.39 (dd, J
F-P
= 59.4
Hz, J
H-F
= 46.7 Hz, 2F), -152.07(s, 1F), -152.12(s, 3F).
13
C NMR (CDCl
3
/DMSO-d
6
):
24.9, 26.0, 26.4, 29.3 (d, J = 32.3 Hz), 113.7(dt, J
C-F
= 267.0 Hz, J
C-P
= 67 Hz), 119.1(m),
137.5(m), 167.8 (d, J
C-F
=263.7 Hz).
31
P NMR (CDCl
3
/DMSO-d
6
): 32. 46 (t,
2
J
P-F
= 59.4
Hz).
71
3.5 Chapter 3: Representative Spectra
1
H NMR spectrum of 13
ppm (t1)
0.0 5.0 10.0
20.30
4.12
53.62
4.62
CH2Cl2
CHCl3
ppm (t1)
2.20 2.30 2.40 2.50
1.00
1.03
2.02
ppm (t1)
7.50 8.00
1.00
2.03
1.06
20.30
4.12
1H Spectrum
S
CF
2
H
BF
4
72

13
C NMR spectrum of 13

ppm (t1)
0 50 100 150 200
ppm (t1)
17.0 18.0 19.0 20.0 21.0 22.0
13C Spectrum
ppm (t1)
116.0 117.0 118.0 119.0 120.0 121.0 122.0
ppm (t1)
130.0 131.0 132.0 133.0
13C Spectrum
S
+
CF
2
H
B F F
F
F
73

1
H NMR spectrum of difluoromethyl 4-Methylbenzenesulfonate

ppm (f1)
0.0 5.0 10.0
1.80
1.90
0.81
3.00
1H Spectrum
S O O
O
CF
2
H
74
19
F NMR spectrum of difluoromethyl 4-methylbenzenesulfonate

ppm (f1)
-200 -150 -100 -50 0
19F Spectrum
ppm (f1)
-85.40 -85.30 -85.20 -85.10 -85.00 -84.90
S O O
O
CF
2
H
75
13
C NMR spectrum of difluoromethyl 4-methylbenzenesulfonate

ppm (f1)
0 50 100 150 200
13C Spectrum
ppm (f1)
111.0 112.0 113.0 114.0 115.0 116.0 117.0
S O O
O
CF
2
H
76
1
H NMR spectrum of N-(Difluoromethyl)triethylammonium Tetrafluoroborate

ppm (t1)
0.0 5.0 10.0
17.9
26.7
4.91
H2O
DMSO
ppm (t1)
7.10 7.20 7.30 7.40 7.50
1H Spectrum
ppm (t1)
3.500 3.550 3.600 3.650
ppm (t1)
1.150 1.200 1.250 1.300 1.350 1.400
N
CF
2
H
BF
4
77

19
F NMR spectrum of N-(Difluoromethyl)triethylammonium Tetrafluoroborate

78
13
C NMR spectrum of N-(Difluoromethyl)triethylammonium Tetrafluoroborate

ppm (f1)
0 50 100 150 200
13C Spectrum
ppm (f1)
115.0
13C Spectrum
N
CF
2
H
BF
4
79
1
H NMR spectrum of N, N’-Bis(difluoromethyl)imidazolium Tetrafluoroborate
Hemihydrate

ppm (f1)
0.0 5.0 10.0
1.00
2.18
2.03
1.26
1H Spectrum
H2O
DMSO
N
N
CF
2
H
CF
2
H
BF
4
80
19
F NMR spectrum of N, N’-Bis(difluoromethyl)imidazolium Tetrafluoroborate
Hemihydrate

81
13
C NMR spectrum of N, N’-Bis(difluoromethyl)imidazolium Tetrafluoroborate
Hemihydrate

ppm (t1)
0 50 100 150 200
13C Spectrum
ppm (t1)
105.0 110.0
N
N
CF
2
H
CF
2
H
BF
4
82

1
H NMR spectrum of P-(Difluoromethyl)triphenylphosphonium Tetrafluoroborate

ppm (f1)
0.0 5.0 10.0
1.00
3.02
12.67
1H Spectrum
ppm (f1)
8.30 8.40 8.50 8.60 8.70
1.00
DMSO
P CF
2
H
BF
4
83
19
F NMR spectrum of P-(Difluoromethyl)triphenylphosphonium Tetrafluoroborate

84
13
C NMR spectrum of P-(Difluoromethyl)triphenylphosphonium Tetrafluoroborate

ppm (t1)
0 50 100 150 200
ppm (t1)
131.0 132.0 133.0 134.0 135.0 136.0 13 7. 0
13C Spectrum
ppm (t1)
111.0 112.0 113.0 114.0 115.0 116.0 117. 0 118.0
P CF
2
H
BF
4
85
3.6 Chapter 3: References

1. Li, Y.; Hu, J. Angew. Chem. Int. Ed. 2005, 44, 5882.
2. Filler, R.; Kobayashi, Y. Biomedical Aspects of Organofluorine Chemistry; Kodansha
and Elsevier Biomedical: Amsterdam, Netherlands, 1983.
3. Langlois, B. R.; Rhone-Poulenc, R. C.; Saint-Fosh, S. J. Fluorine Chem. 1988, 41,
247.
4. Lee, H.; Kim, H. S.; Lee, W. K.; Kim, H. J. Fluorine Chem. 2001, 133.
5. Chen, Q.-Y.; Wu, S.-W. J. Org. Chem. 1989, 54, 3023.
6. Mitsch, R. A.; Robertson, J. E. J. Het. Chem. 1965, 2, 152.
7. Kirsch, P. Modern Fluoroorganic Chemistry; Viley-VCH Verlag GMBH & Co
KGaA: Weinheim, Germany, 2004.
8. Yagupol'skii, L. M.; Kondratenko, N. Y.; Timofeeva, G. N. Zh. Org. Khim. 1984, 20,
115.
9. Umemoto, T.; Ishihara, S. J. Am. Chem. Soc. 1993, 115, 2156.
10. Umemoto, T.; Ishihara, S.; Adachi, K. J. Fluorine Chem. 1995, 74, 77.
11. Umemoto, T.; Ishihara, S. J. Fluorine Chem. 1999, 98, 75.
12. Umemoto, T.; Adachi, K. J. Org. Chem. 1994, 59, 5692.
13. Yang, J. J.; Kirchmeier, R. L.; Shreeve, J. M. J. Org. Chem. 1998, 63, 2656.
14. Ma, J.-A.; Cahard, D. J. Org. Chem. 2003, 68, 8726.
15. Endel'man, E. S.; Danilenko, V. S.; Trinus, F. P.; Yufa, P. A.; Fadeicheva, A. G.;
Muravov, I.I.; Fialkov, Y. A.; Yagupol'skii, L. M. Khimiko-Farmatsevticheskii
Zhurnal. 1973, 7, 15.
16. Prakash, G. K. S.; Hu, J.; Wang, Y. Org. Lett. 2004, 6, 4315.
17. Prakash, G. K. S.; Hu, J.; Mathew, T.; Olah, G. A. Angew. Chem. Int. Ed. 2003, 42,
5216.
86

18. Pasenok, S. V.; Kirij, N. V.; Yagupolskii, Y. L.; Naumann, D.; Tyrra, W.; Fitzner, A.
Z. Anorg. Allg. Chem. 1999, 625, 834.
19. Pritzkow, H.; Klaus, R.; Reimann-Andersen, S.; Sundermeyer, W. Angewandte
Chemie 1990, 102, 80.
20. Koch, V. R.; Nanjundiah, C.; Carlin, R. T. Patent WO9702252 1995, CAN:
126:201666.
21. Kirij, N. V.; Pasenok, S. V.; Yagupolskii, Y. L.; Fitzner, A.; Tyrra, W.; Naumann, D.
J. Fluorine Chem. 1999, 94, 207.

87
4 Chapter 4: New Solid-phase Bound Electrophilic
Difluoromethylating Reagent
4.1 Chapter 4: Introduction

Fluoroorganics have played a key role in pharmaceutical, agrochemical and
materials science.
1
It is estimated that about 20-25% of drug candidates in the
pharmaceutical pipelines contain at least one fluorine atom.
2
This may be related to the
well known fact that the incorporation of fluorine into organic molecules often drastically
changes the chemical, physical and biological properties of the parent compound. The
discussion of such fluorine effects is the subject of many recent books and reviews.
3, 4, 5, 6,
7, 8
In spite of the increasing understanding of the fluorine effects and the recent
development of computer aided drug discovery programs, prediction of the influence of
fluorine substitution on the pharmacological parameters of a drug candidate remains
basically a trial and error process. A large number of organofluorine compounds have to
be synthesized and tested to identify an efficient and promising drug candidate with
prominent fluorine effect. Due to rare natural occurrence of organofluorine compounds,
introduction of new methods for developing fluorine containing building blocks has
become more important.
Compound libraries have an important role in the drug discovery process. While large
member diverse libraries became crucial in the hit identification phase, focused small
libraries are widely used in hit-to-lead and lead optimization stage. In 2005, 110 small
libraries disclosing biological activities have been published.
9
Fluorine containing hit and
lead compounds have been identified too (Figure 4.1).
10, 11
In the same year there were
88
104 candidates from HTS (high-throughput screening) based on the response to a
survey.
12

N
S
H
N
O
F
NC
IC
50
= 19 nM
NPY5 receptor antagonist
N
N
O
O
OH
O
I
CF
3
Cl
IC
50
= 670 nM
HMD2-p53 protein-protein antgonists

Figure.4.1 Fluorine Containing Lead Compounds Identified by Screening
Compound Libraries
Solid-phase bound reagents are important tools in compound library synthesis as they
enable effective automation. Nevertheless, to the best of our knowledge, only one solid-
phase bound reagent for introduction of fluorine containing building block has been
published before. Umemoto synthesized a solid-bound (perfluoroalkyl)phenyliodonium
trifluoromethanesulfonate and used it to transfer perfluoroalkyl groups to aromatic and
heteroaromatic compounds.
13
Now, we wish to disclose a convenient, simple synthesis of
a new solid-bound reagent and its application for the direct introduction of the
difluoromethyl building block into certain oxo or azo nucleophiles.
Until 2005, 39 difluoromethyl derivatives have been registered to be in different
developmental phases of the drug discovery process (including compounds in preclinical
phase, clinical phase and on the market).
14
This attests to the major significance of
difluoromethyl group in medicinal chemistry.
89

N
HN
S
N
O
CF
2
H
MeO
MeO
O
Pantoprazole
H
+
/K
+
ATPase inhibitor
HF
2
CO
CF
3
Cl
membrane
permeability
inhibitor
Isoflurane
N
O
O
N
H
S
HF
2
C
O
H O
Me
S N
N
N
N
HO
O
HO
Flomoxef
beta-lactamase-stable cephamycine
H
2
N
O
OH
HF
2
C
H
2
N
Eflornithine
ornithine decarboxylase
inhibitor

Figure.4.2 Difluoromethyl Group Containing Drugs on the Market

Various difluoromethylation methods are discussed in several books and papers.
15,
16
In the previous chapter, the development and the use of a new electrophilic
difluoromethylating reagent (solution phase) has been described.
17
It has been
demonstrated that the synthesis of difluoromethyl sulfonates, N-difluoromethyl
ammonium, imidazolium and P-difluoromethyl phosphonium salts can be achieved in
moderate to excellent yields using this reagent. (Scheme 4.1)
The key step in the synthesis of the S-difluoromethyl diaryl sulfonium salt is the reaction
of difluoromethyl phenyl sulfoxide with 1,2,3,4-tetramethylbenzene in the presence of
triflic anhydride. Although our reagent is featured by a convenient three step synthesis
and it can be used under mild reaction conditions, separation and purification of
difluoromethylated product from the free sulfide has been difficult.
90
S
CF
2
H O
+
1. Tf
2
O, Et
2
O
2. NaBF
4
S
CF
2
H
BF
4 RS
O
O
O CF
2
H
R
3
PCF
2
H
BF
4
R
3
NCF
2
H
N
N
CF
2
H
HF
2
C
BF
4
BF
4
R = alkyl, aryl
- Ph-S-C
6
HMe
4
-
+
+
-
+
-
+
-

Scheme 4.1 Solution-phase Difluoromethylation of O-, N- and P-nucleophiles with the
New S-difluoromethyl Sulfonium Reagent.

This prompted us to explore a solid-phase approach by which the time consuming
chromatographic step can be avoided and our reagent can be used more efficiently in
terms of easy adaptation to automation and library construction.
4.2 Chapter 4: Results and Discussion
Keeping in mind that difluoromethyl phenyl sulfoxide reacted readily not only
with tetramethylbenzene but with benzene as well, the idea of using cross linked
polystyrene instead of tetramethylbenzene seemed to be a quite reasonable approach. The
reaction was conducted under an argon atmosphere in dichloromethane at 0-5 °C by
drop-wise addition of one equivalent of triflic anhydride. The detection of difluoromethyl
trifluoromethanesulfonate in the solution, similar to the previous experiments, is a clear
indication of the formation of the expected difluoromethyl sulfonium compound and its
subsequent reaction with the triflate anion formed from triflic anhydride. To eliminate
91
this undesired side reaction, the triflate salt was converted at once into tetrafluoroborate
by washing the resin repeatedly with dichloromethane containing excess amount of
tetraethylammonium tetrafluoroborate (Scheme 4.2).
Scheme 4.2 Preparation of Polystyrene-bound -S-Difluoromethyl phenyl
sulfonium Reagent
S
HF
2
C O
/ Tf
2
O
S
HF
2
C
- TfOH
+ TfOCF
2
H
-
NEt
4
BF
4
/ CH
2
Cl
2
-NEt
4
Tf
1.02 - 1.16 mmol/ g
S
S
HF
2
C
TfO
polystyrene
1% cross linked
+
-
BF
4
+
0.64 - 0.84 mmol/g
CH
2
Cl
2
CH
2
Cl
2

The loading of the S-difluoromethyl phenyl sulfonium tetrafluoroborate salt in the resin
and the disulfide formed by decomposition of the salt was determined based on
microanalysis (sulfur and fluorine content) and was found to be 1.02 – 1.16 mmol/g of
polymer bound sulfonium salt. Similar to the solution-phase approach, dichloromethane
and acetonitrile were found to be the best solvents for the solid-phase difluoromethylation
reactions. No significant loss in reactivity of the reagent was observed after being stored
for many weeks under argon atmosphere in a refrigerator.

92
Table 4.1 Difluoromethylation of Sulfonic Acids Using Polymer Bound
Difluoromethylating Reagent

BF
4
S S
HF
2
C
CH
3
CN
R S
O
O
O M
R S
O
O
O CF
2
H
+
+
R = alkyl, aryl, M = Na, K
+ MBF
4
-+
+
-

SO
3
Na
SO
3
Na
HO SO
3
Na
SO
3
Na
SO
3
K
SO
3
K
SO
3
Na
O
2
N
SO
3
Na
O
NaO
3
S
SO
3
CF
2
H
SO
3
CF
2
H
HO SO
3
CF
2
H
SO
3
CF
2
H
SO
3
CF
2
H
SO
3
CF
2
H
SO
3
CF
2
H
O
2
N
SO
3
CF
2
H
O
HF
2
CO
3
S
entry starting material product
3
4
5
6
7
8
9
conditions
60
o
C/3 days
rt/3 days
rt/3 days
rt/3 days
rt/1 day
60
o
C/3 days
rt/3 days
rt/2 days
yield(%)
a
96
85
61
79
97
81
60
95
SO
3
Na SO
3
CF
2
H
1
60
o
C/1 day
61
2
a
isolated yields

93
Reactions with aryl and alkyl sulfonic acid salts afforded the desired
difluoromethyl sulfonates in good yield under reaction conditions similar to the ones used
in solution-phase (Table 4.1). Although we could not achieve complete conversion in all
cases, filtration of the reaction mixture followed by dilution with dichloromethane,
washing with sodium carbonate solution and water, afforded the pure products.
Since imidazole derivatives were found to be easily difluoromethylated on both
nitrogen atoms in solution-phase, our newly developed solid-phase polymer bound
reagent was also tested, and was found to be very effective. However, the use of 1.4
equivalents of difluoromethylating agent with solid supported tertiary amine was
necessary to achieve 100% conversion. We surmise that the solid-supported base
enhances the reaction by selectively deprotonating the salts of imidazoles without
deprotonating the reagent and thus prevents its decomposition (Table 4.2).
Reaction with triethylamine resulted in the decomposition of the reagent and
afforded triethyl ammonium tetrafluoroborate as a major product. Although the expected
(difluoromethyl)triethylammonium tetrafluoroborate was also detected by
1
H and
19
F
NMR, it was evident that this reaction is not suitable for the preparation of the desired
compounds without further purification step. Similar results were obtained with
triphenylphosphine. Although the reagent reacted readily with triphenylphosphine in the
presence of DIAD (azodicarboxylic acid diisopropylester) even at room temperature, the
concomitant decomposition of the reagent led to the protonation and thus deactivation of
the DIAD. On the other hand, the use of solid supported tertiary amine resulted in the
94
partial deprotonation of the (difluoromethyl)triphenylphosphonium cation affording a
mixture of (difluoromethyl)phosphonium salt and (difluoromethyl)phosphonium ylide.

Table 4.2 Difluoromethylation of Imidazoles Using Solid-phase Polymer Bound
Difluoromethyl Sulfonium Reagent.
N N
R
3
CF
2
H
R
2
BF
4
S
HF
2
C
BF
4
+
-
+
-
R
3
= H, CF
2
H, R
2
=H, Me
N N
R
1
R
2
+
R
1
= H, Me, R
2
= H, Me
CH
3
CN, rt
N O
Yield: 86-96%
+
S

N N
H
H
N N
HF
2
C
H
CF
2
H
BF
4
1
93
N N
H
CH
3
N N
HF
2
C
CH
3
CF
2
H
BF
4
96
N N
H
3
C
H
N N
H
3
C
H
CF
2
H
BF
4
90
N N
H
3
C
CH
3
N N
H
3
C
CH
3
CF
2
H
BF
4
86
2
3
4
5
6
7
entry starting material product yield(%)
a
N N
C
2
H
5
H
N N
C
2
H
5
H
CF
2
H
BF
4
89
N N
Ph
H
N N
Ph
H
CF
2
H
BF
4
90
N N
C
4
H
9
H
N N
C
4
H
9
H
CF
2
H
BF
4
86
a
isolated yields

95
On comparing the reactivity of the reagent described in this article with the
difluoromethylating power of the previously described S-(difluoromethyl)-S-phenyl-
2,3,4,5-tetramethylphenylsulfonium tetrafluoroborate, we conclude that the acidity of the
difluoromethyl derivative and the basicity of the nucleophilic substrate are crucial
parameters. We surmise that by tuning the acidity of the (difluoromethyl)sulfonium
cation the scope of the reagent can be widened and difluoromethylation of various
structurally diverse nucleophiles can be achieved.
Once we established that our solid-phase polymer bound regent is suitable for
difluoromethylation of certain O-, and N- -nucleophiles we decided to investigate
whether our newly developed solid-phase approach can be applied in trifluoromethylation
of nucleophiles using S-trifluoromethyl sulfonium type trifluoromethylation reagents,
which are known to be widely used in solution-phase reactions.
18, 19, 20, 21, 22, 23, 24
Scheme 4.3 Preparation and Reactivity of Solid-phase Polymer Bound S-Trifluoromethyl
sulfonium reagent. The conversions are based on the parent compounds.

S
F
3
C O
/ Tf
2
O
S
F
3
C
- TfOH
+ TfOH
S
TfO
polystyrene
1% cross linked
NH
2
NH
2
+
NH
2
+
CF
3
CF
3
Loading: 1.67 mmmol/g
conv.: 6.5% 2.1%
/ THF
90
o
C, 3 days
50%
1/3
SH
DMF, t-BuOK, rt, 1day
1/2
S
CF
3
conv.: 62%
S
+ TfOH
+
48%
+
-
CH
2
Cl
2

96
Trifluoromethyl phenyl sulfoxide was prepared and reacted with polystyrene under
conditions similar to those used in the case of the difluoromethyl analog (Scheme 4.3.).
Based on microanalysis of the resin (fluorine content), it is found that 1.67 mmol/g
loading was achieved. It is known that the trifluoromethylation power of S-
trifluoromethyl diaryl sulfonium compounds not containing electron withdrawing groups
on the aryl rings is limited. Moderate yield was reported with thiophenol and only trace
amount of C-trifluoromethylated product was detected with aniline. In light of these
results, it was not unreasonable to carry out the reaction with 2 equivalent of the reagent
to achieve moderate yield in case of thiophenol. However, conversion with aniline was
still poor. Although the trifluoromethylation power of the solid-phase polymer bound S-
trifluoromethyl sulfonium compound was found to be limited, these preliminary results
reveals the possible application of this solid-phase approach in trifluoromethylation
chemistry as well.
4.3 Chapter 4: Conclusion

In conclusion, first solid-phase bound electrophilic difluoromethylating agent has
been developed by an efficient, short, two step synthetic route from commercially
available reagents. It has been shown that the reagent can be used for O-
difluoromethylation of sulfonic acids and N-difluoromethylation of imidazoles affording
pure product without further purification. This reagent may provide a valuable collection
of molecules for pharmacological and materials screening through target and/or diversity
oriented manual or automated library synthesis.
97
4.4 Chapter 4: Experimental

4.4.1 General
Unless otherwise mentioned, all reagents were purchased from commercial
sources. Dry dichloromethane and acetonitrile were used as received (from Aldrich,
water content < 50 ppm). In some cases dichloromethane and acetonitrile were dried by
distilling over P
2
O
5
under nitrogen.
1
H,
13
C and
19
FNMR spectra were recorded on Varian
Mercury-400 NMR spectrometer.
1
H NMR chemical shifts were determined relative to
the signal of internal standard tetramethylsilane (TMS) at 0.00 or to the signal of a
residual protonated solvent: CHCl
3
δ 7.26.
13
C NMR chemical shifts were determined
relative to the signal of internal TMS at 0.00 or to the
13
C signal of solvent: CDCl
3
δ
77.16, CD
3
CN: 118.26. CFCl
3
was used as internal standard for
19
F-NMR. High
resolution mass spectral data were recorded in the EI mode on a high resolution
micromass spectrometer at Department of Chemistry, University of Arizona.
Abbreviations: TDA: tris[2-(2-methoxyethoxy)ethyl]amine, m-CPBA: m-
Chloroperbenzoic acid, DCM: dichloromethane.
4.4.2 Preparation of Difluoromethyl Phenyl Sulfide

Finely powdered NaOH (40 g, 1.0 mol, powdered in glove box) and TDA (6 g,
0.0185 mmol) were added to thiophenol (42 g, 0.36 mol) was dissolved in hexane (500
mL) at room temperature under argon. The reaction mixture was warmed up to 65 ˚C
with constantly bubbling CF
2
HCl gas into the stirred mixture in the reaction vessel from a
98
cylinder for 6h. Progress of the reaction was monitored by GC-MS. When all of the
starting material was converted into the product, the mixture was cooled down to room
temperature. The solid was filtered off and dissolved in aqueous sodium carbonate
solution (10%, 300 mL). The resulting solution was extracted with hexane (2 × 300 mL).
The combined organic layer was further washed with sodium carbonate solution (10 %, 1
× 200 mL), water (1× 200 mL), brine (1× 200 mL) and was dried over anhydrous
magnesium sulfate. The drying agent was filtered off and the solvent was removed in
vacuum to give the crude product (53.7 g, GC purity 93%) as colorless oil. Crude product
on careful vacuum distillation yielded pure product (45.3 g, 79%).
1
HNMR (CDCl
3
): 6.84
(t, 1H, J
H-F
= 57.04 Hz), 7.36-7.48 (m, 3H), 7.56-7.64 (m, 2H).
19
FNMR (CDCl
3
): -91.88
(d, 2F, J
H-F
= 56.46 Hz).
13
CNMR (CDCl
3
): 121.2 (t, J
C-F
= 275.0 Hz), 126.3, 129.5,
129.9, 135.5. GC-MS (EI, m/z): 160 (M
+
).
4.4.3 Preparation of Difluoromethyl Phenyl Sulfoxide

To a solution of difluoromethyl phenyl sulfide

(44.0 g, 0.275 mol) in
dichloromethane (300 mL) m-CPBA (100 g, 0.32 mol) dissolved in DCM (600 mL) was
added at 0-3 ˚C over a period of 5h. The reaction mixture was washed with aqueous
sodium carbonate solution (10%, 3 × 300 mL), water (1 × 300 mL) followed by brine (1
× 300 mL). The organic layer was dried over anhydrous magnesium sulfate and filtered.
The solvent from the filtrate was removed in vacuum to give the crude product as a
colorless oil (46.4 g, GC purity 91 %). 10 g of this product was purified by gradient silica
gel column chromatography (500 g silica gel, A eluent: n-hexane, B-eluent: ethyl-acetate,
99
B was increased from 1 to 5% at a flow rate of 0.25 ml/min.cm
-2
to give the pure product
(8.3 g 80%).
1
HNMR (CDCl
3
): 6.04 (t, 1H, J
H-F
= 55.11 Hz), 7.50-7.62 (m, 3H), 7.65-
7.73 (m, 2H).
19
FNMR (CDCl
3
): 119.56 (dd, 1F, J
F-F
= 261.78 Hz, J
H-F
= 55.11 Hz),
120.33 (dd, 1F, J
F-F
= 261.78, J
HF
= 55.11 Hz),
13
CNMR (CDCl
3
): 120.9 (t, J
C-F
= 289.0
Hz), 125.5, 129.6, 132.9, 136.6. GC-MS (EI, m/z): 176 (M
+
).
4.4.4 Preparation of Solid-phase Polymer Bound S-
Difluoromethyl(diphenyl)sulfonium Tetrafluoroborate

Poly(styrene-co-divinylbenzene) (5.0 g, 1 % cross-linked, mesh 100-200) was
washed with dry dichloromethane (3 × 50 mL) followed by addition of
difluoromethylphenylsulfoxide (9.6 g, 0.05 mol) in dichloromethane (30 mL) under an
argon atmosphere. The reaction mixture was cooled to 0-5 °C under argon and
trifluoromethanesulfonic acid anhydride (8.5 mL, 0.05 mol) was added dropwise over a
period of 2 hours. The reaction was allowed to warm up to 15 °C, the resin was filtered
off and washed sequentially with dichloromethane, acetonitrile and again with
dichloromethane (3 × 100 mL each). To exchange the trifluoromethanesulfonate anion to
tetrafluoroborate the resin was washed with tetraethylammonium tetrafluoroborate
solution in dichloromethane (c = 0.1 M, 10 × 100 mL). The first washing sequence was
repeated again with dichloromethane and acetonitrile. The solvent was evaporated from
the last filtrate, the remaining material was dissolved in CDCl
3
and was checked by
1
HNMR. If no trace of tetraethylammonium ion or other impurity was found, the washing
procedure was considered to be effective and the resin was dried in a vacuum desiccator
100
to give 7.0 – 7.4 g of the solid-phase bound reagent as a brown resin.
19
FNMR (CDCl
3
): -
96 to -106 br s, -146 to -154 br s. Microanalysis: F: 11.7% - 13.2% (6.15 - 6.96 mmol/g).
S: 5.42 - 6.42% (1.70 - 2.0 mmol/g).
Loading (referred to difluoromethylsulfonium cation) = 1.02 - 1.16 mmol/g.
Loading (referred to diaryl sulfide) = 0.68 - 0.84 mmol/g
FTIR (polystyrene background): 950-1150 cm
-1
(C-F strech).
4.4.5 Difluoromethylation of Alkyl- and Arylsulfonates Using Solid Phase Bound
Reagent

To a solution of lithium, sodium or potassium salt of an alkyl- or arylsulfonic acid
(0.35 mmol) in dry acetonitrile (3.0 mL) was added resin (500 mg, 0.58 mmol solid-
phase polymer bound S-difluoromethyl-S-diarylsulfonium tetrafluoroborate salt) and the
mixture was stirred for 1-3 days between rt and 60 °C (see Table 1). The resin was
filtered off and washed with dichloromethane (4 × 5 mL). The combined filtrate was
wahed with sodium carbonate solution (1 × 30 mL, 10 %). In the case of 4-
hydroxybenzenesulfonic acid, sodium hydrogen carbonate was used instead of sodium
carbonate. The solvent was removed in vacuum at room temperature to give the expected
difluoromethyl alkyl/ arylsulfonates as colorless or yellowish oil or semisolid.
Difluoromethyl Benzenesulfonate. Yield: 61%. Colorless oil.
1
HNMR (CDCl
3
): 6.78 (t,
1H, J = 70.50 Hz), 7.54-7.64 (m, 2H), 7.68-7.76 (m, 1H), 7.90-7.98 (m, 2H).
19
F-NMR: -
84.99 (d, J = 70.19 Hz).
13
C-NMR: 114.1 (t, J = 267.4), 128.1, 129.8, 135.2, 135.9.

101
Difluoromethyl 4-Methylbenzenesulfonate. Yield: 96%. Colorless oil.
1
HNMR
(CDCl
3
): 2.48 (s, 3H), 6.78 (t, 1H, J
H-F
= 70.44 Hz), 7.35-7.45 (m, 2H), 7.81-7.87 (m,
2H).
19
FNMR (CDCl
3
): -85.02 (d, J
H-F
= 70.44 Hz).
13
CNMR (CDCl
3
): 21.9, 114.1 (t, J
C-F
= 266.5), 128.2, 130.4, 132.8, 146.7.
Difluoromethyl 4-Vinylbenzenesulfonate. Yield: 85%. Colorless oil.
1
HNMR (CDCl
3
):
5.52 (d, 1H, J = 10.99 Hz), 5.95 (dd, 1H,
3
J
H-H
= 17.58,
2
J
H-H
= 0.36 Hz), 6.77 (dd, 1H,
3
J
H-H
= 10.99 Hz,
3
J
H-H
= 17.58 Hz), 6.79 (t, 1H, J
H-F
= 71.15 Hz), 7.56-7.64 (m, 2H),
7.86-7.94 (m, 2H),
19
FNMR (CDCl
3
): -85.01 (d, J
H-F
= 71.15 Hz).
13
CNMR (CDCl
3
):
114.1 (t, J
C-F
= 267.3 Hz), 119.2, 127.3, 128.5, 134.3, 135.0, 144.4. HRMS calculated for
C
9
H
8
F
2
O
3
S: 234.0162; Found: 234.0167.
Difluoromethyl 4-Hydroxybenzenesulfonate. Yield: 61%. Colorless semisolid.
1
HNMR (CDCl
3
): 6.00-6.40 (br s, 1H), 6.74 (t, J
H-F
= 70.44 Hz, 1H), 6.95-7.05 (m, 2H),
7.75-7.90 (m, 2H)
19
F-NMR (CDCl
3
): -85.06 (d, J
H-F
= 70.44 Hz).
13
CNMR (CDCl
3
):
113.9 (t, J
C-F
= 266.6 Hz), 116.4, 126.8, 130.8, 161.6. HRMS calculated for C
7
H
6
F
2
O
4
S:
23.9955; Found: 223.9945.
Difluoromethyl 2,4,6-Trimethylbenzenesulfonated. Yield: Colorless oil. 79%.
1
HNMR
(CDCl
3
): 2.34 (s, 3H), 2.64 (s, 6H), 6.70 (t, 1H, J
H-F
= 70.96), 6.99 (s, 1H).
19
FNMR -
(CDCl
3
): -85.38 (d, J
H-F
= 70.56 Hz).
13
CNMR (CDCl
3
): 21.3, 22.7, 113.9 (t, J
C-F
= 265.9
Hz), 130.9, 132.2, 140.3, 145.0. HRMS calculated for C
10
H
12
F
2
O
3
S: 250.0475; Found:
252.0476.
Bis(difluoromethyl) o-benzenedisulfonate. Yield: 97%. Colorless oil.
1
HNMR (CDCl
3
):
6.97 (t, 2H, J
H-F
= 70.04 Hz), 7.90-8.10 (m, 2H), 8.30-8.50 (m, 2H).
19
FNMR (CDCl
3
): -
102
84.66 (d, J
H-F
= 70.04 Hz).
13
CNMR (CDCl
3
): 114.4 (t, J
C-F
= 270.8 Hz), 133.5, 134.8,
135.7. HRMS calculated for C
8
H
6
F
4
O
6
S
2
: 337.9542; Found: 337.9544.
Difluoromethyl 3-nitrobenzenesulfonate. Yield: 81%. Yellowish oil.
1
HNMR (CDCl
3
):
6.84 (t, 1H, J
H-F
= 70.18 Hz), 7.85 (t, 1H, J = 8.07 Hz), 8.24-8.30 (m, 1H), 8.54-8.60 (m,
1H), 8.74-8.80 (m, 1H). ).
19
FNMR (CDCl
3
): -84.68 (d, J
H-F
= 70.18 Hz).
13
CNMR
(CDCl
3
): 114.1 (t, J
C-F
= 270.1 Hz), 123.4, 129.5, 131.3, 133.4, 137.8, 148.4.
Difluoromethyl 2-naphthalenesulfonate. Yield: 60%. Colorless oil.
1
HNMR (CDCl
3
):
6.85 (t, 1H, J
H-F
= 70.50 Hz), 7.60-7.80 (m, 2H), 7.8-8.2 (m, 4H), 8.55 (s, 1H).
19
FNMR
(CDCl
3
): -84.78 (d, J
H-F
= 70.19 Hz).
13
CNMR (CDCl
3
):114.2 (t, J
C-F
= 267.4), 122.2,
128.3, 128.4, 129.8, 130.3, 130.4, 130.5, 132.0, 132.6, 136.0. HRMS calculated for
C
11
H
8
F
2
O
3
S: 258.0162; Found: 258.0167.
Difluoromethyl 10-camphorsulfonate. Yield: 95%. Colorless oil.
1
HNMR (CDCl
3
):
0.88 (s, 3H), 1.09 (s, 3H), 1.40-1.50 (m, 1H), 1.67-1.78 (m, 1H), 1.96 (d, 1H, J = 19 Hz),
2.00-2.18 (m, 2H), 2.30-2.45 (m, 2H), 3.23 (d, 1H, J = 15 Hz), 3.75 (d, 1H, J = 15 Hz),
6.81 (t, 1H, J
F-H
= 70.53 Hz).
19
FNMR (CDCl
3
): -84.78 (dd, J
F-F
= 225.83 Hz, J
F-H
= 70.53
Hz), -85.23 (dd, J
F-F
= 225.83 Hz, J
F-H
= 70.53 Hz).
13
CNMR (CDCl
3
): 19.8, 19.9, 25.4,
27.0, 42.5, 43.0, 48.3, 51.2, 58.4, 114.2 (t, J
C-F
= 267.4 Hz), 213.5. HRMS calculated for
C
11
H
16
F
2
O
4
S: 282.0737; Found: 282.0735.

103
4.4.6 Difluoromethylation of Imidazoles Using Solid-Phase Polymer Bound
Reagent

To a solution of imidazole derivative (0.25 mmol) in dry acetonitrile (4 mL) solid-
phase polymer bound difluoromethylating reagent (for N-alkyl imidazoles 300 mg, 0.35
mmol resin, for N-unsubstituted imidazoles 600 mg, 0.7 mmol resin and
morpholinimethylpolystyrene for N-alkyl imidazoles 100 mg, 0.4 mmol resin), for N-
unsubstituted imidazoles 200 mg, 0.8 mmol resin were added. The reaction mixture was
stirred for 24 hours at room temperature. The resin was filtered off and washed with
acetonitrile (5 × 5 mL). The solvent was removed in vacuum to give the expected product
as a white solid or colorless semisolid.
N,N’-Bis(difluoromethyl)imidazolium Tetrafluoroborate.
Yield: 93%. Yellowish semi solid.
1
HNMR (CD
3
CN): 7.64 (t, J
H-F
= 59.10 Hz, 2H), 7.96
(s, 2H), 9.52 (s, 1H).
19
FNMR (CD
3
CN): -97.04 (d, 4F, J
H-F
= 59.10 Hz), -150.18 (s, 1F),
-150.23 (s, 3F).
13
CNMR (CD
3
CN): 109.7 (t, J
C-F
= 261.3 Hz), 121.1, 136.6. HRMS
calculated for C
5
H
5
F
2
N
4
: 169.0389; Found: 169.0383.
N-Difluoromethyl-N’-methylimidazolium Tetrafluoroborate. Yield: 96%. Colorless
semi-solid.
1
HNMR (CD
3
CN): 3.92 (s, 3H), 7.54 (t, J
H-F
= 59.51 Hz, 1H), 7.55 (s, 1H),
7.75 (s, 1H), 8.97 (s, 1H).
19
FNMR (CD
3
CN): -95.83 (d, J
H-F
= 59.51 Hz, 2F), -150.05 (s,
1F), -150.10 (s, 3F).
13
CNMR (CD
3
CN): 37.5, 109.4 (t, J
C-F
= 257.5 Hz), 119.4, 126.0,
136.7 (br s). HRMS calculated for C
5
H
7
F
2
N
2
: 133.0577; Found: 133.0574.
N,N’-Bis(difluoromethyl)-2-methylimidazolium Tetrafluoroborate. Yield: 90%.
White solid.
1
HNMR (CD
3
CN): 2.89 (s, 3H), 7.59 (t, J = 57.41, 2H), 7.81 (s, 2H).
104
19
FNMR (CD
3
CN): -97.67 (J = 57.71, 4F), -150.51 (s, 1F), -150.57 (s, 3F).
13
CNMR
(CD
3
CN): 12.0, 109.4 (t, J = 259.4 Hz), 119.8.
1-Difluoromethyl-2,3-dimethylimidazolium Tetrafluoroborate. Yield: 86%. White
solid.
1
HNMR (CD
3
CN): 2.68 (s, 3H), 3.76 (s, 3H), 7.41 (d, J
H-F
= 2.40 Hz,1H), 7.50 (t,
J
H-F
= 56.0 Hz, 1H), 7.61 (d, J = 2.40 Hz, 1H).
19
FNMR (CD
3
CN): -96.69 (d, J
H-F
= 61.60
Hz, 2F), -150.49 (s, 1F), -150.55 (s, 3F).
13
CNMR (CD
3
CN): 11.0, 35.9, 109.4 (t, J
C-F
=
254.0 Hz), 118.0, 124.7, 148.7.
1
HNMR (DMSO-d
6
): 2.75 (s, 3H), 3.81 (s, 3H), 7.83 (d,
J
H-F
= 2.29 Hz,1H), 8.07 (t, J
H-F
= 56.93 Hz, 1H), 8.09 (d, J = 2.29 Hz, 1H).
19
FNMR
(DMSO-d
6
): -95.95 (d, J
H-F
= 58.65 Hz, 2F), -147.65 (s, 1F), -147.71 (s, 3F).
13
C-NMR
(DMSO-d
6
): 11.0, 36.0, 112.0 (t, J
C-F
= 255.9 Hz), 118.1, 124.8, 147.0. HRMS calculated
for C
6
H
9
F
2
N
2
: 147.0734; Found: 147.0741.
N-Difluoromethyl-N’-Ethylimidazolium Tetrafluoroborate.
1
H NMR (CD
3
CN): 1.49
(t, 3H, J= 7Hz), 4.27 (q, 2H, J=7 Hz), 7.54 (t, 1H, J =59 Hz), 7.60 (s, 1H), 7.76 (s, 1H),
9.01 (s, 1H).
19
F NMR (CD
3
CN) -95.85 (d, 2F, J= 59.03 Hz), -150.1 (s, 1F), -150.2 (s,
3F).
13
C NMR (CD
3
CN): 14.9, 46.9, 110.0 (t, J= 257.6 Hz), 118.4, 119.6, 121.7, 136.0.
HRMS calculated for C
6
H
9
N
2
F
2
: 147.0734; Found: 147.0735.
N-Difluoromethyl-N’-Butylimidazolium Tetrafluoroborate.
1
H NMR (CD
3
CN): 0.95
(t, 3H, J= 7Hz), 1.35 (m, 2H), 1.86 (m, 2H), 4.23 (t, 2H, J=7 Hz), 7.55 (t, 1H, J=59 Hz),
7.60 (s, 1H), 7.77 (s, 1H), 9.02 (s, 1H).
19
F NMR (CD
3
CN) -96.00 (d, 2F, J= 59.08 Hz) -
150.1 (s, 1F), -150.2 (s, 3F).
13
C NMR (CD
3
CN): 13.4, 19.7, 31.9, 51.2, 109.5 (t, J =
258.4 Hz), 118.2, 125.0, 136.5. HRMS calculated for C
8
H
13
F
2
N
2:
175.1047; Found:
175.1049.
105
N-Difluoromethyl-N’-Phenylimidazolium Tetrafluoroborate.
1
H NMR (CD
3
CN):
7.62 (t, 1H, J=59 Hz), 7.66 (5H), 7.94 (s,1H), 7.96 (s,1H), 9.41 (s,1H).
19
F NMR
(CD
3
CN):-95.5 (d, J=59 Hz), -150.1 (s, 1F), -150.2 (s, 3F).
13
C NMR (CD
3
CN): 109.9 (t,
J= 258.4 Hz), 118.4, 120.5, 124.0, 124.6, 131.4, 132.1, 135.9. HRMS calculated for
C
10
H
9
N
2
F
2
: 195.0734; Found: 195.0740.
4.4.7 Preparation of Solid-phase Bound S Trifluoromethyl(diphenyl)sulfonium
Tetrafluoroborate
Poly(styrene-co-divinylbenzene) (2.4 g, 1 % cross-linked, mesh 100-200) was
washed with dry dichloromethane (3×20 mL) followed by addition of dichloromethane
(20 mL) and trifluoromethyl phenyl sulfoxide (3.0 g, 15.5 mmol) under argon
atmosphere. The reaction mixture was cooled to 0-5 °C under argon and
trifluoromethanesulfonic acid anhydride (2.6 mL, 15.5 mmol) was added dropwise over a
period of 1 hour. The reaction was allowed to warm up to room temperature, and was
stirred for 20 hours. The resin was filtered off and washed with dichloromethane,
acetonitrile and with dichloromethane again (3 × 40 mL each). The solvent was
evaporated from the last filtrate, the remaining material was dissolved in CDCl
3
and was
checked by
1
H-NMR. If no trace of impurity was found, the washing procedure was
considered to be effective and the resin was dried in a vacuum desiccator to give 5.2 g of
the solid-supported reagent as a brown resin.
19
FNMR (CDCl
3
): -42 to -60 (br s), -77 to -
82 (br s). Microanalysis: Fluorine 19.1% 10.05 mmol/g. Sulfur 11.8% (1.84 mmol/g).
Loading (based on trifluoromethylsulfonium cation)= 1.67 mmol/g.
Loading (based on diarylsulfide)= 0.017 mmol/g.
106
FTIR: 1000-1150 cm
-1
(C-F stretch), 1150-1200 cm
-1
, 1250-1400 cm
-1
(S-O, S=O).
4.4.8 Reaction of the Resin-bound S trifluoromethylsulfonium Triflate with
Aniline
A mixture of resin (100 mg, 0.17 mmol, S-trifluoromethylsulfonium triflate),
aniline (18 mg, 0.19 mmol) and pyridine (16 mg, 0.19 mmol) in THF (1 mL) was stirred
at 90 °C for 24 hours. The resin was filtered off and washed with THF.
Trifluoromesitylene was added to the filtrate as a standard and the mixture was analyzed
by
19
F NMR spectroscopy (see spectrum).
19
F-NMR (THF): -61.3 (s), -63.0 (s), -78.9 (s)
19
F-NMR (DMSO): o-trifluoromethylaniline: -59.3 (s), p-trifluoromethylaniline: -61.7.
4.4.9 Reaction of the Resin-bound S-trifluoromethylsulfonium Triflate with
Thiophenol
A potassium salt of thiophenol (22 mg, 0.2 mmol) was prepared by adding
potassium t-butoxide (22.4 mg, 0.2 mmol) to a solution of thiophenol (22 mg, 0.2 mmol)
in DMF (1 mL). S-trifluoromethylsulfonium triflate resin (200 mg, 0.34 mmol S-CF
3
)
was added and the reaction mixture was stirred at room temperature for 16 hours. The
resin was filtered off and washed with THF. Trifluoromesitilene was added to the filtrate
as a standard and the mixture was analyzed by
19
F NMR spectroscopy.
19
F-NMR (DMF):
-42.8 (s), -78.0 (s) .
19
F-NMR: -41.7 (s).

107
4.5 Chapter 4: Representative Spectra

FTIR spectrum of the solid supported reagent

108
19
F NMR spectrum of the solid supported reagent

109
1
H NMR spectrum of difluoromethyl benzenesulfonate

ppm (f1)
0.0 5.0 10.0
7.263
1.577
1.254
0.071
0.000
2.00
3.05
0.94
TMS
silicone
grease
grease
wa ter
CDCl3
1H Spectrum
S O O
O
CF
2
H
110

19
F NMR spectrum of difluoromethyl benzenesulfonate

ppm (f1)
-200 -150 -100 -50 0
19F Spectrum
ppm (f1)
-90.0 -85.0 -80.0
S O O
O
CF
2
H
111
13
C NMR spectrum of difluoromethyl benzenesulfonate

ppm (f1)
0 50 100 150 200
13C Spectrum
S O O
O
CF
2
H
112
1
H NMR spectrum of N-Difluoromethyl-N’-Butyl imidazolium Tetrafluoroborate
.

ppm (f1)
1.0 2.0 3.0 4.0 5.0 6.0 7.0 8.0 9.0
1H spectrum
ppm (f1)
7.00 7.50 8.00
N N
C
4
H
9
CF
2
H
BF
4
113
9
F NMR spectrum of N-Difluoromethyl-N’-Butyl imidazolium Tetrafluoroborate

ppm (f1)
-250 -200 -150 -100 -50 0
1.00
2.04
19 F Spectrum
ppm (f1)
-100.0 -99.0 -98.0 -97.0 -96.0 -95.0 -94.0
1.03
N N
C
4
H
9
CF
2
H
BF
4
114
13
C NMR spectrum of N-Difluoromethyl-N’-Butyl imidazolium Tetrafluoroborate

ppm (f1)
0 50 100
ppm (f1)
95.0 100.0 105.0 110.0 115.0
13 C spectrum
N N
C
4
H
9
CF
2
H
BF
4
115
4.6 Chapter 4: References

1. Kirsch, P., Modern Fluoroorganic Chemistry; Wiley-VCH: Weinheim Germany,
2004. Chapter 4. p 203-278.
2. Isanbor, C.; O'Hagan, D J. Fluorine Chem. 2006, 127, 303.
3. Shimizu, M.; Hiyama, T. Angew. Chem. Int. Ed. 2005. 44, 214.
4 Kirsch, P., Modern Fluoroorganic Chemistry; Chapter 1.4. p. 8-24. Wiley-VCH
Weinheim, Germany, 2004.
5. ChemBioChem, 2004, 5, 557-726.
6. Reichenbaecher, K.; Suss, H. I.; Hulliger, J. Chem. Soc. Rev. 2005, 34, 22.
7. Hiyama, T., Organofluorine Compounds, Chapter 5.1.p.137-141. SpringerVerlag
Berlin , Heidelberg, Germany 2000.
8. Uneyama, K. Organofluorine Chemistry, Chapters 1.2. p 10-100. Chapter 4. 173-185.
Blackwell publishing Ltd. Oxford, UK.
9. Dolle, R. E.; Le Bourdonnec, B.; Morales, G. A.; Moriarty, K. J.; Salvino, J. M. J.
Comb. Chem. 2006, 8, 597.
10. Guba, W.; Neidhart, W., Nettekoven, M. Bioorg. Med. Chem. Lett. 2005, 15, 1599.
11. Parks, D. J.; La France, L. V.; Calvo, R. R.; Milkiewicz, K. L.; Gupta, V.; Lattanze,
J.;Ramachandren, K.; Carver, T.; Petrella, E. C.; Cummings, M. D.;Maguire, D.;
Grasberger, B. L.; Lu, T. Bioorg. Med. Chem. Lett. 2005, 15, 765.
12. Macarron, R. Drug Discovery Today, 2006, 11, 277.
13. Umemoto, T. Chem. Lett. 1984. 25, 81.
14. Integrity, 2005. The same search in Pharmaproject revealed 24 hits.
15. Kirsch, P. Modern Fluoroorganic Chemistry; Wiley-VCH: Weinheim, Germany,
2004. Chapter 2.3.1. p. 141.
16. Uneyama, K. Organofluorine Chemistry, Chapter 7.2. p. 257-291. Blackwell
Publishing Ltd. Oxford, UK.
17. Prakash, G.K. S, Weber, C, Chacko, S, Olah, G, A. Org. Lett. 2007, 9, 1863.
116

18. Yagupol'skii, L. M.; Kondratenko, N. Y.; Timofeeva, G. N. Zh. Org. Khim. 1984, 20,
115.
19. Umemoto, T.; Ishihara, S. J. Am. Chem. Soc. 1993, 115, 2156.
20. Umemoto, T.; Ishihara, S.; Adachi, K. J. Fluorine Chem. 1995, 74, 77.
21. Umemoto, T.; Ishihara, S. J. Fluorine.Chem. 1999, 98, 75.
22.Umemoto, T.; Adachi, K. J. Org. Chem. 1994, 59, 5692.
23. Yang, J. J.; Kirchmeier, R. L.; Shreeve, J. M. J. Org. Chem. 1998, 63, 2656.
24. Ma, J.-A.; Cahard, D. J. Org. Chem. 2003, 68, 8726.
117
5 Chapter 5: Regioselective Synthesis of Phenols and Halo
phenols from Arylboronic Acids Using Solid Poly(N-
vinylpyrrolidone)/H
2
O
2
and poly(4-vinyl pyridine)/H
2
O
2

Complexes
5.1 Chapter 5: Introduction

Hydrogen peroxide is a widely used oxidant and in most cases, dilute aqueous
solutions of H
2
O
2
are preferred due to the explosive nature of H
2
O
2
in higher
concentration. One of the other commonly used oxidation reagent is m-chloroperbenzoic
acid (mCPBA) and has become a popular reagent for oxidation of alkenes. It has major
disadvantages like shock sensitivity and explosive nature in the condensed phase. Sodium
perborate is a large scale industrial chemical and used in mild antiseptic and mouthwash.
Its potential as an effective oxidizing agent has attracted the attention of the scientific
world. Prakash and co-workers have reported the use of sodium perborate/ triflic acid
system for the electrophilic hydroxylation of aromatics.
1
Olah et al. have reported the use
of sodium percarbonate/triflic acid as an effective oxidising agent for the Baeyer-Villeger
oxidation of ketones to esters.
2
More recently magnesium monoperoxyphthalate
hexahydrate (MMPP) is used as safer oxidising agent because it is non-shock sensitive
and non-deflagrating.
3
Many attempts have been made to find a safer way to increase the
effective concentration of H
2
O
2
in a reagent system and this has remained a challenge.
Complexing H
2
O
2
with compounds like urea is found to be a very convenient approach,
which makes the oxidant safer and a more effective reagent. Realizing the advantages of
safer solid oxidant system, urea-H
2
O
2
1:1 complex (urea hydroperoxide, carbamide
118
peroxide) has been extensively explored for various synthetic applications such as
epoxidation of alkenes, oxidation of various functional groups such as nitriles, oximes,
sulfides, aldehydes, ketones etc. under thermal as well as microwave
conditions.
4,5,6,7,8,9,10,11,12,13,14,15
Bis(trimethylsilyl) peroxide (BTMSPO) has often been
described as the masked form of 100% hydrogen peroxide, which can be synthesized
from 1, 4-diazabicyclo[2, 2, 2]octane(DABCO)-hydrogen peroxide complex (formed
from 35% hydrogen peroxide and DABCO) and trimethylsilyl chloride. Jackson reported
an improved synthesis of BTMSPO by using urea-hydrogen peroxide instead of
DABCO-hydrogen peroxide.
16
Ricci and co-workers have reported using
bis(trimethylsilyl) peroxide for hydroxylation of organolithium compounds.
17
It is also
used as a mild aprotic oxidizing agent for the transformation of sulfides into the
corresponding sulfoxides,
18,19
phosphines into phosphine oxides,
20,21
in the oxidation of
alcohols to aldehydes
22
and in the Baeyer-Villiger reaction.
23
Olah and co-workers have
reported the use of BTMSPO in presence of triflic acid for hydroxylation of neutral
aromatic systems.
24
Poly(N-vinylpyrrolidone) (povidone, PVD) has also been found to
form complexes with H
2
O
2
which are mainly used for medical and biological applications
such as preservation of blood, tissues and biological fluids, treatment of agne vulgaris
and in many modern disinfectants.
25,26,27,28,2930,31,32,33
PVD-H
2
O
2
complex has been widely
used in teeth whitening dentrifices and as a protective coating material in dental
bleaching devices.
34, 35, 36, 37, 38

Urea hydrogen peroxide is an unstable 1:1 combination of urea and hydrogen
peroxide in equal amounts. It is soluble in water, alcohol, and ethylene glycol.
119
It decomposes at 75-85
o
C or by moisture and is used as a source of water-free hydrogen
peroxide. On the other hand PVD forms a free flowing solid complex with aqueous H
2
O
2

(upto 70% H
2
O
2
) in which monomer-H
2
O
2
composition can go upto 1:4.5. Unlike Urea,
povidone can be easily recovered and recycled. Presence of water in the complex makes
it safer and easier to handle. Synthetic applications of this complex have not been well
explored. It has been used in organic reactions as a free radical initiator in polymerization
processes.
39
Recently, Pourali et al. have used povidone supported hydrogen peroxide
(PVD-H
2
O
2
) as an efficient reagent in the epoxidation of α, β-unsaturated ketones and
direct iodination of aromatic compounds.
40
Ab initio calculations on PVD-H
2
O
2
complex
by Panarin et al.
41
showed that H
2
O
2
molecules form stronger H-bond with the carbonyl
oxygen of PVD than with hydroxyl oxygen in water and therefore a stable complex is
formed from PVD and aqueous H
2
O
2
. Since H
2
O
2
is capable of strong self association
due to two hydrogen bonds between adjacent molecules, formation of complexes with
higher H
2
O
2
content is possible. Our extensive studies on poly(4-vinyl pyridine)
complexes showed that it can be used as a very effective solid support for many acidic
reagents through complexation.
42
Our attempts to complex PVP with H
2
O
2
also resulted
in the formation of a new solid PVP-H
2
O
2
complex with monomer-H
2
O
2
ratio of 1: 4
During our continued efforts to develop efficient environmentally friendly
polymer supported reagents, we found that synthesis of phenols could be achieved in
excellent yields by the direct regioselective ipso-hydroxylation of arylboronic acids,
using solid H
2
O
2
complexes of poly(N-vinylpyrrolidone) and pol(4-vinylpyridine). In this
120
chapter, we discuss the efficient ipso-hydroxylation of boronic acids achieved using solid
H
2
O
2
complexes of poly (N-vinylpyrrolidone) and poly(4-vinylpyridine). The complexes
were also used for the one pot synthesis of halophenols from aryl boronic acids. DFT
calculations have been carried out on H
2
O
2
complexes of N-ethylpyrrolidone and 4-
ethylpyridine as models to get a better understanding of the greater activity and
selectivity of H
2
O
2
complexes of the polymers PVD and PVP compared to aqueous H
2
O
2
.
5.2 Chapter 5: Results and Discussion

Arylboronic acid act as one of the most efficient and versatile synthon for facile
regioselective functional group transformation.
43, 44, 45, 46, 47
We have already reported the
ipso-halogenation,
48
ipso-nitration
49
and ipso-hydroxylation
50
of arylboronic acids. An
efficient ipso-nitration procedure for arylboronoc acids under mild condition has been
reported recently.
51
Polymer supported reagents for synthetic purpose is also becoming
important and a very useful tool in synthetic organic chemistry.
52, 53, 54, 55, 56, 57
The
polymer support, not only makes the reaction simple, easy and environmentally benign,
but also helps sometimes to modulate the reactivity of the reagents towards different
reactions. However, complexes formed by polymer supports with various reagents, which
can easily deliver the reagent in the reaction medium and permit recycling of the support
make the reactions more environmentally friendly and a critical tool for sustainable
development. Recently, we have successfully used poly(4-vinylpyridine)-SO
2
complex as
an effective polymer supported mild acid catalyst in three component Strecker reaction
for the synthesis of α–aminonitriles.
58
Based on the amount of H
2
O
2
loaded on the
121
polymer a chromatographic column packed with a definite amount of the complex can be
used as the major reagent for several reactions irrespective of the nature of the substrate
(boronic acid) till substantial drop in H
2
O
2
concentration occurs. Polymer support can be
reloaded with H
2
O
2
and recycled for further reactions. Products are separated in high
yields and purity by simple reomoval of the solvent. No further work-up or purification
is required.

(a) (b)
Figure 5.1 (a) Surface of PVD (b) Surface of PVD-H
2
O
2
complex

(a) (b)
Figure 5.2 (a) Surface of PVP (b) Surface of PVP-H
2
O
2
complex

122
Both PVP- and PVD- H
2
O
2
complexes were synthesized using varying amounts of these
polymers and 50% aqueous H
2
O
2
. 2% Divinyl benzene cross linked PVP and PVD were
used for preparation of these complexes, which is made by carefully adding the required
amount of the polymer to 50% hydrogen peroxide in a Nalgene bottle kept in a bath at -
78
o
C with thorough stirring. These complexes remain as free flowing wet powders.
However, non-cross linked PVD and PVP did not form free-flowing solid complexes.
PVD-H
2
O
2
complexes with various composition has been prepared and it is found that
the complex remains as a wet powder upto 1:4.5 mole ratio composition of PVD and
H
2
O
2
. PVP-H
2
O
2
complex remains as a wet fine powder till the composition reaches
1:3.5 mole ratio. The hydrogen peroxide content in these complexes was confirmed by
quantitative titration with aqueous potassium permanganate, (reduction of potassium
permanganate (KMnO
4
) by hydrogen peroxide in sulfuric acid) there by ruling out the
possibility of any reaction between the polymer support and H
2
O
2
which may lead to
oxidation products including N-oxide. The change in morphology of the polymer samples
due to complexation was investigated through Scanning Electron Microscope (Figure 5.1
and 5.2). Surface morphology of the complexes clearly shows the overall uniform
interaction of H
2
O
2
on the polymer.
In a previous report, our group has shown that phenols can be obtained from
arylboronic acids using aqueous H
2
O
2
(30%). This method needs several hours for the
completion of the reactions and further workup and purification is needed. Other methods

known for this transformation have also similar kind of limitations.
59,60,61,62
In our new
technique using PVD-H
2
O
2
and PVP-H
2
O
2
complex regioselective hydroxylation of aryl
123
boronic acids to corresponding phenols can be achieved in higher yields at a much more
faster rate (Scheme 5-1) as mentioned earlier.

B(OH)
2
OH
R
R
Solid-H
2
O
2
Complex
CH
2
Cl
2
,RT

Scheme 5.1 Ipso-hydroxylation of arylboronic acids using solid H
2
O
2
complexes
of poly(N-vinyl 2-pyrrolidone) and poly(4-vinyl pyridine).

For reactions in 1mmol scale, a small chromatographic column fitted with cooling
jacket was filled partially with PVD-H
2
O
2
complex (5g, column diameter- 2cm; Figure
5.3). The arylboronic acids were dissolved in CH
2
Cl
2
and passed through this column
slowly. For arylboronic acids, which are partially soluble in CH
2
Cl
2
, the slurry of the
compound in CH
2
Cl
2
was prepared and used. The column was continuously eluted with
CH
2
Cl
2
till TLC showed no product during elution. All the organic layers were combined
and dried over Na
2
SO
4
and the solvent was evaporated to get the phenol in almost
analytically pure form. Both electron rich and electron poor arylboronic acids were found
to undergo ipso-hydroxylation to give the corresponding phenols in good yields. For
example, 4-acetylphenylboronic acid was converted to 4-hydroxyacetophenone (4-
acetylphenol) quantitatively.

124

Figure 5.3 Schematic diagram for the preparation of phenols from boronic acids

We have also investigated the recovery and recycling of the solid hydrogen
peroxide complex. After the first reaction, the product is eluted completely out with
enough amount of CH
2
Cl
2
as eluent and the column is set ready for the next reaction. The
procedure was repeated for other substrates. It is observed that the column is very
efficient for three successive reactions. For the forth run the yield is found to drop down,
but the phenols formed are very pure. This is due to the drop in the H
2
O
2
loading and the
unreacted boronic acid remains in the column when the amount of H
2
O
2
in the complex is
decreased after three or four successive reactions. The results are summarized in Table
5.2.

Water inlet
Polymer-hydrogen peroxide
complex
Boronic acid in CH 2Cl 2
Phenol in CH 2Cl 2
Water outlet
125
Table 5.1 Regioselective hydroxylation of of arylboronic acids

B
OH
OH
OH
B
OH
OH
OH
Cl Cl
B
OH
OH
OH
Br Br
B
OH
OH
OH
B
OH
OH
OH
H
3
C H
3
C
B
OH
OH
OH H
3
CO H
3
CO
B
OH
OH
OH Cl Cl
B
OH
OH
OH
B
OH
OH
OH
B
OH
OH
OH
F F
O
2
N O
2
N
191
295
3 85
4 95
5 97
6 99
7
94
890
993
10 80
Entry Boronic acids Phenols
Yield (%)
a
A: Yield from Reaction with PVD-H
2
O
2
Complex;
a
Isolated yields
B: Yield from reaction with PVP-H
2
O
2
Complex
97
73
81
80
80
81
60
65
55
49
A B
C
O
H
3
C
C
O
H
3
C

126
Table 5.2 Efficiency of PVD-H
2
O
2
complex as solid H
2
O
2
equivalent and recycling of
PVD.
B
B
OCH
3
B
Cl
B
OH HO
OH HO
HO OH
HO OH
OH
OH
OCH
3
OH
Cl
OH
1
2
3
4
96
99
97
95
92
98
94
90
89
96
94
92
72
90
70
87
1
st
Run 2
nd
Run 3
rd
Run 4
th
Run
Yield (%)
a
Phenols Boronic Acids Entry
a
Isolated yield

Tribromophenols (TBP) and its derivatives are used as flame retardants for
plastics, paper and textiles. These compounds also find applications in wood
preservatives and general fungicides.
63
Triiodophenol known as Bobel-24 has been found
to have anti-inflammatory properties in various animal models and also is a 5-
lipoxygenase inhibitor.
64,65
Triiodophenol and its derivatives are potential candidates in
therapeutic developments for leukaemia.
66

127
Table 5.3 Synthesis of halophenols from boronic acids

Entry Boronic acids Products Yields (%)
B(OH)
2
OH
Br Br
Br
OH
Br Br
Cl
OH
Br Br
CN
OH
Br Br
CF
3
OH
Br Br
Br
Br
OCH
3
OH
I I
I
OH
I I
Cl
CF
3
Br
OCH
3
Br
+
B(OH)
2
Cl
B(OH)
2
CN
B(OH)
2
CF
3
B(OH)
2
CF
3
B(OH)
2
OCH
3
80
79
90
88
85
85
77
B(OH)
2
B(OH)
2
Cl
1
2
3
4
5
6
a
7
8
37 (26)
b
a
Yield caclulated by NMR;
b
Yield of the dibromo derivative
1:1

128
Realizing the importance of halophenols, we further expanded the versatility of
this reagent for the one pot synthesis of halophenols directly from aryl boronic acids. A
series of boronic acids were treated with a 20 % bromine solution (in dicholoromethane)
and PVD-H
2
O
2
at room temperature, the corresponding tribromophenols were obtained in
high yields (Table 5.3, Entries 1-6). The corresponding triiodophenols were also obtained
when iodine solution was used in place of bromine solution (Table 5.3, Entries 7 and 8).
However, our attempt to synthesize various fluorophenols using electrophilic fluorinating
agents such as Selectfluor, Synfluor and N-fluoro benzene sulfonamide along with PVD-
H
2
O
2
under different conditions was not successful.
5.3 Chapter 5: Density Functional Theory (DFT) Study of N-
ethylpyrrolidone-H
2
O
2
Complexes Compared with 4-ethyl
Pyridine-H
2
O
2
Complexes as Models for the Polymer- H
2
O
2

Complexes

We were also interested to study the nature of the polymer bound H
2
O
2

complexes using DFT calculations. The complexes of N-ethylpyrrolidone {N-
ethylpyrrolidone was used as a model for poly(N-vinyl pyrrolidone)} with H
2
O
2
were
calculated using density functional theory method (DFT) at the B3LYP/6-311+G** level.
Two structures, 1a and 1b, were found to be as minima for 1:4 complex of N-
ethylpyrrolidone and H
2
O
2
(Figure 5.4). Structure 1a with a C=O
….
H bond distance of
1.672 Å and the structure 1b with a C=O
….
H bond distance of 1.591 Å are hydrogen-
bonded structures. Energetically 1b was found to be 3.7 kcal/mol more stable than 1a at
the B3LYP/6-311+G**//B3LYP/6-311+G** + ZPE level (Table 5.4). Complexation
129
energy of N-ethylpyrrolidone and four H
2
O
2
was calculated to be exothermic by 36.4
kcal/mol.

Table 5.4 Total energies (-au), ZPE
a
and relative energies (kcal/mol)
b

------------------------------------------------------------------------------------
no. B3LYP/6-31G**// ZPE B3LYP /6-311+G** rel. energy
B3LYP /6-31G** B3LYP /6-311+G** (kcal/mol)
------------------------------------------------------------------------------------
1a 971.53182 172.3 971.83846 3.7
1b 971.54263 173.0 971.84545 0.0

2a 933.18599 158.7 933.47640 3.9
2b 933.19721 159.4 933.48378 0.0

3a 1123.09605 190.3 1123.45604 0.0
3b 1123.09608 190.0 1123.45436 0.7

Pyrrolidone 365.27530 101.1 365.36589
Pyridine 326.93086 87.6 327.00441
H
2
O
2
151.54319 15.9 151.60206
------------------------------------------------------------------------------------
a
zero point vibrational energies (ZPE) at B3LYP/6-31G**//B3LYP/6-31G**
scaled by a factor of 0.96;
b
at B3LYP/6-311+G**//B3LYP/6-311+G**+ ZPE level

For comparison we have also calculated complexes of 4-ethylpyridine {ethylpyridine was
used as a model for poly(N-vinylpyridine)} and H
2
O
2
at the B3LYP/6-311+G** level.
Similar to N-ethylpyrrolidone complexes, two structures, 2a and 2b, were also found to
be as minima for 1:4 complex of 4-ethyl pyridine and H
2
O
2
(Figure 5.4). Structure 2a
with a C=O
….
H bond distance of 1.731 Å and the structure 2b with a C=O
….
H bond
distance of 1.644 Å are hydrogen-bonded structures. Energetically 1b was also found to
130
be 3.9 kcal/mol more stable than 2a at the B3LYP/6-311+G**//B3LYP/6-311+G** +
ZPE level, showing that PVD-H
2
O
2
complexation are more effective than PVP-H
2
O
2

complexation. Complexation energy of pyridine and four H
2
O
2
was calculated to be
exothermic by 36.5 kcal/mol.
Two structures, 3a and 3b, were also found to be as minima for 1:5 complex of
ethyl pyrrolidone and H
2
O
2
. However, unlike 1:4 complexes, energetically 3b was found
to be 0.7 kcal/mol less stable than 3a at the B3LYP/6-311+G**//B3LYP/6-311+G** +
ZPE level. Complexation energy of N-ethylpyrrolidone and five H
2
O
2
was calculated to
be exothermic by 40.4 kcal/mol.

5.3.1 Calculational Methods

Calculations were performed using the Gaussian 03 program.
67
The geometry
optimizations and vibrational frequency calculations were performed using density
functional theory (DFT) method
68
at the B3LYP/6-311+G** level.
69
Vibrational
frequencies were used to characterize stationary points as minima (number of imaginary
frequency, NIMAG = 0) and to evaluate zero point vibrational energies (ZPE) which
were scaled by a factor of 0.96. Final energies were calculated at the B3LYP/6-
311+G**//B3LYP/6-311+G** + ZPE level.

131

1a, C1 1b, C1

2a, C1 2b, C1

3a, C1 3b, C1

Figure 5.4 B3LYP/6-311+G** calculated structures of 1 - 3.

132
5.4 Chapter 5: Conclusion

In summary, we have successfully developed a milder and new technique to
regioselectively transform aryl boronic acids to the corresponding phenols in excellent
yields and high purity, using a solid PVD-H
2
O
2
complex, which can be reused further for
several runs. Solid PVP-H
2
O
2
complex was also prepared in the same fashion and its
efficacy was studied for the same reaction. Further, this methodology can be successfully
applied to synthesize halophenols from boronic acids in a one pot fashion. High level DFT
calculations were also performed on model systems to study and understand the nature of
these complexes. It is anticipated that these complexes can be utilized as effective
oxidizing agents for other oxidation reactions in chemical synthesis.
5.5 Chapter 5: Experimental

5.5.1 Preparation of the PVD-H
2
O
2
and PVP-H
2
O
2
complex
In a Nalgene container 50% H
2
O
2
(34 g, 0.5 mol) was taken and the solution was
cooled to –78
o
C. Keeping the temperature constant, 2% cross linked polyvinyl
pyrrolidone (PVD) was added slowly with vigorous shaking. The morphology of the
complex changed during the course of the addition and formed a fine wet powder till the
ratio of polyvinylpyrrolidone to H
2
O
2
went upto 1:4.5. The complex was kept under cool
(–20
o
C) dry conditions. The PVP-H
2
O
2
complex was also prepared in a similar way
using 2% cross linked poly(4-vinyl pyridine) and 50% H
2
O
2
(1:3.5 molar ratio).

133
5.5.2 Typical procedure for ipso-hydroxylation of aryl boronic acids
In a small water-jacketed chromatographic column, 5.4 gm of the solid complex
was taken and filled it partially. A solution of arylboronic acid (1 mmol) in 10 mL of
CH
2
Cl
2
was poured in the column. The solution was kept in the column in contact with
the solid complex for two minutes and then slowly passed through the column and
collected in a flask. The column was then eluted with excess CH
2
Cl
2
and the eluant was
checked continuously by TLC for any remaining product. The solvent fractions were
combined and dried over anhydrous sodium sulfate. The solvent was evaporated to give
the phenols in analytically pure form. After rinsing the column with CH
2
Cl
2
, the same
column can be used for next run.

5.5.3 Typical procedure for the synthesis of halophenols from aryl boronic acids
In a 100 mL round bottom flask, a solution of 1 mmol of aryl boronic acid in 10
mL of CH
2
Cl
2
was taken. To this solution, 5 equivalents of bromine in dichloromethane
was added slowly along with 1-2 g of the solid complex. The whole mixture is stirred at
room temperature and the reaction was monitored using TLC. Once the whole starting
material is converted, the solid complex was separated by filtration. The filtrate was
washed three times with sodium thiosulfate solution and then with water. The organic
phase was separated and was dried using anhydrous sodium sulfate. The solvent was
evaporated to give the halophenols in analytically pure form. In certain cases, the
halophenols were passed through a flash column using CH
2
Cl
2
as eluent to separate any
impurities present.
134
5.6 Chapter 5: References

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139

6 Chapter 6: Efficient 1, 4-addition of α-substituted α-fluoro-
(phenylsulfonyl)methane derivatives to α, β -unsaturated
compounds
6.1 Chapter 6: Introduction

Compounds with a monofluoromethyl moiety are of great importance with
regards to isostere-based drug design.
1,2,3,4
Consequently, synthesis of new functionalized
α-monofluorine-substitued active methylene derivatives has attracted considerable
attention particularly in the field of medicinal chemistry.
5,6
One of the major interests in
our group has focused on developing new fluorinating reagents or fluorinated building
blocks for preparation of fluorine-substituted compounds.
7, 8, 9
As part of our ongoing
effort to extend the applications of fluorine-containing (phenylsulfonyl)methane
derivatives, we envisaged that 1-fluoro-(phenylsulfonyl)methane, α-substituted by nitro,
or phenylsulfonyl group would be useful for the synthesis of functionalized
monofluoromethylated compounds, which would further undergo various
transformations. New synthetic methods for the synthesis of α-substituted α-fluoro-
(phenylsulfonyl)methane derivatives under mild reaction conditions, using convenient
starting materials, are still desirable. Fluorinated carbanions are in principle “hard”
nucleophiles that readily undergo 1, 2-addition with Michael type acceptors instead of 1,
4-addition.
10, 11, 12
Different strategies have been employed to achieve 1, 4-addition,
which is still percieved to be a challenge. For instance, Yamamoto
13
and Röshenthaler
14,
15
have made use of bulky aluminum Lewis acids to protect the carbonyl of Michael
140
acceptors and thus sucessfully transferred the trifluoromethyl anion generated from the
“Ruppert-Prakash reagent” (TMS-CF
3
) in a 1, 4-manner rather than the favored 1, 2-
addition. Portella et al.
16
have shown that, 1, 4-addition of difluoroenoxysilanes to enones
can be used to introduce difluoromethylene moiety, while Kumadaki and coworkers
17, 18

have used bromodifluoroacetate with copper catalyst to introduce the CF
2
functionality.
There also exist few reports on the 1, 4- addition of monofluoromethylene moeities to α,
β -unsaturated compounds.
19,20
Takeuchi and coworkers
21
have shown that α-fluoro α-
nitroalkanes can undergo 1, 4- addition to methyl vinly ketone and acrylonitirile to afford
the dialkylated products.
6.2 Chapter 6: Results and Discussion

In this chapter, the facile reaction of α-fluoro-(phenylsulfonyl)methane
derivatives and various Michael acceptors is disclosed. α-Fluoro
bis(phenylsulfonyl)methane was prepared following a literature procedure by fluorinating
bis(phenylsulfonyl)methane, which is commercially available. Alkylation of this
compound is reported to be a challenge because the combined carbanion-stabilizing
abilities of the two strong electron-withdrawing groups are not sufficient to overcome the
well-known carbanion destabilization by the adjacent fluorine. In addition, the presence
of electron withdrawing groups such as the phenylsulfonyl group can be exploited to
generate a carbanion that can act as a “soft” nucleophile. The phenylsulfonyl group
delocalises the electron density on the fluorinated carbanion center, which makes the
resulting nucleophile softer and more suitable for 1, 4- addition with Michael acceptors.
141
Hence, we explored the possibility of a base induced Michael addition reaction. Among
the various bases and solvent combination that we tried, K
2
CO
3
/DMF system was found
to be very efficient both in terms of conversions as well as reaction times.
The reactions were carried out at room temperature and the completion was
observed within 2 hours. The reaction was found to be versatile for various α, β -
unsaturated compounds such as ketones, esters, nitriles and sulfones (Table 6.1). In the
case of α, β -unsaturated aldehydes the reaction was found to be not clean and too many
fluorine peaks appeared in the
19
F NMR even when the reaction was carried out at low
temperatures. On the other hand, α, β -unsaturated nirtiles underwent a second Michael
addition of the product (1h).
During the study, it was observed that the steric factor affects the addition of the
pronucleophile to the Michael acceptor. Substitution at the α position of the Michael
acceptor affects the reactivity of the nucleophile generated by K
2
CO
3
/DMF system. The
reaction of 1-fluoro(bisphenylsulfonyl)methane with methyl crotonate was found to give
only 50% conversion based on
19
F NMR after 36 hours and methyl cinnamate did not
react at all at room temperature using K
2
CO
3
/DMF system. Attempted reductive
desulfonylation on compound 1d using Mg/CH
3
OH was not selective as simultaneous
reduction of the carbonyl group was also observed.

142
Table 6.1 K
2
CO
3
/DMF catalyzed 1, 4-addition of α-fluoro (bisphenylsulfonyl)methane
and α-nitro, α-fluoro phenylsulfonylmethane to α, β -unsaturated esters, ketones,
sulfone, and nitriles

Entry Substrate Product Yield
a
(%)
1
2
3
4
5
6
7
O
O
O
O
O
O
O
O
S
O
2
CN
O
O
(PhSO
2
)
2
FC
(PhSO
2
)
2
FC O
O
O
O
(PhSO
2
)
2
FC
O
CF(SO
2
Ph)
2
H
(PhSO
2
)
2
FC
O
(PhSO
2
)
2
FC
O
2
S
(PhSO
2
)
2
FC
CN
(PhSO
2
)
2
FC
CN
CH
2
CH
2
CN
71
90
79
60
70
70
R
PhSO
2
PhSO
2
PhSO
2
PhSO
2
PhSO
2
PhSO
2
PhSO
2
54 (1:2)
8 NO
2
PhO
2
S
F
45
NO
2
O
O
O
O
1a
1b
1c
1d
1e
1f
1g
1h
1i
a
- isolated yield

143
Both α-fluoro-(bisphenylsulfonyl)methane and α-nitro, α-fluoro-
phenylsulfonylmethane were added to propynoates under similar conditions. As
expected, a mixture of both cis and trans products were obtained as shown in Table 6-2.
Interestingly, in the case of α-nitro, α-fluoro-phenylsulfonylmethane only the trans
isomer (1l) was obtained in an appreciable amount while only trace amount of the cis
product was observed. Attempted reductive desulfonylation on compound 1d using
Mg/CH
3
OH was not selective as simultaneous reduction of the carbonyl group was also
observed.
Table 6.2 K
2
CO
3
/DMF catalyzed 1, 4-addition of α-fluoro (bisphenylsulfonyl)methane
and α-nitro, α-fluoro phenylsulfonylmethane to propynoates

PhSO
2
R
F
H
H EWG
K
2
CO
3
,DMF
rt, 2h
CF
EWG
PhO
2
S
R
Entry Substrate Product Yield
a
(%) R
O
O
O
O
PhSO
2
PhSO
2
1
2
NO
2
H
H
PhSO
2
FC
O
O
NO
2
46
c
3
O
O
O
O
(PhSO
2
)
2
FC
O
O
(PhSO
2
)
2
FC
76 (2:3)
b
60 (1:1)
b
a
Isolated Yield,
b
cis:trans ratio,
c
only trace of cis isomer observed
1j
1k
1l

144
6.3 Chapter 6: Conclusions

In summary, a convenient protocol for the nucleophilic addition of α-fluoro- α-
phenylsulfonyl-substituted methane derivatives to a variety of Michael acceptors such as
α, β unsaturated esters, ketones, sulfone, nitriles has been demonstrated . This
methodology has been further extended to propynoates to give the corresponding adducts
in moderate yields.
6.4 Chapter 6: Experimental

Unless otherwise mentioned, all other reagents were purchased from commercial
sources. Diethyl ether and THF were all distilled under nitrogen over
sodium/benzophenone prior to use. Toluene was distilled over sodium. Column
chromatography was carried out using silica gel (60-200 mesh).
1
H,
13
C and
19
F NMR
spectra were recorded on Varian Mercury 400 NMR spectrometers.
1
H NMR chemical
shifts were determined relative to internal (CH
3
)
4
Si (TMS) at δ 0.0 ppm or to the signal of
a residual proton containing solvent: CDCl
3
δ 7.26 ppm.
13
C NMR chemical shifts were
determined relative to internal TMS at δ 0.0 ppm or to the
13
C signal of solvent: CDCl
3
δ
77.16 ppm.
19
F NMR chemical shifts were determined relative to internal CFCl
3
at δ 0.0
ppm
6.4.1 Typical Procedure for the 1, 4 addition of α-fluoro-(phenylsulfonyl)methane
derivatives to various Michael acceptors

To a solution of fluorine-substituted active methylene derivative (0.16 mmol, 1
equivalent) and α, β -unsaturated compound (0.16 mmol, 1 equivalent ) in DMF (2 mL)
145
was added potassium carbonate (0.36 mmol, 0.050g) at room temperature and the
progress of the reaction was monitored by
19
F NMR. Aqueous work up followed by
extraction with dichloromethane (3x 15 mL) afforded the crude product. The pure
product was obtained by column chromatography using silica gel (60-200 mesh).
4,4-Bis-benzenesulfonyl-4-fluoro-2-methyl-butyric acid methyl ester (1a)
(PhSO
2
)
2
FC O
O

As colorless oil in 70 % yield isolated.
1
H NMR (CDCl
3
): δ 1.18 (d, J = 6.8 Hz, 3H),
2.44-2.58 (m, 1H), 2.50-2.58 (m, 1H), 2.92 (dd, J = 29.4 Hz, 0.5 Hz, 1H), 2.96-3.11 (m,
2H), 3.51 (s, 3H), 7.55-7.61 (m, 4H), 7.71-7.77 (m, 2H), 7.87-7.99 (m, 4H).
13
C NMR
(CDCl
3
): δ 18.99, 32.84 (d, J = 17.5 Hz), 34.74 (d, J = 5.8 Hz), 51.95, 114.80 (d, J =
268.6 Hz), 128.96, 129.01, 130.93, 130.95, 134.41, 134.77, 135.28, 135.32, 175.07
19
F
NMR (CDCl
3
): δ -146.50 (dd, J = 22.8 Hz, 10.5 Hz, 1F) HRMS: (FAB) calcd for
C
18
H
19
FO
6
S
2
415.0685 (M+1) found: m/z 415.0668.
Ethyl 5-fluoro-2-oxo-5,5-bis(phenylsulfonyl)pentanoate (1b):

OEt
O
S
O
O
F
S
O
O

A white solid in 71 % yield isolated.
1
H NMR (CDCl
3
): δ 1.20 (t, J = 7.2 Hz, 3H), 2.62-
2.71 (m, 2H), 2.78-2.83 (m, 2H), 4.04-4.09 (m, 2H), 7.51-7.56 (m, 2H), 7.68-7.72 (m,
146
1H), 7.88-7.90 (m, 2H).
13
C NMR (CDCl
3
): δ 14.22, 26.01 (d, J = 19.4 Hz), 27.69 (d, J =
7.7 Hz), 61.06, 114.75 (d, J = 266.1 Hz), 129.21, 130.96, 134.85, 135.52, 171.43.
19
F
NMR (CDCl
3
): δ -142.91 (t, J = 15.8 Hz, 1F). HRMS: (FAB) calcd for C
18
H
20
FO
6
S
2

415.0685 (M+1) found: m/z 415.0673.
4,4-Bis-benzenesulfonyl-4-fluoro-2-methyl-butyric acid tert-butyl ester (1c)

O
O
(PhSO
2
)
2
FC

A white solid in 70 % yield isolated.
1
H NMR (CDCl
3
): δ 1.13 (d, J = 7.1Hz, 3H), 1.34
(s, 9H), 2.43 (ddd, J =23.5 Hz, 15.8 Hz, 3.9 Hz, 1H), 2.80-2.90 (m, 1H), 2.91-3.02 (m,
1H), 7.54-7.62 (m, 4H), 7.70-7.77 (m, 2H), 7.88-8.00 (m, 4H).
13
C NMR (CDCl
3
): δ
19.03, 27.75 (d, J = 11.9 Hz), 32.81 (d, J = 17.3 Hz), 35.76 (d, J = 5.7 Hz), 80.52, 115.11
(d, J = 268.4 Hz), 128.96, 129.01, 130.96, 134.53, 134.95, 135.23, 135.26, 173.93.
19
F
NMR (CDCl
3
): δ -146.17 (dd, J = 10.7 Hz, 23.6 Hz, 1F) HRMS: (FAB) calcd for
C
21
H
25
FO
6
S
2
457.1155 (M+1) found: m/z 457.1147.
3-(Bis-benzenesulfonyl-fluoro-methyl)-cyclohexanone (1d)

O
CF(SO
2
Ph)
2
H

As white solid in 90 % yield isolated.
1
H NMR (CDCl
3
): δ 1.40-1.56 (m, 1H), 2.15-2.25
(m, 1H), 2.30-2.47 (m, 3H), 2.52-2.80 (m, 3H), 3.03-3.13 (m, 1H), 7.48-7.57 (m, 4H),
7.68-7.7.75 (m, 2H), 7.77-7.83 (m, 2H), 7.85-7.91 (m, 2H)
13
C NMR (CDCl
3
): δ 25.10,
25.15, 41.07, 41.36 (d, J = 6.9 Hz), 42.67 (d, J = 17.2 Hz), 114.41 (d, J = 266.4 Hz),
147
114.45, 128.83, 129.09, 130.58, 130.59, 130.76, 130.78, 134.87, 135.20, 135.34, 135.77,
207.82.
19
F NMR (CDCl
3
): δ -136.36 (s, 1F) HRMS: (FAB) calcd for C
19
H
19
FO
5
S
2

411.0736 (M+1) found: m/z 411.0740.
6,6-Bis-benzenesulfonyl-6-fluoro-hexan-3-one (1e)

(PhSO
2
)
2
FC
O

A white solid in 79 % yield isolated.
1
H NMR (CDCl
3
): δ.1.04 (d, J = 7.4 Hz, 3H), 2.46
(q, J = 7.3 Hz, 2H), 2.58-2.68 (m, 2H), 3.00-3.08 (m, 2H), 7.55-7.62 (m, 4H), 7.70-7.77
(m, 2H), 7.90-7.95 (m, 4H)
13
C NMR (CDCl
3
): δ 24.75 (d, J = 18.4 Hz), 35.00, 35.05,
35.82, 115.03 (d, J = 264.5 Hz), 129.06, 130.83, 130.85, 134.79, 135.37, 207.99.
19
F
NMR (CDCl
3
): δ -140.74 (t, J = 15.9 Hz, 1F) HRMS: (FAB) calcd for C
18
H
19
FO
5
S
2

399.0736 (M+1) found: m/z 399.0742.
3,3-Bis-benzenesulfonyl-3-fluoro-methane sulfonyl-propane (1f)

(PhSO
2
)
2
FC
O
2
S

As white solid in 60 % yield isolated.
1
H NMR (CDCl
3
): δ.2.77-2.87 (m, 2H), 2.99 (s,
3H), 3.60-3.67 (m, 2H), 7.57-7.63 (m, 4H), 7.74-7.80 (m, 2H), 7.91-7.96 (m, 4H)
13
C
NMR (CDCl
3
): δ 24.01(d, J = 20.7 Hz), 40.99, 48.12 (d, J = 6.9 Hz), 113.11 (d, J =
266.1Hz), 129.29, 130.94, 134.01, 135.82
19
F NMR (CDCl
3
): δ -140.35 (t, J = 14.0 Hz,
1F) HRMS: (FAB) calcd for C
16
H
17
FO
6
S
3
421.0249 (M+1) found: m/z 421.0262.

148
4,4-Bis-benzenesulfonyl-4-fluoro-butyronitrile (1g)

(PhSO
2
)
2
FC
CN

A white solid.
1
H NMR (CDCl
3
): δ 2.70-2.79 (m, 2H), 2.91-2.97 (m, 2H), 7.56-7.63 (m,
4H), 7.80-7.74 (m, 2H), 7.88-7.93 (m, 4H).
13
C NMR (CDCl
3
): δ 12.07 (d, J = 9.2 Hz),
26.94 (d, J = 18.4 Hz), 113.00 (d, J = 267.6 Hz), 117.561, 129.34, 130.83, 134.10,
135.82.
19
F NMR (CDCl
3
): δ -145.04 (t, J = 15.5 Hz, 1F) HRMS: (FAB) calcd for
C
16
H
14
FNO
4
S
2
368.0426 (M+1) found: m/z 368.0445.
2-(2,2-Bis-benzenesulfonyl-2-fluoro-ethyl)-pentanedinitrile (1h)

(PhSO
2
)
2
FC
CN
CH
2
CH
2
CN

A white solid.
1
H NMR (CDCl
3
): δ 1.90-2.20 (m, 2H), 2.43-2.68 (m, 2H), 2.76-2.88 (m,
2H), 3.32-3.42 (m, 1H), 7.55-7.64 (m, 4H), 7.74-7.82 (m, 2H), 7.84-7.88 (m, 2H), 7.93-
7.97 (m, 2H).
13
C NMR (CDCl
3
): δ 15.09, 25.95 (d, J = 5.4 Hz), 28.81, 32.13 (d, J =
17.6 Hz), 112.95 (d, J = 269.9 Hz), 117.37, 118.56, 129.32, 129.51, 130.80, 131.01,
133.35, 133.95, 135.95.
19
F NMR (CDCl
3
): δ -146.55 (dd, J = 19.5 Hz, 12.9 Hz, 1F)
HRMS: (FAB) calcd for C
19
H
17
FN
2
O
4
S
2
421.0692 (M+1) found: m/z 421.0688.
4,4-Bis-benzenesulfonyl-4-fluoro-but-2-enoic acid methyl ester (1j)
cis
O
O
(PhSO
2
)
2
FC

149
1
H NMR (CDCl
3
): δ 3.75 (s, 3H), 5.97 (d, J = 15.7 Hz, 1H), 7.27 (dd, J = 23.1 Hz, 15.7
Hz, 1H), 7.55-7.61 (m, 4H), 7.72-7.78 (m, 2H), 7.91-7.96 (m, 4H).
13
C NMR (CDCl
3
): δ
52.43, 112.86 (d, J = 269.1 Hz), 129.12, 129.77 (d, J = 9.2 Hz), 130.59 (d, J = 14.6 Hz),
130.89, 134.40, 135.79.
19
F NMR (CDCl
3
): δ -150.93 (d, J = 23.1 Hz, 1F) HRMS:
(FAB) calcd for C
17
H
15
FO
6
S
2
399.0372 (M+1) found: m/z 399.0379.

trans
O
O
(PhSO
2
)
2
FC

1
H NMR (CDCl
3
): δ 3.42 (s, 3H), 6.18 (dd, J = 12.9 Hz, 1.3 Hz, 1H), 6.44 (dd, J = 28.5
Hz, 12.9 Hz, 1H), 7.56-7.62 (m, 4H), 7.73-7.78 (m, 2H), 7.93- 7.98 (m, 4H).
13
C NMR
(CDCl
3
): δ 51.96, 113.53 (d, J = 273.0 Hz), 121.26 (d, J = 13.80 Hz), 128.98, 130.78 (d,
J = 3.07 Hz), 131.06, 134.48, 135.54, 164.13.
19
F NMR (CDCl
3
): δ -150.60 (d, J = 28.5
Hz, 1F) HRMS: (FAB) calcd for C
17
H
15
FO
6
S
2
399.0372 (M+1) found: m/z 399.0379.
4,4-Bis-benzenesulfonyl-4-fluoro-but-2-enoic acid ethyl ester (1k)
cis
O
O
(PhSO
2
)
2
FC

A white solid.
1
H NMR (CDCl
3
): δ 1.28 (t, J = 7.1 Hz, 3H), 4.19 (q, J = 7.1 Hz, 2H), 5.96
(dd, J = 15.7 Hz, 0.4 Hz, 1H), 7.25 (dd, J = 23.1 Hz, 15.7 Hz, 1H), 7.55-7.62 (m, 4H),
7.72-7.78 (m, 2H), 7.91-7.96 (m, 4H).
13
C NMR (CDCl
3
) : δ 14.00, 61.44, 112.80 (d, J =
150
269.1 Hz), 129.06, 130.09 (d, J = 9.1 Hz), 130.21 (d, J = 3.2 Hz), 130.79, 134.31,
135.75, 163.23.
19
F NMR (CDCl
3
): δ -150.90 (d, J = 23.1 Hz, 1F) HRMS: (FAB) calcd
for C
18
H
17
FO
6
S
2
413.0529 (M+1) found: m/z 413.0543.

Trans

O
O
(PhSO
2
)
2
FC

A white solid.
1
H NMR (CDCl
3
): δ 1.07 (dt, J = 7.1 Hz, 0.4 Hz, 3H), 3.91 (q, J = 7.1Hz,
2H), 6.17 (dd, J = 12.9 Hz, 1.3 Hz, 1H), 6.41 (dd, J = 28.7 Hz, 13.0 Hz, 1H), 7.56-7.62
(m, 4H), 7.73-7.78 (m, 2H), 7.94-7.98 (m, 4H).
13
C NMR (CDCl
3
): δ 13.85, 61.08,
113.63 (d, J = 274.0 Hz), 120.68 (d, J = 13.8 Hz), 128.97, 130.98, 130.99, 131.26 (d, J =
2.9 Hz), 134.55, 135.50, 163.69.
19
F NMR (CDCl
3
): δ -150.32 (d, J = 28.7 Hz, 1F)
HRMS: (FAB) calcd for C
18
H
17
FO
6
S
2
413.0529 (M+1) found: m/z 413.0543.
4-Benzenesulfonyl-4-fluoro-4-nitro-but-2-enoic acid ethyl ester (1l)
H
H
PhSO
2
FC
O
O
NO
2

A white solid.
1
H NMR (CDCl
3
): δ 1.23 (t, J = 7.1 Hz), 4.16 (q , J = 7.2 Hz), 6.50 (dd, J
= 12.4, 2.4 Hz, 1H), 6.79 (dd, J = 18.7, 12.3 Hz, 1H), 7.63-7.69 (m, 2H), 7.81-7.87 (m,
1H), 7.92-7.97 (m, 2H).
13
C NMR (CDCl
3
): δ 13.78, 61.94, 123.83 (d, J = 15.3 Hz),
129.68, 131.17, 131.50 (d, J = 288.3 Hz), 136.56, 163.12.
19
F NMR (CDCl
3
): δ -119.05
(d, J = 18.3 Hz, 1F) HRMS: (FAB) calcd for C
12
H
12
FNO
6
S 318.0447 (M+1) found: m/z
318.0445.
151
6.5 Represenatative Spectra

1H Spectrum of Fluoro(nitro)methylsulfonyl)benzene

7.961
7.959
7.941
7.938
7.873
7.870
7.866
7.851
7.847
7.835
7.832
7.696
7.691
7.677
7.675
7.661
7.658
7.656
6.504
6.383
12 10 8 6 4 2 0 PPM
Ph
S NO
2
O O
F
152
19
F Spectrum of Fluoro(nitro)methylsulfonyl)benzene

-0.009
-141.874
-142.118
-142.248
0 -50 -100 -150 -200 PPM
Ph
S NO
2
O O
F
153
13
C Spectrum of Fluoro(nitro)methylsulfonyl)benzene

136.841
131.425
130.715
130.055
113.219
110.406
77.464
77.145
76.821
200 150 100 50 0 PPM
Ph
S NO
2
O O
F
154
1H Spectrum of 3-(Bis-benzenesulfonyl-fluoro-methyl)-cyclohexanone

ppm (t1)
2.0 3.0 4.0 5.0 6.0 7.0
2.00
2.03
2.05
4.10
1.04
3.14
3.20
1.08
1.06
155
13
C Spectrum of 3-(Bis-benzenesulfonyl-fluoro-methyl)-cyclohexanone

ppm (t1)
0 50 100 150 200
156
19
F Spectrum of 3-(Bis-benzenesulfonyl-fluoro-methyl)-cyclohexanone

ppm (t1)
-200 -150 -100 -50 0
157
19
F Spectrum

ppm (t1)
-200 -150 -100 -50 0
ppm (t1)
-150.50
158
13
C Spectrum

ppm (t1)
0 50 100 150 200
159
1
H Spectrum

ppm (t1)
3.0 4.0 5.0 6.0 7.0 8.0
4.00
2.12
4.14
1.13
1.07
3.11
160
6.6 Chapter 6: References

1. Organofluorine Chemistry: Principles and Commercial Applications (Eds.: R. E.
Banks, B. E. Smart, J. C. Tatlow), Plenum, New York, 1994, chap. 3.
2. Smart, B. E. J. Fluorine Chem. 2001, 109, 3.
3. Kirsch, P. Modern Fluoroorganic Chemistry; Wiley-VCH Verlag GMBH & Co
KGaA: Weinheim, Germany, 2004.
4. Kirk, K. L. J. Fluorine Chem. 2006, 127, 1013.
5. Biomedical Frontiers Chemistry: ACS Symp. Ser. 1996, 639.
6. Organofluorine Conmpounds in Medicinal Chemistry and Biomedical Applications
(Eds.: R. Filler, Y. Kobayashi, L. M. Yagupolskii), Elsevier, Amsterdam, 1993.
7. Prakash, G. K. S.; Hu, J.; Olah, G. A. J. Org. Chem. 2003, 68, 4457.
8. Prakash, G. K. S.; Mandal, M. J. Am. Chem. Soc. 2002, 124, 6538.
9. Prakash, G. K. S.; Mandal, M.; Olah, G. A. Angew. Chem. Int. Ed. 2001, 40, 589.
10. Prakash, G. K. S.; Hu, J. New Nucleophilic Fluoroalkylation Chemistry. Fluorine-
Containing Synthons; Soloshonok, V. A., Ed.; American Chemical Society, DC,
2005.
11. Prakash, G. K. S.; Yudin, A. K. Chem. Rev. 1997, 97, 757.
12. Prakash, G. K. S.; Mandal, M. J. Fluorine Chem. 2001, 112, 123.
13. Maruoka, K.; Shimada, I.; Akakura, M.; Yamamoto, H. Synlett, 1994, 847.
14. Sevenard, D. V.; Sosnovskikh, V. Y.; Kolomeitsev, A. A.; Königsmann, M.H.;
Röschenthaler, G-V. Tetrahedron Lett. 2003, 44, 7623.
15. Sosnovskikh, V. Y.; Usachev, B. I.; Sevenard, D. V.; Röschenthaler, G-V. J. Org.
Chem. 2003, 68, 7747.
16. Lefebvre, O.; Brigaud, T.; Portella, C. Tetrahedron, 1998, 54, 5939.
17. Sato, K.; Nakazato, S.; Enko, H.; Tsujota, H.; Fujita, K.; Yamamoto, T.; Omote, M.;
Ando, A.; Kumadaki, I. J. Fluorine Chem. 2003, 121, 105.
161

18. Sato, K.; Omote, M.; Ando, A.; Kumadaki, I. J. Fluorine Chem. 2004, 125, 509.
19. Kitazume, T.; Nakayam, Y. J. Org. Chem. 1986, 51, 2795.
20. Bridge, C. F.; O’Hagan, D. J. Fluorine Chem. 1997, 82, 21.
21. Takeuchi, Y.; Nagata, K.; Koizumi, T. J. Org. Chem. 1989, 54, 5453.

162
7 Chapter 7: Synthesis of Nano sized Magnetite coated Poly
(Vinylpyridine) Nanospheres of varying size and
Applications

7.1 Chapter 7: Introduction

Nanotechnology is defined as the scientific and engineering technology on atomic
and molecular scale. In essence, it involves the manipulation and utilization of materials
and devices considered to exist on the smallest possible scale. The majority of all
consumer products featuring nanotechnology are related to the class of nanoparticles
defined as objects with at least one dimension less than a micron (1000 nm). Nanoparticle
technology is currently an area of intense scientific interest, due to a wide variety of
potential applications in biomedical, optical, and electronic research. Monodisperse
polymer nanoparticles continue to receive a lot of attention as a solid support for
heterogeneous catalysis. Stabilization of noble metal colloids on synthetic polymers have
been reported by Nord and coworkers.
1
Hirai et al. described the synthesis of catalytically
active metal colloids supported on a polymer in 1978.
2
Polybenzimidazole supported Mo
catalysts
3
and polyimide supported Pd catalysts
4
were reported by Sherrington. In 1998,
Akashi developed polystyrene-supported Au/Pt bimetallic colloids.
5
Polymeric
microspheres have also been used in multicolor optical coding in biological assays.
6

Zincsulfide-capped cadmium selenide quantum dots embedded in microspheres at
precisely controlled ratios have been synthesized, producing luminescent microspheres.
Study of DNA hybridization and single nucleotide polymorphisms using polymeric
nanospheres and microspheres have also gained in prominence.
7
A few applications and
163
research areas that are currently most attractive to clinicians and researchers alike
primarily involves in vivo-targeted drug delivery,
8, 9
tissue engineering and replacement,
magnetic resonance imaging contrast agents
10, 11
and magnetic hyperthermia.
12,13
The
different carriers for such in vivo applications include polybutylcyanoacrylate, starch
based polymers, liposome, dextran, and iron activated carbon microparticles.
Magnetic functional polymeric microspheres have attracted attention because of
their current and potential application in biomedicine. These nanoparticles can easily be
collected with the application of a magnetic field, and the coupling of appropriate ligands
to such micro spheres provides an effective tool to achieve rapid, simple and specific
biological separation such as cell isolation, enzyme immobilization, protein and enzyme
purification, immunoassay and guided site specific drugs.
14, 15, 16, 17, 18
Different
approaches have been used for the fabrication of magnetic nanospheres such as emulsion
polymerization, seed polymerization, miniemulsion polymerization and silanization.
19, 20,
21, 22, 23
Among these, suspension polymerization is extensively used to prepare magnetic
polymeric microspheres. Unfortunately, with a conventional mechanical stirring method,
the size distribution of the prepared magnetic polymeric microspheres is likely to be quite
wide, and therefore they are not be ideally suitable for applications in the field of bio
separation and biomedicine. Hence, the size of the microsphere should be tailored for
various applications.
Efforts have currently been aimed at the fabrication of organic polymer
nanoparticles. Emulsion polymerization has been found to be a convenient method to
synthesize polymer nanoparticles. However, the presence of surfactants on the polymer
164
nanospheres after the reaction, and its removal, becomes problematic. Hence, emulsifier-
free emulsion polymerization has been developed. It is found that factors like monomer
concentration, initiator concentration, ionic strength and temperature of the
polymerization can affect the final nanosphere size. Synthesis of nanospheres of
polystyrene by emulsifier-free emulsion polymerization has been reported by our group.
24

Magnetic nanoparticles of iron have been explored for biological applications as tags in
sensing and imaging, as well as activity agents in hyperthermia therapy. Also, these
particles have been reported to demonstrate a therapeutic heating effect on several types
of tumors in animals and cell cultures.
25

As a part of targeted drug-delivery system, magnetic nanospheres can provide
carriers with unique characteristics to be non-invasively and selectively guided to and
concentrated within a desired body location using internal or external magnetic fields.
26,
27
For example, nanospheres designed for receptor-mediated targeting of blood-borne
toxins, such as radionuclide or biological antigens may be selectively removed from
circulation in compact, magnetic filters.
28
Furthermore, several research groups have
reported the unique of magnetic carrier technologies (MCTs), recently. An attractive
property of MCT is that the carriers can be separated easily from a complex multiphase
system by an external magnetic device. However, the magnetic forces exerted on these
magnetic particles are extremely weak for any substantial migration of the particles to a
desired location. Thus, it is desirable to synthesize clusters of the nanoparticles that can
be operated by an external magnetic device without compromising the surface area
determining adsorptive capacity. One way to accomplish this synthesis involves
developing a method of assembling colloidal magnetic particles on polymer spheres.
165
In this chapter, the preparation of poly(vinylpyridine) nanospheres of different
sizes, using an emulsifier-free emulsion polymerization technique and an assembly of
colloidal magnetite on these nanospheres, resulting in magnetic naospheres of various
sizes, is discussed. This work is an extension of the previous work done by Greci, Ryan
and coworkers.
24, 29, 30

7.2 Chapter 7: Results and discussion

Prakash and co-workers have successfully developed methodologies for the
stabilization of Pd, Pt and Au metal colloids onto polystyrene microspheres.
31
The same
group also synthesized monodisperse poly(p-hydroxystyrene) by grafting the p-
acetoxystyrene monomer on polystyrene bead core by emulsifier-free emulsion
polymerization in a core-shell fashion, followed by hydrolysis of the acetoxy group by a
base.
32
Poly(vinylpyridine) nanospheres have also been synthesized from 4-vinyl pyridine
as the monomer in 500 nm range particle diameter by the same group and these
nanospheres were coated with Pd from a colloidal Pd solution. This heterogeneous
catalyst was used for the Pd catalyzed C-C coupling methodologies such as Suzuki, Stille
and Heck Reactions.
33
In this chapter, the fabrication of poly(vinylpyridine) nanospheres
with specific particle diameter is disclosed. The nanospheres were cross-linked using 4
mol% of divinylbenzene. This percentage of cross-linking was chosen because it
decreases the solubility and swelling of the polymer beads while maintaining the
monodisperse character of the nanospheres. It has been reported that monodisperse
poly(vinylpyridine) nanospheres can be synthesized at 80
o
C using 7 mL of vinylpyridine
in 70 mL of water with 4 mol% crosss-linking with divinyl benzene.
166
Extensive studies have been conducted to fabricate polystyrene nanospheres of
various diameters in a controlled fashion. Prakash and Desousa have found that by
changing the initiator concentration, monomer ratio, temperature, reaction time and ionic
strength of the medium, the particle size can be controlled.
24
Based on these results, the
fabrication of poly(vinylpyridine) nanospheres by varying reaction conditions was
attempted. Since the reactivity of the vinylpyridine monomer is different from that of
styrene monomer, the reaction conditions for the fabrication of monodisperse polymer
nanoparticles had to be reoptimized to obtain particles of the desired diameter range.
First, the initiator concentration was varied while keeping monomer ratio constant. When
the initiator concentration was increased from 0.06 g, the polymerization reaction gave
polydisperse nanospheres at 80
o
C. By controlling the temperature, the initiator
concentration was varied, and found that, at 65
o
C with 0.12 g of the initiator,
monodisperse nanospheres of diameter 250 nm can be fabricated. Conditions were
optimized for the synthesis of monodisperse nanospheres of diameter 250, 380, and 580
nm. The details of this study is shown in Table 7.1. The diameters of various
nanospheres synthesized for this study were measured using scanning electron
microscopy. (Figure 7.1, 7.2, and 7.3).

167
Table 7.1 Reaction conditions for the synthesis of poly(vinylpyridine) nanospheres

Entry Amount of Monomer
(mL)
Amount of initiator
(g)
Temperature
(
o
C)
Diameter
(nm)
1 7.0 0.06 80 490
2 7.0 0.12 80 polydisperse
3 7.0 0.12 75 polydisperse
4 7.0 0.12 65 250
5 9.0 0.06 80 polydisperse
6 9.0 0..06 70 polydisperse
7 9.0 0.06 65 580
8 6.0 0.06 80 polydisperse
9 6.0 0.055 65 380
168

Figure 7.1 SEM pictures of 250 nm poly(vinylpyridine)nanopsheres
169

Figure 7.2 SEM pictures of 350 nm poly(vinylpyridine)nanopsheres
170

Figure 7.3 SEM pictures of 580 nm poly(vinylpyridine)nanopsheres
171
It has been reported that poly(vinylpyridine)nanopsheres can be coated using Pd
from a colloidal Pd Soultion.
33
The purpose of this study was to extend the chemistry to
Fe
3
O
4
coverage of PVP nanospheres using a Fe
3
O
4
colliodal solution. The Fe
3
O
4
colloidal
solution was prepared from of FeCl
2
⋅4H
2
O solution and FeCl
3
⋅6H
2
O solutions. The
nanospheres were thoroughly mixed with the colloidal solution and centrifuged, followed
by repeated sonication, until there was no loosely bound Fe
3
O
4
on the surface of the
nanospheres.
34
These Fe
3
O
4
-coated poly(vinylpyridine)nanopsheres were examined using
Transmission Electron Microscopy (TEM) to confirm the uniform coating of Fe
3
O
4
on
the surface of the nanospheres. (Figure 4, 5 and 6)

Figure 7.4 Fe
3
O
4
coated poly(vinyl pyridine)nanopsheres- 580 nm

172

Figure 7.5 Fe
3
O
4
coated poly(vinylpyridine)nanopsheres- 380 nm

173

Figure 7.6 Fe
3
O
4
coated poly(vinylpyridine)nanopsheres- 250 nm

174
The coverage was found to be highly uniform. A strong interaction between Iron
in the Fe
3
O
4
and the nitrogen lone pair in pyridine leads to a stronger binding of these
beads to the Fe
3
O
4
nanoparticles. Cu K α X-ray powder diffraction data for the Fe
3
O
4

loaded PVP nanoparticles shows clearly the presence of Fe
3
O
4
on the PVP nanospheres
as shown in Figure 7.7. Most intense peak of Fe
3
O
4
with a index (311) is clearly seen at
an angular 2 θ value of 35
0
. Position and relative intensities of the peaks are consistent
with the characteristics of magnetite as clearly seen from the peaks observed in the 2 θ
range of 30-65
0
. Peaks at angles 30, 43, 53, 57, and 63 corresponds to the indexes (220),
(400), (422) (511) and (440) of Fe
3
O
4
, respectively, clearly indicating the inverse cubic
spinel structure.

Figure 7.7 XRD data of Fe
3
O
4
coated poly(vinylpyridine)nanopsheres
In a preliminary study, these nanospheres were injected into neuroblastoma cells
and found to be taken in by the cells in appreciable quantities. A time dependant study on
the intake of these nanospheres in neuroblastoma cells was also performed, showing that
175
there is a direct correlation between the time and the amount of nanoparticle that are
taken inside the cell. (Figure 7.8)

Control
176

After 24 hours

After 45 hours
Figure 7.8 Time dependant study of intake of Fe
3
O
4
coated
poly(vinylpyridine)nanopsheres in neuroblastoma cells
177
It was also observed that the cells survived longer than 45 hours in spite of the
absence of any biocompatible coating on the particles. Further study is currently
underway. Dr. John Wood and co-workers at Childrens Hospital, Los Angeles are
currently studying the use of these nanoparticles for certain MRI experiments for
quantitative study of Iron content in cells.
7.3 Chapter 7: Conclusions

Poly(vinylpyridine) nanospheres have been synthesized using an emulsifier-free
emulsion polymerization technique. By changing the concentration of the monomer and
initiator, the size of the nanospheres can be varied. These nanospheres are highly uniform
in size and shape. Poly(vinylpyridine) nanospheres were used as stable support for
dispersing the magnetite nanoparticles by a one step adsorption from colloidal solution.
7.4 Chapter 7: Experimental

All polymer syntheses were carried out in a 250 mL reaction kettle. The kettle was
fitted with a condenser, an argon inlet valve, and a mechanical stirring apparatus. The
mechanical stirrer used was the IKA Euro star power control-visc. Analysis was carried
out on a Cambridge 360 scanning electron microscope at 15 kV and the JEOL 100CX
Transmission Electron Microscope TEM microscope. SEM samples were prepared by
placing drop of sample diluted with water, on a sample holder and allowing it to dry via
evaporation. The sample was then sputter-coated with gold. The vinylpyridine and
divinylbenzene used were purchased from Aldrich. The vinylpyridines were vacuum
distilled from calcium hydride to remove the inhibitor and any trace of moisture. The dry
divinylbenzene was vacuum distilled to remove the inhibitor. Potassium persulfate was
178
purchased from Aldrich and used as received. TEM samples were prepared in epoxy resin
at Center for Electron Microscope and Microanalysis, University of Southern California.
7.4.1 Synthesis of Poly(vinylpyridine) nanospheres

A 250 mL reaction kettle, equipped with a condenser, gas inlet and mechanical
stirrer, containing 70 mL of water was heated to 80
o
C, stirred at 300 rpm and degassed
with Ar for 1h. After 1h, the gas flow was turned off and 7 mL of vinylpyridine and 0.8
mL of divinylbenzene (4 %) were added to the water. The reaction mixture was stirred
for 20 minutes to bring the monomer and cross linker to the appropriate temperature,
followed by the addition of 0.06 g of potassium persulfate dissolved in 2 mL of water
(initiator). The milky white reaction mixture was stirred at 300 rpm at 80
o
C for 1 to1.5 h
and then stopped. The reaction mixture was cooled to room temperature and centrifuged
to isolate the polymer nanospheres. The resulting nanospheres were then characterized by
SEM to determine the size and integrity of the nanospheres. TEM samples were prepared
in epoxy resin and cross-sectional view was observed in JEOL 100CX Transmission
Electron Microscope
7.4.2 Magnetite nanoparticulate synthesis

Solutions of 1g of FeCl
2
⋅4H
2
O in 4 mL of water and 2g of FeCl
3
⋅6H
2
O in 4 mL
water were combined, and 4.5mL of ammonium hydroxide was added under vigorous
stirring. The resulting black precipitate of magnetite was settled by placing a magnet
below the beaker and the supernatant solution was decanted. The precipitate was washed
several times with water to remove ammonium hydroxide until neutrality was achieved,
as monitored using a pH paper.
179
7.4.3 Immobilization of Magnetite on PVP Nano-spheres

The magnetite colloids used for the surface derivatization of PVP nanospheres were
ranged between 10-20 nm in diameter. Immobilization was acheived by the adsorption of
magnetite dispersed in water on the PVP nanoparticles dispersed in water. The resulting
mixture was sonicated and centrifuged to remove excess magnetite particles. The
sequence was repeated until the colloids were exhaustively deposited, as observed by the
absence of brown-black color in the supernatant. The sample was then centrifuged and
dried at room temperature under a flow of nitrogen.

180
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3. Sherrington, D. C.; Miller, M. M.; Simpson, J. J. Chem. Soc., Perkin Trans. 1994,
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4. Sherrington, D. C.; Ahn, J. Macromolecules 1996, 29, 4164.
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Langmuir 2002, 18, 7245.
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Portier, J.; Pollert, E.; Duguet, E. Prog. Solid State Chem. 2006, 34, 237
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Abstract (if available)

Abstract This dissertation describes the development of new methodologies for nucleophilic monofluoromethylation, electrophilic difluoromethylation, ipsohydorxylation, nucleophilic addition reactions and synthesis of polymeric nanospheres.

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University of Southern California Dissertations and Theses

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Asset Metadata

Creator Chacko, Sujith (author)

Core Title Novel nucleophilic and electrophilic fluoroalkylation reactions and related chemistry

School College of Letters, Arts and Sciences

Degree Doctor of Philosophy

Degree Program Chemistry

Degree Conferral Date 2008-05

Publication Date 04/10/2008

Defense Date 03/05/2008

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

Tag electrophilic,fluoroalkylation,nucleophilic,OAI-PMH Harvest,synthesis

Language English

Advisor Prakash, G.K. Surya (committee chair), Olah, George A. (committee member), Shing, Katherine S. (committee member)

Creator Email chacko@usc.edu

Permanent Link (DOI) https://doi.org/10.25549/usctheses-m1101

Unique identifier UC1165108

Identifier etd-Chacko-20080410 (filename),usctheses-m40 (legacy collection record id),usctheses-c127-55720 (legacy record id),usctheses-m1101 (legacy record id)

Legacy Identifier etd-Chacko-20080410.pdf

Dmrecord 55720

Document Type Dissertation

Rights Chacko, Sujith

Type texts

Source University of Southern California (contributing entity), University of Southern California Dissertations and Theses (collection)

Repository Name Libraries, University of Southern California

Repository Location Los Angeles, California

Repository Email cisadmin@lib.usc.edu