University of Southern California Dissertations and Theses

Selective fluoroalkylations using sulfur and silicon based reagents

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Selective fluoroalkylations using sulfur and silicon based reagents

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Content SELECTIVE FLUOROALKYLATIONS USING SULFUR AND
SILICON BASED REAGENTS

by

Ying Wang

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)

December 2007

Copyright 2007 Ying Wang

ii
DEDICATION

TO
MY PARENTS,
MY HUSBAND AND MY SON,
MY SISTER AND BROTHER-IN-LAW,
AND LITTLE NIECE

iii
ACKNOWLEDGEMENTS

It is difficult to use this small amount of space to express gratitude to all those
who have made invaluable contributions to my time at USC. I would like to begin
by expressing my gratitude to Professor G. K. Surya Prakash. The freedom, which
Prof. Prakash grants to the members of his group allows them to progress beyond
the role of a mere student and leads them to become true participants in the
scientific enterprise. Prof. Prakash provides valuable inputs at the right moment,
and encourages research to run its natural course, when necessary.
I also would like to thank Professor George A. Olah for his support and
encouragement. His profound knowledge in both chemistry and philosophy has
definitely inspired me. I hope to emulate his serious and honest attitude in my
career.
I would like to give a special thanks to my best friend, Prof. Jinbo Hu, who
was a Postdoc in Olah-Prakash groups, when I joined in. He taught me and helped
in all possible ways during my first three years at USC. I have learned a lot, both
scientific and non scientific, from him. Without his help and guidance, my
research would not have been possible.
There are of course many other coworkers in Olah-Prakash groups who have
made great impact on my day-to-day laboratory life. I especially appreciate the
great support and guidance of Drs. Petr Beier, Thomas Mathew, Chiradeep Panja,

iv
Ping Yan, Bo Yang and Tiejun Li. These people were always available with
inexhaustible patience, when I had many questions.
I have also enjoyed sharing time in the group with many others: Drs.
Robert A. Aniszfeld, Golam Rasul, Alain Geoppert, Patrice Batamack, Masashi
Tashiro, Hideki Tashiro, Saitoh Akihisa, Roman Kultyshev, Marckus Ezkorn, Ryo
Mogi, Pooja Bhalla, Gabriela Foggassy, Csaba Weber and Stephane Walspurger. I
am thankful to my other collogues, Drs. Ryan Desousa, Kimberly McGrath, Iris
Cheung, Farzaneh Paknia, Rehana Ismail, Habiba Vaghoo, Sujith Chacko,
Federico Viva, Mike Ziblinsky, Kiah Smith, Kevin Glinton and Fang Wang.
Professors Robert Bau, Thieo Hogen-Esch, Roy A. Periana and John A.
Petruska are thanked for their service as my Ph.D. committee members.
I am also thankful to Rong Yang, Xiaofan Ren, Kevin Jin, Feng Liu, and
Wei Huang for their helpful discussions and help. I would also like to thank many
other friends and colleagues including Qi Cai, Jingguo Shen, Arisa Oki, Thomas
M. Gädda, Jasim Uddin, Fotini Liepouri, and others.
I would like to thank other staff members of the Chemistry Department
and Loker Hydrocarbon Institute, especially Michele Dea, Heather Connor, Jessy
May, Carole Philips, Ralph Pan and David Hunter for their kind support. Allan
Kershaw and Jim Merit are also acknowledged for their technical help with NMR
and glass blowing.

v
Last, but certainly not least, I would like to convey my deep appreciation
to my parents and husband. Their selfless support to me over the years is the most
valuable gift in my life.

vi
TABLE OF CONTENTS
DEDICATION ....................................................................................................... II

ACKNOWLEDGEMENTS .................................................................................. III

LIST OF TABLES ................................................................................................VI

LIST OF SCHEMES............................................................................................XII

ABSTRACT........................................................................................................ XV

Chapter 1 Introduction-Organofluorine Chemistry ............................................ 1

1.1 History of fluorine chemistry ........................................................................ 1
1.2 Properties of fluorine and fluorinated compounds ........................................ 6
1.3 Applications of fluorinated compounds......................................................... 9
1.4 Fluorination reactions.................................................................................. 11
1.4.1 Direct fluorination................................................................................. 13
1.4.2 Organofluorine building blocks method ............................................... 15
1.5 Prospective................................................................................................... 23
1.6 Chapter 1 references .................................................................................... 24

Chapter 2 Nucleophilic Reactions of Difluoromethyl Phenyl Sulfone
(PhSO
2
CF
2
H) with Alkyl Halides .................................................. 299

2.1 Introduction ................................................................................................. 29
2.2 Results and discussion................................................................................. 32
2.2.1 Reactions (S
N
2) of PhSO
2
CF
2
H and alkyl halides................................ 32
2.2.2 Facile preparation of 1,1-difluoro-1-alkenes ........................................ 36
2.2.3 Facile preparation of difluoromethyl alkanes ....................................... 38
2.3 Conclusions ................................................................................................. 40
2.4 Experimental section ................................................................................... 40
2.5 Chapter 2 references .................................................................................... 54

vii
Chapter 3 Nucleophilic Reactions of Difluoromethyl Phenyl Sulfone
(PhSO
2
CF
2
H) with Carbonyl Compounds ....................................... 58

3.1 Introduction ................................................................................................. 58
3.2 Results and discussion................................................................................. 59
3.2.1 Reactions (S
N
2) of PhSO
2
CF
2
H and carbonyl compounds................... 61
3.2.2 Facile preparation of difluoromethyl compounds................................. 64
3.3 Conclusions ................................................................................................. 67
3.4 Experimental section ................................................................................... 68
3.5 Chapter 3 references .................................................................................... 86

Chapter 4 Nucleophilic Reactions of Difluoromethyl Phenyl Sulfone
(PhSO
2
CF
2
H) with Imines ............................................................... 88

4.1 Introduction ................................................................................................. 88
4.2 Results and discussion................................................................................. 90
4.2.1 Nucleophilic substitution reactions of PhSO
2
CF
2
H and aldimines ...... 90
4.2.2 Preparation of β-hydroxy- α, α-difluoroalkyl imines............................. 92
4.2.3 Preparation of α-difluoromethyl amines ............................................... 95
4.3 Conclusions ................................................................................................. 96
4.4 Experimental section ................................................................................... 96
4.5 Chapter 4 references .................................................................................. 107

Chapter 5 Nucleophilic Reactions of Bromodifluoromethyl Phenyl
Sulfone (PhSO
2
CF
2
Br) with Aldehydes......................................... 109

5.1 Introduction ............................................................................................... 109
5.2 Results and discussion............................................................................... 111
5.2.1 Nucleophilic reactions between PhSO
2
CF
2
Br and aldehydes............. 111
5.2.2 Desulfonylation of (benzenesulfonyl)difluoromethyl alcohols .......... 114
5.2.3 Julia-olefination of (benzenesulfonyl)difluoromethyl alcohols.......... 115
5.3 Conclusions ............................................................................................... 117
5.4 Experimental section ................................................................................. 118
5.5 Chapter 5 references .................................................................................. 127

viii
Chapter 6 Fluoride-Induced Nucleophilic Reactions of
[Difluoro(phenylthio)methyl]trimethylsilane (TMSCF
2
SPh)
with Carbonyl Compounds ............................................................ 129

6.1 Introduction ............................................................................................... 129
6.2 Results and discussion............................................................................... 130
6.3 Conclusions ............................................................................................... 135
6.4 Experimental section ................................................................................. 136
6.5 Chapter 6 references .................................................................................. 142

Chapter 7 Nucleophilic Perfluoroalkylation of Imines, Aldehydes,
Ketones and Alkyl Iodides with Perfluoroalkyl Sulfones .............. 143

7.1 Introduction ............................................................................................... 143
7.2 Results and discussion............................................................................... 146
7.2.1 Reactions between PhSO
2
CF
2
CF
3
and imines .................................... 146
7.2.2 Reactions between PhSO
2
CF
2
CF
3
and carbonyl compounds ............. 149
7.2.3 Nucleophilic reactions between PhSO
2
CF
2
CF
3
and alkyl iodide ....... 151
7.2.4 Nucleophilic reactions between PhSO
2
CF
3
and imines...................... 151
7.3 Conclusions ............................................................................................... 153
7.4 Experimental section ................................................................................. 153
7.5 Chapter 7 references .................................................................................. 167

Chapter 8 (Trifluoromethyl)trimethylsilane: A New Source of Singlet
Difluorocarbene for the Preparation of
gem-Difluorocyclopropanes.. …………………………………….169

8.1 Introduction ............................................................................................... 169
8.2 Results and discussion............................................................................... 170
8.3 Conclusions ............................................................................................... 174
8.4 Experimental section…..………………………………………………....174
8.5 Chapter 8 references .................................................................................. 178

Chapter 9 Difluoromethyl Phenyl Sulfone and Bromodifluoromethyl
Phenyl Sulfone as Difluorocarbene Reagents and Their
Reactions with Phenols .................................................................. 179

9.1 Introduction ............................................................................................... 179
9.2 Results and discussion............................................................................... 181
9.3 Conclusions ............................................................................................... 183

ix
9.4 Experimental section ................................................................................. 183
9.5 Chapter 9 references .................................................................................. 186

Bibliography........................................................................................................ 188

x
LIST OF TABLES
Table 1.1 Some properties of fluorine and other elements ......................... 7

Table 1.2 Volumes (cm
3
/mol) of atoms and simple groups bonded to
carbon.......................................................................................... 9

Table 2.1 Optimization of the reaction conditions for the
nucleophilic substitution of 1 with alkyl halides ...................... 33

Table 2.2 Preparation of substituted difluoromethyl sulfones 4 from
1 (1 equiv.), alkyl iodides (4 equiv.), and t-BuOK (2 equiv)
in DMF at -50 ºC for 1 hour...................................................... 35

Table 2.3 Preparation of 1,1-difluoro-1-alkenes 10 by
deprotonation-elimination reactions using 4 and t-BuOK
in THF at temperatures ranging from -20 ºC to room
temperature. .............................................................................. 38

Table 2.4 Preparation of difluoromethylalkanes by desulfonylations
of 4 using Na(Hg)/MeOH ranging from -20 ºC to 0 ºC............ 39

Table 3.1 Nucleophilic reaction of sulfone 1 (1.0 equiv) with
carbonyl compounds 2 (2.0 equiv) in the presence of
LHMDS (2.0 equiv) in THF-HMPA (10:1 v/v) at – 78
o
C. ...... 63

Table 3.2 Reductive desulfonylation of carbinols 3 using Na(Hg)
amalgam (10 wt. % Na in Hg, 5 equiv) and Na
2
HPO
4
(5
equiv) in methanol at – 20 ~ – 10
o
C...................................... 66

Table 4.1 Preparation of substituted difluoromethyl sulfones 3 from
1 (1 equiv.), aldimines 2 (1.2 equiv.), and LHMDS (2 equiv)
in THF/HMPA at -78 ºC for 1 hour........................................... 91

Table 4.2 Preparation of β-hydroxy- α,α-difluoroalkyl imines 8 from
3 (1 equiv.), aldehydes (2 equiv.), and t-BuOK (4 equiv) in
DMF at -50 ºC for 1 hour.......................................................... 94

Table 4.3 Reductive desulfonylation of fluorinated amines 3 using
Na(Hg) amalgam (10 wt. % Na in Hg, 5 equiv) and
Na
2
HPO
4
(5 equiv) in methanol at –20
o
C................................ 95

xi
Table 5.1 Nucleophilic (benzenesulfonyl)difluoromethylation of
aldehydes using PhSO
2
CF
2
Br/TDAE in DMF at -30 °C ~
RT under sun-lamp irradiation. ............................................... 112

Table 5.2 Desulfonylation of (benzenesulfonyl)difluoromethyl
alcohols 3 using Na(Hg) amalgam.......................................... 115

Table 5.3 Julia-Olefination reactions of
(benzenesulfonyl)difluoromethyl alcohols 3 .......................... 117

Table 6.1 Nucleophilic (phenylthio)difluoromethylation of carbonyl
compounds with TMS–CF
2
SPh (after desilylation). .............. 132

Table 7.1 Modification of reaction condition for the introduction of
CF
3
CF
2
group into imines....................................................... 146

Table 7.2 Reaction of PhSO
2
CF
2
CF
3
1 (1.5 equiv.) with imines 3 (1.0
equiv.) and t-BuOK (4.5 equiv.) in THF between -75 °C
and -70 °C for 1.5 hrs.............................................................. 148

Table 7.3 Pentafluoroethylation of carbonyl compounds by using
PhSO
2
CF
2
CF
3
......................................................................... 150

Table 7.4 Pentafluoroethylation of Alkyl Iodides (1 equiv) by using 1
(1.5 equiv) in the presence of t-BuOK (4.5 equiv) in THF
at -75 °C.................................................................................. 151

Table 7.5 Trifluoromethylation of Imines by using PhSO
2
CF
3
.............. 152

Table 8.1 Difluorocarbene addition of alkenes using TMSCF
3
/TBAT
in THF at -50 °C ~ RT for 1 hour............................................ 172

Table 9.1 Difluoromethylation of phenols 3 with reagent 1 or 2............ 181

xii
LIST OF SCHEMES

Scheme 1.1 Swarts reaction........................................................................2

Scheme 1.2 Reactions to prepare “Teflon
®
” ............................................... 2

Scheme 1.3 Reactions of CoF
3
with organic compounds ........................... 3

Scheme 1.4 Process to manufacture UF
6
.................................................... 4

Scheme 1.5 9- α-Fluorohydrocortisone acetate ........................................... 5

Scheme 1.6 Conversion of SAM to 5’-FDA............................................... 6

Scheme 1.7 Biological effects of fluorine atom and
fluorine-containing groups..................................................9

Scheme 1.8 Fluorine-containing drugs.....................................................10

Scheme 1.9 Naturally occurring fluoroorganic compounds.....................12

Scheme 1.10 Examples of direct fluorination............................................. 13

Scheme 1.11 Nucleophilic reagents for direct fluorination......................... 14

Scheme 1.12 Electrophilic reagents for direct fluorination ........................ 15

Scheme 1.13 Formation of gem-difluoro substituted anions ...................... 16

Scheme 1.14 Nucleophilic reactions with difluoroenolates........................ 17

Scheme 1.15 Nucleophilic gem-difluoromethylations with
difluorophosphonyl anion ..................................................... 17

Scheme 1.16 Electrophilic introduction of the gem-difluoromethylene
groups.................................................................................... 18

Scheme 1.17 Radical gem-difluoromethylations ........................................ 19

Scheme 1.18 Singlet carbene additions to alkenes ..................................... 19

Scheme 1.19 Nucleophilic trifluoromethylations with TMSCF
3
................ 20

xiii

Scheme 1.20 Electrophilic trifluoromethylations with trifluoromethyl
dibenzoheterocyclic salts ...................................................... 21

Scheme 1.21 Generation of the trifluoromethyl radical.............................. 22

Scheme 1.22 Radical trifluoromethylation.................................................22

Scheme 1.23 Examples of perfluoroalkylation reactions............................ 23

Scheme 2.1 Biological effects of fluorine-containing groups................... 30

Scheme 2.2 Preparation of 1,1-difluoro-1-alkenes and
difluoromethyl alkanes from PhSO
2
CF
2
H ............................ 31

Scheme 2.3 Generation of (benzenesulfonyl)difluoromethide from
PhSO
2
CF
2
H and a base ......................................................... 32

Scheme 2.4 Nucleophilic substitution with elemental halogens............... 36

Scheme 2.5 Nucleophilic substitution with perfluoroalkyl iodide............ 36

Scheme 2.6 Nucleophilic substitution using difluoromethyl phenyl
sulfoxide.............................................................................. 366

Scheme 2.7 Formation of 1,1-difluoro-1-alkenes ..................................... 37

Scheme 2.8 Preparation of difluoromethylalkanes 11 by
desulfonylation of 4 ............................................................ 399

Scheme 3.1 Difluoromethylation of carbonyl compounds using 1........... 61

Scheme 4.1 Preparation of β-hydroxy- α,α-difluoro imines and
difluoromethyl amines .......................................................... 90

Scheme 4.2 Reaction of PhSO
2
CF
2
Br with imine .................................... 92

Scheme 4.3 Proposed mechanism of reaction between fluorinated
amines 3 and aldehydes......................................................... 93

Scheme 5.1 Difluoromethylation of aldehydes using 1. ......................... 110

Scheme 5.2 Mechanism of nucleophilic reaction of aldehydes with
PhSO
2
CF
2
Br/TDAE reagent ............................................... 113

xiv
Scheme 5.3 Reductive desulfonylation and Julia olefination of 3.......... 114

Scheme 6.1 Preparation of TMS–CF
2
SPh. ............................................. 130

Scheme 6.2 Nucleophilic (phenylthio)difluoromethylation with
TMS–CF
2
SPh...................................................................... 131

Scheme 6.3 (Phenylthio)difluoromethylation of diphenyl disulfide
and methyl benzoate............................................................ 133

Scheme 6.4 Preparation of difluoromethyl alcohols (10) from 4. .......... 134

Scheme 6.5 Proposed mechanism of the
(phenylthio)difluoromethylation of carbonyl
compounds with TMS–CF
2
SPh. ......................................... 135

Scheme 7.1 Mechanistic Consideration.................................................. 145

Scheme 7.2 Synthesis of PhSO
2
CF
2
CF
3
................................................. 145

Scheme 8.1 Singlet difluoromethylene insertion to alkenes using
TMSCF
3
. ............................................................................. 170

Scheme 8.2 Proposed mechanism of difluorocarbene addition of
alkene with TMSCF
3
/TBAT reagents. ................................ 171

Scheme 9.1 Reaction of 1 or 2 with phenols........................................... 180

Scheme 9.2 Plausible reaction mechanisms of 1 and 2 with phenol ...... 182

xv
ABSTRACT

In chapter 1, the history of fluorine chemistry, properties and applications
of fluorine-containing compounds, as well as the fluorination reactions are
reviewed. Some of the landmark discoveries and accomplishments in the field of
fluorine chemistry are mentioned. The important chemical and biological
properties of fluorine and fluorinated compounds are described leading to the
wide and versatile applications of fluorine compounds in industry. The
fluorination reactions, including direct fluorinations and organofluorine building
block fluorinations, are introduced. Indeed, fluorine chemistry has played a
significant role in many technology fields and its future will remain bright.
In chapter 2, a facile and efficient nucleophilic substitution reactions (S
N
2)
using difluoromethyl phenyl sulfone with primary alkyl halides, elemental
halogens, perfluoroalkyl halides have been disclosed through the in situ-generated
(benzenesulfonyl)difluoromethyl anion in the presence of a base. The obtained
(benzenesulfonyl)difluoromethylalkanes are useful intermediates for the
preparation of 1,1-difluoro-1-alkenes and difluoromethylalkanes. Thus,
difluoromethyl phenyl sulfone acts as both “=CF
2
” and “CF
2
H” synthons.
In chapter 3, a general and efficient nucleophilic difluoromethylation of
carbonyl compounds (both enolizable and non-enolizable aldehydes and ketones)
with difluoromethyl phenyl sulfone has been achieved by using a nucleophilic

xvi
(phenylsulfonyl)difluoromethylation-reductive desulfonylation strategy, which
promises to be a highly useful synthetic tool for many potential applications.
In chapter 4, the nucleophilic substitution of difluoromethyl phenyl
sulfone with aldimines has been reported, which allows a facile and efficient
synthesis of β-hydroxy-α,α-difluoro imines and α-difluoromethyl amines through
the intermediates (benzenesulfonyl)difluoromethylated amines. The methodology
provides convenient and efficient ways to introduce gem-difluoromethylene
building block (-CF
2
-) and difluoromethyl group (-CF
2
H) into nitrogen-containing
organic compounds with potential bioactivity.
In chapter 5, tetrakis(dimethylamino)ethylene (TDAE) promoted
nucleophilic reactions of bromodifluoromethyl phenyl sulfone with aldehydes
have been presented. The resulting (benzenesulfonyl)difluoromethylated alcohols
can be further transformed into difluoromethyl substituted alcohols and
1,1-difluoro-1-alkenes via reductive desulfonylation and Julia olefination
respectively.
In chapter 6, a fluoride-induced nucleophilic (phenylthio)difluoro-
methylation method using TMS-CF
2
SPh has been achieved. This new
methodology efficiently transfers “PhSCF
2
” group into both enolizable and
non-enolizable aldehydes and ketones to give the corresponding
(phenylthio)difluoromethylated alcohols in good to excellent yields. Diphenyl
disulfide can also be (phenylthio)difluoromethylated into PhSCF
2
SPh in high

xvii
yield. The reaction with methylbenzoate, however, gives only low yield of
(phenylthio)difluoromethyl phenyl ketone. The above-obtained
PhSCF
2
-containing alcohols can be further transformed into difluoromethyl
alcohols using an oxidation-desulfonylation procedure. This new type of
nucleophilic (phenylthio)difluoromethylation methodology may have other
potential applications in the medicinal and agrochemical fields.
In chapter 7, successful alkoxide-induced nucleophilic
pentafluoroethylation and trifluoromethylation of imines, aldehydes, ketones and
primary alkyl iodides have been presented by using pentafluoroethyl phenyl
sulfone (PhSO
2
CF
2
CF
3
) and trifluoromethyl phenyl sulfone (PhSO
2
CF
3
).
Remarkably, the chiral sulfinylimines, when subjected to this
pentafluoroethylation and trifluoromethylation, gave high diastereoselectivity.
In chaper 8, Ruppert-Prakash reagent, (trifluoromethyl)trimethylsilane
(TMSCF
3
), as a new source of singlet difluorocarbene at low temperature (-50 °C),
has been explored to prepare gem-difluorocyclopropanes from the corresponding
alkenes. The reaction took place in the presence of catalyst tetrabutylammonium
triphenyldifluorosilicate (TBAT) and gave moderate to good yields of
gem-difluorocyclopropanes from the electron rich alkenes: tetra-, tri-, and
1,1-dialkyl substituted alkenes.
In chapter 9, difluoromethyl phenyl sulfone (PhSO
2
CF
2
H) and
bromodifluoromethyl phenyl sulfone (PhSO
2
CF
2
Br) are used as novel

xviii
difluorocarbene reagents to react with phenols, which provide a beneficial way to
introduce difluoromethoxy (OCF
2
H) building block into organic compounds.

1
Chapter 1
Introduction-Organofluorine Chemistry

In the past two decades, organofluorine chemistry has developed fast to
become a very significant field in the area of life science research. Organofluorine
compounds are widely used in agrochemicals, pharmaceuticals and material fields.
As reported,
1
30~40% of agrochemicals and 20% of pharmaceuticals available in
the market are estimated to contain fluorine, including half of the top drugs sold
in 2005. Fluorine atom, due to its small size and high electronegativity, can
dramatically change molecule’s chemical and biological properties, such as the
stability, lipophilicity, and bioavailability, which has attracted a lot of synthetic
interest in introducing fluorine or a fluorinated moiety into organic compounds.
2

However, convenient and selective incorporation of fluorine into a molecule is
still considered as a big challenge.

1.1 History of fluorine chemistry

The first isolation of elemental fluorine has been successfully carried out by
Henri Moissan in 1886.
3
In 1892, Belgian chemist F. Swarts discovered the Cl/F
exchange chemistry of antimony trifluoride (SbF
3
), which along with other
similar type of halogen exchange reactions are commonly called Swarts reaction

2
(Scheme 1.1).
4
This reaction has been improved to be an industrial process to
prepare organofluorine compounds. A variety of organofluorine compounds are
synthesized and commercialized through Swarts reaction.
5

R
1
C
R
2
R
3
Cl
+SbF
3
R
1
C
R
2
R
3
F
+SbF
2
Cl

Scheme 1.1 Swarts reaction.

The growth of fluorine chemistry was very slow during 19th century. The
great development of fluorine chemistry began in the middle of the 20th century.
Since then, fluorine has played a distinctive role in many significant and highly
diverse technological developments. The landmark discoveries and
accomplishments in the field of fluorine chemistry after 1920 include:
In 1928, Midgley invented “Freons” for the purpose of refrigeration.
6

CF
2
HCl
-600 C °
-HCl
F
2
CCF
2
F
2
CCF
2
initiator
heat
*
F
2
C
F
2
C
n
"Teflon "
®
CF
2
:
*

Scheme 1.2 Reactions to prepare “Teflon
®
”

In 1938, Roy Plunkett at DuPont discovered “Teflon
®
” (Scheme 1.2),
7
which
opened up the largest commercial application of organofluorine chemistry, the

3
field of fluoropolymers. Fluoropolymers have unique combination of properties,
such as high thermal stability, low dielectric constant, low moisture absorption,
excellent weatherability, low flammability and low surface energy, excellent
biocompatibility and outstanding resistance to most chemicals. They are broadly
used as thermoplastics, elastomers, coatings, fluids and membranes.
8

In 1947, Fowler discovered the CoF
3
based method of perfluorination
(Scheme 1.3),
9
which launched the fluorinations using high-valency metal
fluorides and their complexes (AgF
2
, VF
5
, MnF
3
, K
3
NiF
6
, K
2
AgF
4
, KCoF
4
,
CsCoF
4
and so on). This method can not only be used for the complete
fluorination of hydrocarbons, but also for the fluorination of aromatic rings,
amines, ethers, cycloalkanes, cycloalkenes and heterocycle compounds.
10

nC
4
H
10
nC
4
F
10
CoF
3
CoF
3
CH
3
CF
3
F F
High Temp.

Scheme 1.3 Reactions of CoF
3
with organic compounds

In 1940’s, the development of nuclear science in United States led to the
preparation of UF
6
, which subsequently led to the enrichment of
235
U from
abundant
238
U via a gaseous diffusion process. This expanded the application of

4
fluorine in the nuclear field. Now about 60% of F
2
produced in the world is used
for the synthesis of UF
6
. So elemental fluorine can be considered as an important
element in the energy industry. The process to manufacture UF
6
from the ores is
described in Scheme 1.4.
11

U
3
O
8
HNO
3
UO
2
(NO
3
)
2
UO
3
H
2
UO
2
UF
4
UF
6
HF F
2
∆Τ
mixture of
235
U and
238
U

Scheme 1.4 Process to manufacture UF
6

In 1949, Simons discovered the electrochemical fluorination. By using a
solution of hydrogen fluoride, electrolysis is performed at a voltage lower (5-6V)
than that is required to generate fluorine gas. At the nickel anode (oxidative
fluorination takes place): C-H → C-F.
12
This method is very easy to conduct
industrially, and the products have wide commercial uses. The Simon’s cell
process is believed to involve high valency nickel fluorides (NiF
3
and NiF
4
), and
these were demonstrated to be powerful fluorinating agents.
In 1954, Josef Fried found that fluorine substitution at the 9 position of
hydrocortisone (Scheme 1.5) increased its anti-inflammatory potency, which
initiated the pioneering work in the medicinal fluorine chemistry.
13

5
OCOCH
3
O
O
HO
F
OH

Scheme 1.5 9- α-Fluorohydrocortisone acetate

In 1962, Neil Bartlett produced the first noble-gas compound (XePtF
6
).
14

Prior to this work, conventional scientific wisdom had long held that chemical
compounds could not be formed from noble gases because of their stable filled
electronic configuration. Bartlett rocked the chemistry world, when he showed
that platinum hexafluoride, a highly reactive compound, combining with xenon
can form a stable salt.
In 1974, F. Sherwood Rowland and Mario Molina published the model of
ozone depletion by chlorofluorocarbons, which spurred the creation of the world's
first global environmental agreement.
15

In 1970s, Lagow, Adcock and co-workers
16
developed aerosol fluorination
process, which can control the perfluorination reaction efficiently and effectively.
This technology shortens the reaction time, minimizes residual organic hydrogen
and fragmentation, and promotes the produt yields at low fluorine concentration.
In 2003, O
’
Hagan and co-workers isolated and later characterized the first
fluorinase enzyme,
17
which can catalyze carbon-fluorine bond formation between
an organic substrate and fluoride ion. Scheme 1.6 shows the conversion of

6
S-adenosylmethionine (SAM) to 5’-fluoro-5-deoxyadenosine (5’-FDA) by this
fluorinase enzyme. This discovery opens up novel biotechnological opportunities
for the preparation of organofluorine compounds.

O
H
OHOH
N
N
N
N
S
Me
O
O
H
3
N
NH
2
SAM
F
-
Fluorinase
O
H
OHOH
N
N
N
N
NH
2
F
5'-FDA

Scheme 1.6 Conversion of SAM to 5’-FDA

The gap between 1979 and 2003 doesn’t mean that no significant
accomplishments were made in these years. Actually it means that the fluorine
chemistry has developed so rapidly during this period and much great work has
been carried out and it is not possible to list every important accomplishment in
this chapter.

1.2 Properties of fluorine and fluorinated compounds

Fluorine is the most electronegative element with Pauling’s electronegativity
value (EN) of 4.0 and is the second smallest atom after hydrogen with van der
Waal’s radius of 1.35 Å (Table 1.1).
18
The carbon-fluorine bond is

7
extraordinarily strong (the homolytic carbon-fluorine bond dissociation energy is
116 kCal/mol.).

Table 1.1 Some properties of fluorine and other elements.
16

The small size and strong electronegativity of fluorine atom as well as the
high C-F bond strength provide organofluorine compounds special chemical,
physical and biological properties
19
(Figure 1.1
20
). Based on the Pauling’s
atomic van der Waals radii (H=1.20, F=1.35 Å), a C-F bond is considered
isosteric to a C-H bond. More recently, studies on Bondi-derived van der Waals
volumes
21
revealed that C-F group and C-O group are more nearly isosteric
(Table 1.2). Difluoromethylene group (-CF
2
-) is known to be isosteric and
isopolar to ethereal oxygen atom.
16
Difluoromethyl group (-CF
2
H) is isosteric and
isopolar to carbinol (CH
2
OH) (Scheme 1.7).
17(j)
The widespread mimicing ability
of fluorine and fluorine block in bioactive molecules plays a major role in drug
Element EN
(Pauling)
r
v
(Å)
(Pauling)
r
v
(Å)
(Bondi)
BE(CH
3
-X)
(kCal/mol)
CH
3
-X
(Å)
H 2.1 1.20 1.20 99 1.09
F 4.0 1.35 1.47 116 1.39
Cl 3.0 1.80 1.75 81 1.77
Br 2.8 1.95 1.85 68 1.93
O (OH) 3.5 1.40 1.52 86 1.43
S (SH) 2.5 1.85 1.80 65 1.82

8
design. Incorporating fluorine at a particular position in a molecule can enhance
its metabolic stability or modulate its physicochemical properties, such as its
lipophilicity, acidity or basicity. The replacement of hydrogen by fluorine can
increase the lipid solubility of bioactive molecules. The high lipophilicity can
favorably change in vivo a drug’s transport and absorption rates, hence increasing
drug’s bioavailability.
22

fluorine effects
high C-F bond strength perfluorocarbons (PFCs)
* high thermal stability
* high oxidative stability
* weatherability
* low polarity
* weak intermolecular interactions
* small surface tension
* small refractive indices
increased lipophilicity to
enhance bioavailability
isoelectronic effects
to -O
-
and -OH
blocking effect in metabolic transformations mimicking of enzyme substrates

Figure 1.1 Fluorine effects in biologically active agents and materials
18

9
Table 1.2 Volumes (cm
3
/mol) of atoms and simple groups bonded to carbon
18

-H -F -Cl -Br -I
CH CF COH O CH
2
C O CF
2
CH
3
CH
2
F CHF
2
CF
3
3.3 5.72 11.62 14.40 19.18
6.8 9.5 11.4 3.7 10.2 11.7 15.3
13.7 16.0 18.8 21.3

Scheme 1.7 Biological effects of fluorine atom and fluorine-containing groups

CF
CH CO
1.38 Å
1.10 Å 1.43 Å
mimic

CF
2
O (ethereal)
isosteric
isopolar
CF
2
H
CH
2
OH
isosteric
isopolar

1.3 Applications of fluorinated compounds

Due to the special properties of fluorinated compounds discussed above,
fluorine-containing compounds are widely used in the fields of pharmaceuticals,
agrochemicals and material science.
17

The application of fluorinated compounds in pharmaceutical and
agrochemical fields was initiated by Fried about 35 years ago. His pioneering

10
work in this field revealed the potential importance of fluorine substituents in
enhancing the efficacy of drugs.
12
Now, in the market there are 30~40% of
agrochemicals and 20% of pharmaceuticals containing fluorine. Two well-known
examples of fluorine-containing drugs are shown below:
23

HN
N N
F
O
CO
2
H
O
H
N
CH
3
F
3
C
Ciprofloxacin
(CIPRO )
®
Fluoxetine
(PROZAC ) ®

Scheme 1.8 Fluorine-containing drugs

In the area of medicinal chemistry, fluorinated compounds are developed to
be new anti-cancer, anti-viral, anti-inflammatory, anti-hyperintensive and
anti-fertility agents as well as central nervous system drugs.
24, 17(b)
Besides drugs,
organofluorine compounds, such as fluoroxene (CF
3
CH
2
OCH=CH
2
), halothane
(CF
3
CHClBr), methoxyflurane (CH
3
OCF
2
CHCl
2
), enflurane (CHFClCF
2
OCHF
2
),
are also used as anesthetics.
17(d)
Another important medical application is the use
of
18
F radioisotope (half-life of 110 minutes) in positron emission tomography
(PET), which has been employed to study biochemical transformations, drug
pharmacokinetics, pharmacodynamics, and survey living tissue in animals and
humans.
25
In the area of agrochemistry, fluorinated compounds are developed to
be herbicides, insecticides and fungicides.
26

11
In the field of material science, besides the applications of fluoropolymers, as
mentioned in the previous discussions, fluorinated compounds, such as
heptafluoropropane (CF
3
CHFCF
3
), are also used as efficient and safe
fire-extinguishing agents due to their non-flammable, non-toxic properties and
high density.
17(d)
Recently, fluorinated resins have been developed to be new
materials for microchip manufacture, microlithography, fiber optics and fuel
cells.
27, 17(d)
Fluorinated material also plays a very important role in the field of
liquid crystals. The presence of fluorine in a liquid crystal can greatly promote the
permittivity with minimum change in molecular shape, which makes the
‘flat-screen’ LCD display technology possible.
28, 17(d)

1.4 Fluorination reactions

In nature, fluorine exists as fluoride forms such as fluorite (CaF
2
), cryolite
(Na
3
[AlF
6
]), and phosphorite (Ca
5
[F,Cl][PO
4
]
3
). It is a very common element in
Earth’s crust (13
th
most abundant) ⎯ the abundance of fluorine is high, about five
times that of chlorine. However, natural fluorinated products are rare. Only twelve
natural products are found to contain fluorine.
29
Some of them are presented in
Scheme 1.9.
21
Potassium monofluoroacetate is an extremely toxic compound that
was discovered in the South African plant Dichapetalum cymosum (gifblaar).
Another natural fluorine product is Dichapetalum toxicarium (ratsbane) which

12
contains ω-fluoro-oleic acid CH
2
F-(CH
2
)
7
CH=CH-(CH
2
)
7
COOH. It was found in
a shrub in Sierra Leone and shows high toxicity.

F
O
-
O
fluoroacetate
Principally Dichapetalum
Gastrolobium, Oxylobium spp.
F
CH
3
O
fluoroacetone
Acacia georginea
HO
2
C CO
2
H
HO
2
C OH
F
(2R, 3R)-fluorocitrate
several higher plants
F
CO
2
H
ω-fluoro-oleic acid
Dichapetalum toxicarium
F
O
-
O
F
OH
CO
2
NH
3
fluoroacetate 4-fluorothreonine
O
F
HO OH
N
N
N
N
O
S H
2
N
O
O
NH
2
nucleocidin
Streptomyces calvus
Streptomyces cattleya

Scheme1.9 Naturally occurring fluoroorganic compounds.

Since there are only few natural products containing fluorine, most fluorine
compounds have to be prepared by synthesis, which has inspired chemists to
study and expand the methods to introduce fluorine into organic
molecules.
30 ,17(a),17(c),16
The methods for the synthesis of organofluorine
compounds are roughly divided into two classes: the direct fluorination method
and the building-block method. The direct fluorination method is to replace

13
hydrogen or other atoms and groups (such as halogen atoms, -OH, -SH, -C=O,
-COOH, -NH
2
and so on) of a molecule by fluorine via fluorinating reagents. The
building-block method involves certain chemical transformation starting from
fluorinated small molecules. Usually, when introducing single fluorine into a
molecule, direct nucleophilic and electrophilic fluorination methods are used.
When introducing difluoromethyl (CF
2
H), gem-difluoromethylene (-CF
2
-) or
trifluoromethyl (CF
3
) group into a molecule, either fluorination or building-block
method is used.
1.4.1 Direct fluorination

Direct fluorination methods are widely used to prepare
monofluoro-compound, gem-difluoromethylene compound, trifluoromethyl
compound and perfluorinated compound, and so on. Some examples
31
of direct
fluorination are shown in Scheme 1.10.
H
H
10% F
2
in N
2
CH
3
CN, r.t.
(54% conv.)
F
H
68%
Ph
CO
2
t-Bu
O
DAST
>90%
Ph
CO
2
t-Bu
F F
CCl
3 HF(g)
CF
3
95%
NH
2
F
2
/N
2
20 °C
NF
2
F
15 6.3%

Scheme 1.10 Examples of direct fluorination

14

The direct fluorinations are divided into nucleophilic reactions, electrophilic
reactions, and electrochemical fluorinations. The common nucleophilic
fluorinating reagents include: metal fluoride (MF
n
), hydrogen fluoride (HF) and
related reagents (for example, PPHF, Olah reagent, HF/pyridine = 70:30 w/w, or
ca. 9:1 molar ratio), sulfur tetrafluoride (SF
4
), (diethylamino)sulfur trifluoride
(DAST) and several other fluoride containing reagents (Scheme 1.11).
32,10,16

HF KF CsF CoF
3
SF
4
N
SF
3
DAST
N
F
TBAF
N
F
TMAF
N
Si
F
F
TBAT
S
N N
N
[Me
3
SiF
2
]
-
TASF

Scheme 1.11 Nucleophilic reagents for direct fluorination

The common electrophilic fluorinating reagents include: elemental fluorine
(F
2
), xenon difluoride (XeF
2
), O-F containing reagents (CF
3
OF, ClO
4
F and
others), nitrogen oxide fluorides, selectfluor, and several other hypofluorides
(Scheme 1.12).
33

15

F-F
F
Xe
O
N
F
N
F
TfO
-
Cl
O
O
O
O F
N
F
TfO
-
S
N F
O
O
S
N F
O
O
O
2
N
C
F
F
F
O F
S
N
S
F
O O O O
F
3
C
S
N
S
CF
3
F
O O O O
N
N
Cl
F
2[BF
4
]
-
F

Scheme 1.12 Electrophilic reagents for direct fluorination

Electrochemical fluorination, which was discovered by Simons, has been
discussed previously. It has wide applications in industry.

1.4.2 Organofluorine building blocks method
Seclective difluoromethylation, trifluoromethylation and perfluoroalkylation
can be accomplished by using organofluorine building blocks methods through
nucleophilic, electrophilic and radical reactions. Difluoromethylation can also be
achieved through the carbene route.

16
1.4.2.1 Introduction of difluoromethylene (-CF
2
-) group

(a) Nucleophilic reactions to incorporate difluoromethylene (-CF
2
-)
group
Most nucleophilic difluoromethylations are carried out using difluoroenolates,
difluoroallyl anions and difluorophosphonyl anions (Scheme 1.13) by reacting
them with electrophiles.
29(b)
Both difluoroenolates and difluorophosphonyl anions
are versatile synthons for the nucleophilic difluoromethylation. Their
representative reactions with different organic substrates are demonstrated in
Scheme 1.14 and Scheme 1.15, respectively.
29(b),34

X
R
O
F F
Zn
TMSCl
F OTMS
F R
X= Cl, R= alkyl, allyl
X= I, R= OEt
F
F
SnMe
3
Br
F F
n-BuLi
or
-95 C °
F
F
Li
(RO)
2
P F
Y
F
O
base
THF
(RO)
2
P F
F
O
Li
Y= H, Br
base= LDA, nBuLi
difluoroenolate
difluoroally anion
difluorophosphonyl anion

Scheme 1.13 Formation of gem-difluoro substituted anions

17
F OTMS
F R
R
1
R
2
O
R
1
R
2
OH
R
O
F F
R
1
O
R R
1
O O
F F
MeO
2
CHN CO
2
Me
Cl
R NHCO
2
Me
F F
O CO
2
Me

Scheme 1.14 Nucleophilic reactions with difluoroenolates

(RO)
2
P F
F
O
Li (RO)
2
P R
1
F
F
O
R
1
P(OR)
2
O
FF
R
1
X
R
1
CF
2
P(OR)
2
O
CF
2
P(OR)
2
X
O
R
1
Cl
O
R
1
P
(OR)
2
O O
F F
R
1
NO
2
CF
2
P(OR)
2
O
NO
2
R
1
O
R
1
(RO)
2
P R
1
F
F
OH
O
R
1
R
2
O
R
2
P(OR)
2
O
F F
R
1
OH
R
1
X
R
1
OTf

Scheme 1.15 Nucleophilic gem-difluoromethylations with difluorophosphonyl
anion

18
(b) Electrophilic reactions to introduce difluoromethylene (-CF
2
-) group
Electrophilic difluoromethylations are carried out by using
halodifluoromethanes or difluoroalkenes as reagents (Scheme 1.16).
29(b)
But the
actual reaction mechanism in certain cases may involve simple electron transfer
process.

ON
O
i-Pr
R
O
i) LDA
ii) CF
2
Br
2
ON
O
i-Pr
R
O
CF
2
Br
42-60% yield
67-92% de
R
1
F
R
2
OAc F
CuCN
LiCl
R
1
R
3
R
2
FF
70-95%
E: Z= 95: 5
R
3
MgX

Scheme 1.16 Electrophilic introduction of the gem-difluoromethylene groups

(c) Radical reactions to introduce difluoromethylene (-CF
2
-) group
Radical reactions are very promising for the preparation of complex
fluorinated molecules under mild conditions. Two examples are presented in
Scheme 1.17: the addition of halodifluoroalkyl radicals and the addition of
difluoroacetyl radicals to alkenes.
29(b)

19
R
1
R
2
R
4
R
3
CF
2
Br
2
initiator
Br R
3
F F
R
1
R
2
Br
R
4
initiator: BzOOBz, CuCl, UV light, Et
3
B/O
2
, CrCl
3
/Fe, Mn/e
-
RX
I
F F
O
X= O, CH
2
+
R
1
initiator
RX
R
1
O
F F
I
initiator: Cu, Pd, Ni, UV light

Scheme 1.17 Radical gem-difluoromethylations

(d) Difluorocarbene method for the synthesis of
gem-difluorocyclopropanes
Singlet difluorocarbene (:CF
2
) addition to an alkene has become the most
important method for the synthesis of gem-difluorocyclopropanes. Many reagents
were reported
35
to generate difluorocarbene, which reacts with alkenes very
effectively, such as ClCF
2
COONa, PhHgCF
3
, FSO
2
CF
2
COOTMS. Some
representative examples of difluorocarbene reactions are shown in Scheme 1.18.
BnO OAc
+ ClF
2
COONa
BnO OAc
F F
190°C
11 eq
O
Ph
3
P, CF
2
Br
2
KF, 18-crown-6
25 °C
O
F
F
CO
2
C
4
H
9
+ FSO
2
CF
2
COOTMS
TFDA (1.5 eq)
NaF (cat. 0.012 eq)
110 °C, ~ 2hrs
CO
2
C
4
H
9
F F
83%
85%
73%

Scheme 1.18 Singlet carbene additions to alkenes

20
1.4.2.2 Trifluoromethylation reactions

(a) Nucleophilic reactions to introduce CF
3
group
The common nucleophilic trifluoromethylative reagents are TMSCF
3
and
CuCF
3
. TMSCF
3
based trifluoromethylation reactions, first discovered by Prakash,
Olah, and coworkers,
36
are widely used in the synthesis of pharmaceutical
intermediates and other fluorinated materials.
37
Scheme 1.19 shows the
application of TMSCF
3
for the CF
3
transfer into various types of substrates.

TMS-CF
3
R R'
O
R
R'
F
3
C
OSiMe
3
NO
N OSiMe
3
CF
3
RSO
2
F
RSO
2
CF
3
O CF
3
OSiMe
3
Br
CF
3
NO
2
F
F
F
F
F
CF
3
F F
F
F
F
RCOCOOEt
RCCOOEt
CF
3
OSiMe
3
RCOOMe
R CF
3
O
O
O
O
F
3
C OSiMe
3
N
O
O
Me
N Me
O
CF
3
OSiMe
3
Cu (I) salt, KF, DMF
1.
Bu
S
N
R
1
H
O
t
2. 4N HCl, MeOH
ClH
3
N R
1
CF
3
Ph
O
H
2. O
3
3. Me2S
H
CF
3
H
O
R
1
R
2
NH, R
3
B(OH)
2
F
3
C
R
3
N
R
2
R
1
OH

Scheme 1.19 Nucleophilic trifluoromethylations with TMSCF
3

21
(b) Electrophilic reactions to introduce CF
3
group
The studies on electrophilic trifluoromethylations are limited since
trifluoromethyl cation is difficult to generate due to the very strong
electronegativity of the three fluorine atoms. Trifluoromethyl dibenzoheterocyclic
salts, a class of electrophilic trifluoromethylating agent, were discovered by
Umemoto et al. and can react with a wide range of electron-rich nucleophilic
substrates (Scheme 1.20).
38

A
CF
3
O
O
Na
O
O
CF
3
PhC CLi
PhC C CF
3
COOEt
COOEt
Na
F
3
C
COOEt
COOEt
OSiMe
3
CF
3
O
OH
CF
3
OH
RSNa
RSCF
3
N
H
N
H
CF
3
OTf
A = S, Se, Te

Scheme 1.20 Electrophilic trifluoromethylations with trifluoromethyl
dibenzoheterocyclic salts

22
(c) Radical reactions to introduce CF
3
group
Trifluoromethyl radical can be generated by various means (Scheme 1.21).
39

It is highly reactive towards electron rich aromatic compounds (Scheme 1.22).
40

CF
3
∆ or
hν
t-BuOOH
∆ or
hν
Te(CF
3
)
2
CF
3
COCF
3
CF
3
SO
2
Na
electrolysis
or XeF
2
HO
2
CCF
3
hν
CF
3
N(NO)SO
2
Ph
∆ or
hν
CF
3
N(NO)SO
2
CF
3
electron
donation
(CF
3
CO
2
)
2
ICF
3
∆ or
hν
CF
3
∆ or
hν
t-BuOOH
∆ or
hν
Te(CF
3
)
2
CF
3
COCF
3
CF
3
SO
2
Na
electrolysis
or XeF
2
HO
2
CCF
3
hν
CF
3
N(NO)SO
2
Ph
∆ or
hν
CF
3
N(NO)SO
2
CF
3
(CF
3
CO
2
)
2
ICF
3
∆ or
hν
∆ or
hν
BrCF
3
Hg(CF
3
)
2
CF
3
N=NCF
3
hν
hν

Scheme 1.21 Generation of the trifluoromethyl radical

X
CF
3
X
CF
3
X= Br, Cl, Me, NH
2
, OH

Scheme 1.22 Radical trifluoromethylation

1.4.2.3 Perfluoroalkylations

The common reagents used for perfluoroalkylations are perfluoroalkyl
halides,
41
perfluoroalkyl copper
42
(nucleophilic reagents), (perfluoroalkyl)-

23
aryliodonium
43
(electrophilic reagents) and perfluoroalkyl peroxides
36
(radical
reagents). Scheme1.23 demonstrates the examples of perfluoroalkylations.
n-C
7
F
15
I +
I
Cu
DMSO
110-120 °C
n-C
7
F
15
70%
I
CH
3
Cl C
3
F
7
+
SNa
DMF
SC
3
H
7
81%
(C
3
F
7
CO
2
)
2
+
O
∆
O
C
3
F
7
98%

Scheme 1.23 Examples of perfluoroalkylation reactions

1.5 Prospective

Due to the special properties and reactivity of organofluorine compounds and
the short history of organofluorine chemistry, there is a huge potential for the
growth of fluorine chemistry. With the development of new fluorination methods
with high selectivity, technical safety and environmental benignancy, the future of
fluorine is bright. Fluorine will continue to play a significant role in industry.
More and more fluorinated products will be developed and applied in the fields of
medicine, biology and material sciences.

24
1.6 Chapter 1 references

1. Thayer, A. M. C&E News, 2006, 84, 15.

2. (a) Chambers, R. D. Fluorine in Organic Chemistry, Blackwell: Boca Raton,
FL. 2004. (b) Schlosser, M. Angew. Chem. Int. Ed. 2006, 45, 5432. (c)
Mikami, K.; Itoh, Y.; Yamanaka, M. Chem. Rev. 2003, 104, 1. (d) Mann, J.
Chem. Soc. Rev. 1987, 16, 381. (e) Welch, J. T. Tetrahedron 1987, 43, 3123.

3. Moissan H. Das Fluor und seine Verbindungen (translated by Dr. Theodor
Zettel, author) German Edition, Verlag von M. Krayn, Berlin, 1900.

4. Swarts, F. Bull. Acad. Royal Belge 1892, 24, 309.

5. Henne, A. L. Org. React. 1944, 2, 49.

6. Midgley, T. et al. US 1886339, 1928.

7. Plunkett, R. J. US 2230654, 1941.

8. (a) Modern Fluoropolymers, Scheirs, J. Ed. Wiley: Chichester, 1997. (b)
Ameduri, B.; Boutevin, B. Well-Architectured Fluoropolymers: Synthesis,
Properties and Applications, Elsevier: Amsterdam, 2004.

9. Fowler, R. D.; Burford III, W. B.; Hamilton, J. M. Jr.; Sweet, R. G.; Weber,
C. E.; Kasper, J. S.; Litant, I. Ind. Eng. Chem. 1947, 39, 292.

10. Gerstenberger, M. R. C.; Haas, A. Angew. Chem. Int. Ed. Engl. 1981, 20,
647 and the references therein.

11. Groult, H.; Lantelme, F.; Salanne, M.; Simon, C.; Belhomme, C.; Morel, B.;
Nicolas, F. J. Fluorine Chem. 2007, 128, 285.

12. Simons, J.H. Trans. Electrochem. Soc. 1949, 95, 47.

13. Fried, J. H.; Sabo, E. F. J. Am. Chem. Soc. 1954, 76, 1455.

14. Bartlett, N. Proc. Chem. Soc. 1962, 218.

15. Molina, M. J.; Rowland, F. S. Nature, 1974, 810, 249.

25

16. Synthetic Fluorine Chemistry, Olah, G. A.; Chambers, R. D.; Prakash, G. K.
S. Eds. Wiely: New York, 1992.

17. (a) O’Hagan, D.; Schaffrath, C.; Cobb, S. L.; Hamilton, J. T. G.; Murphy, C.
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18. Hiyama, T. Organofluorine Compounds: Chemistry and Applications,
Springer: New York, 2000.

19. (a) Methods of Organic Chemistry (Houben-Weyl): Organo-Fluorine
Compounds, Baasner, B.; Hagemann, H.; Tatlow, J. C. Eds. Thieme,
Stuttgart, 2000. (b) Biomedical Frontiers of Fluorine Chemistry, ACS
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Plenum Press: New York, 1994. (e) Chemistry of Organic Fluorine
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20. Shimizu, M; Hiyama, T. Angew. Chem. Int. Ed. 2005, 44, 214.

21. Bondi, A. J. Phys. Chem. 1964, 68, 441.

26

22. (a) McCarthy, J. R. Fluorine in Drug Design: A Tutorial Review, 17th
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MacLeod, A. M.; Morrison, D.; Moyes, C. R.; O’Connor, D.; Pike, A.;
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H.; Watt, A. P.; Castro, J. L. J. Med. Chem. 1999, 42, 2087.

23. Dolbier, W. R. Jr. J. Fluorine Chem. 2005, 126, 157.

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Böhm, H.; Banner, D.; Bendels, S.; Kansy, M.; Kuhn, B.; Müller, K.;
Obst-Sander, U.; Stahl, M. ChemBioChem. 2004, 5, 637 and the references
therein.

25. Fowler, J. S. in: Organofluorine Compounds in Medicinal Chemistry and
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26. Jeschke, P. Chem. Biol. Chem. 2004, 5, 570.

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29. O’Hagan, D. in: Proceedings of the International Symposium on Fluorine in
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30. Hudlicky, M. Chemistry of organic fluorine compounds, in: A Laboratory
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27

31. (a) Sandford, G. J. of Fluorine Chem. 2007, 128, 90. (b) Tozer, M. J.; Herpin,
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35. (a) Dolbier, W. R. Jr.; Battiste, M. A. Chem. Rev. 2003, 103, 1071 and the
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36. Prakash, G. K. S.; Krishnamuti, R.; Olah, G. A. J. Am. Chem. Soc. 1989, 111,
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37. (a) Prakash, G. K. S.; Yudin, A. K. Chem. Rev. 1997, 97, 757. (b) Singh, R.
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28

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29
Chapter 2
Nucleophilic Reactions of Difluoromethyl Phenyl
Sulfone (PhSO
2
CF
2
H) with Alkyl Halides

2.1 Introduction
As discussed previously, the selective introduction of fluorine atoms into
organic molecules is of great interest, due to the broad applications of
fluorine-containing compounds in pharmarceutical and agricultural chemistry, and
material science.
1
Recently, two classes of gem-difluoro compounds have
attracted much attention: 1,1-difluoro-1-alkenes and difluoromethylalkanes.
2

1,1-Difluoro-1-alkene (R-CH=CF
2
) functionality has been known to act as a
bioisostere for aldehydes and ketones with reverse reactivity (Scheme 2.1),
3
and
it is critical to many biologically active molecules such as enzyme inhibitors,
4

and pesticides.
5
1,1-Difluoro-1-alkenes are also useful synthetic precursors for
many other fluorinated compounds and polymers.
6
CF
2
H functionality has been
known to be isosteric and isopolar to hydroxyl (OH) group and behaves as a
hydrogen donor through hydrogen bonding.
7, 2(e)
Moreover, CF
2
H group has
similar high lipophilicity as the trifluoromethyl group, which is useful in
applications where a more lipophilic hydrogen bond donor other than OH is

30
required.
7(a)
As a result, CF
2
H group has been frequently incorporated into various
biologically active compounds (such as enzyme inhibitors,
8
sugars,
9
pesticides,
10

and herbicides
11
) and materials (such as liquid crystals
12
and fluoropolymers
13
).
Many CF
2
H-containing compounds have also been used as anesthetics, including
well-known desflurane and isoflurane.
14

R F
F
R
O
R' R'
bioisostere
H R
F
F
H
R O
isosteric and isopolar

Scheme 2.1 Biological effects of fluorine-containing groups

Several methods have been developed for the preparation of
1,1-difluoro-1-alkenes and CF
2
H-containing compounds. Wittig reaction using
difluoromethylene ylides
15
is the most common method to prepare
1,1-difluoro-1-alkenes. Methods to introduce CF
2
H into organic compounds
includes the deoxofluorination of aldehydes using SF
4
, DAST, or SeF
4
,
16

nucleophilic fluorination of gem-bistriflates using TBAF,
17
fluorination of 1,2- or
1,3-dithianes using BrF
3
and other in situ-generated halogen fluorides,
2(e), 18

addition of CF
2
Br
2
, into double bonds,
19
S
RN
1 reaction between a nucleophile and
CF
2
HCl,
20
and hydrogenation of terminal 1,1-difluoroalkenes.
21
Nucleophilic

31
introduction of a CF
2
H group into carbonyl compounds has been reported, using
(difluoromethyl)dimethylphenylsilane,
22
(chlorodifluoromethyl)trimethylsilane,
7(a)

or difluoromethyl phenyl sulfone as the CF
2
H precursors
23
Previously, we have
reported the preparation of difluoromethylsilanes via the magnesium
metal-mediated reductive difluoromethylation of chlorotrialkylsilanes using
difluoromethyl phenyl sulfone.
24
Herein, we would like to disclose simple and
efficient new methods for the preparation of 1,1-difluoro-1-alkenes and
difluoromethyl compounds from readily available primary alkyl halides using
difluoromethyl phenyl sulfone
20, 23
(1) (Scheme 2.2).

Ph S CF
2
CH
2
R
O
O
RCH
2
X
(X=I, Br)
RCH=CF
2
RCH
2
CF
2
H
PhSO
2
CF
2
H (1)

Scheme 2.2 Preparation of 1,1-difluoro-1-alkenes and difluoromethyl alkanes from
PhSO
2
CF
2
H

Alkyl halides are commercially available compounds and have been
extensively used to form new carbon-carbon bonds due to the high reactivity of
carbon-halogen bond.
25
However, their nucleophilic substitution reactions with
fluorine-bearing carbon nucleophiles are generally difficult due to their
unmatched hard-soft nature.
26
The possible solution to this problem is to
introduce a proper auxiliary functional group connected to the fluorinated carbon

32
nucleophile to increase its softness, since the alkyl halide is a soft electrophile.
Furthermore, the proper auxiliary group should be easily removed or transformed
into other functional groups afterwards. The benzenesulfonyl group (PhSO
2
) is
one of the choices, for its softness and its varying chemical reactivities (so-called
“chemical chameleon”).
27
Difluoromethyl phenyl sulfone (1) is the ideal
compound for this purpose, due to the ease of generation of the
(benzenesulfonyl)difluoromethyl anion 2 after deprotonation with a suitable base
(Scheme 2.3). In the section below, we will describe the successful nucleophilic
substitution reactions of difluoromethyl phenyl sulfone 1 with primary alkyl
halides.

S CF
2
H
O
O
B
- BH
S CF
2
O
O
1
2

Scheme 2.3 Generation of (benzenesulfonyl)difluoromethide from PhSO
2
CF
2
H
and a base

2.2 Results and discussion
2.2.1 Nucleophilic substitution reactions (S
N
2) of PhSO
2
CF
2
H and alkyl
halides.
The nucleophilic substitution of difluoromethyl phenyl sulfone 1 with alkyl
bromides, alkyl iodides, and alkyl triflates were examined, to produce alkylated

33
difluoromethyl sulfone 4, with careful modifications of the reaction conditions
(Table 2.1).

Table 2.1 Optimization of the reaction conditions for the nucleophilic substitution
of 1 with alkyl halides

PhSO
2
CF
2
H + RX
base
solvent
PhSO
2
CF
2
R
3 1 4

34
The reactions were typically performed under an argon atmosphere, and a
base was added to a mixture of 1 and 3. The best product yield was obtained when
one equivalent of 1 was treated with four equivalents of primary alkyl iodide and
two equivalents of t-BuOK as a base in DMF at -50 ºC for 1 hour (Table 2.1, entry
5). Primary alkyl bromides are also suitable for this reaction but provide lower
yields (Table 2.1, entries 1-4). A secondary alkyl halide, however, did not give the
anticipated product (Tale 2.1, entry 9), indicating that the reaction proceeds by a
typical S
N
2 pathway. Methyl triflate did not react with 1 to give the expected
product (Table 2.1, entry 10, 11). This may be due to the fast reaction between
DMF, alkyl triflate, and t-BuOK to form the corresponding dialkyl acetal of DMF.
Following optimization of the reaction conditions, a variety of
alkyl-substituted gem-difluoromethyl phenyl sulfones 4 were prepared in good
yields (Table 2.2). Various primary alkyl iodides with different chain lengths were
able to be substituted with (benzenesulfonyl)difluoromethide (in situ-generated
from 1) and t-BuOK (Table 2.2, entries 1-6). Substituted alkyl iodides also behave
in the similar way, which leads to the formation of structurally diverse
gem-difluorinated sulfones (Table 2.2, entries 7-12). Alkyl-substituted
difluoromethyl sulfones themselves are a group of useful compounds used as
nonlinear optical materials.
28
The known available method for their preparation is
by the α-fluorination of sulfoxides bearing α-hydrogen atoms by elemental

35
fluorine in low yields (10~20%).
29
Our current methodology possesses many
advantages such as convenience, safety, cost, and efficiency.
It is worthwhile to mention that the similar nucleophilic substitution reaction
between the in situ-generated (benzenesulfonyl)difluoromethyl anion (from 1 and
t-BuOK) and other electrophiles worked equally well. When excess elemental
iodine was used as the electrophile, PhSO
2
CF
2
I (5) was produced in 92% yield
(Scheme 2.4). Interestingly, when n-perfluorohexyl iodide was applied instead of
I
2
, the same product 5 was produced in 39% yield (Scheme 2.5). Difluoromethyl
phenyl sulfoxide, PhSOCF
2
H, also reacts with n-butyl iodide in the presence of
t-BuOK, to give 1,1-difluoropentyl phenyl sulfoxide (8) in 54% yield (Scheme
2.6).
Table 2.2 Preparation of substituted difluoromethyl sulfones 4 from 1 (1
equiv.), alkyl iodides (4 equiv.), and t-BuOK (2 equiv) in DMF at -50 ºC for 1
hour.

CH
3
(CH
2
)
6
ICH
3
(CH
2
)
6
CF
2
SO
2
Ph (4a) 1 79
RCH
2
IRCH
2
CF
2
SO
2
Ph (4) yield (%)
a
CH
3
(CH
2
)
4
ICH
3
(CH
2
)
4
CF
2
SO
2
Ph (4b) 2 80
CH
3
(CH
2
)
3
ICH
3
(CH
2
)
3
CF
2
SO
2
Ph (4c) 3 84
CH
3
(CH
2
)
2
ICH
3
(CH
2
)
2
CF
2
SO
2
Ph (4d) 4 73
CH
3
CH
2
ICH
3
CH
2
CF
2
SO
2
Ph (4e) 5 62
CH
3
ICH
3
CF
2
SO
2
Ph (4f) 6 42
Ph(CH
2
)
3
IPh(CH
2
)
3
CF
2
SO
2
Ph (4g) 7 71
PhO(CH
2
)
3
IPhO(CH
2
)
3
CF
2
SO
2
Ph (4l) 12 71
a
Isolated yield.
Ph(CH
2
)
4
IPh(CH
2
)
4
CF
2
SO
2
Ph (4h) 8 52
Ph(CH
2
)
5
IPh(CH
2
)
5
CF
2
SO
2
Ph (4i) 9 59
Ph(CH
2
)
6
IPh(CH
2
)
6
CF
2
SO
2
Ph (4j) 10 50
PhO(CH
2
)
4
IPhO(CH
2
)
4
CF
2
SO
2
Ph (4m) 13 60
entry
Ph
2
CH(CH
2
)
2
IPh
2
CH(CH
2
)
2
CF
2
SO
2
Ph (4k) 11 37

36
X
2
1, t-BuOK
DMF, -30 ~ -20 C, 1h
PhSO
2
CF
2
X
X= I, 5 (92%)
= Br, 6 (38%)
°

Scheme 2.4 Nucleophilic substitution with elemental halogens

1, t-BuOK
DMF, -50 C, 1h
PhSO
2
CF
2
I
n-C
6
F
13
I
5 (39%)
°

Scheme 2.5 Nucleophilic substitution with perfluoroalkyl iodide

Ph S CF
2
H
O
+ n-C
4
H
9
I
t-BuOK
DMF, -50
o
C~ r.t.
Ph S CF
2
(CH
2
)
3
CH
3
O
8 (54 %)
7

Scheme 2.6 Nucleophilic substitution using difluoromethyl phenyl sulfoxide

2.2.2 Facile preparation of 1,1-difluoro-1-alkenes from 4
During the preparation of alkyl-substituted difluoromethyl sulfones 4, the
formation of a small amount of 1,1-difluoro-1-alkene as by-product was observed.
This is due to the high acidity of the α-hydrogen atom next to the
difluoromethylene group, which allows the easy deprotonation by t-BuOK to
generate a new carbanion intermediate 9 (Scheme 2.7).

37
R-CH
2
CF
2
SO
2
Ph R-CH
-
CF
2
SO
2
Ph
- PhSO
2
-
t-BuOK
RCH=CF
2
4 9
10

Scheme 2.7 Formation of 1,1-difluoro-1-alkenes

Intermediate 9 readily undergoes β-elimination to eliminate the
benzenesulfonyl group (rather than a fluorine atom) to afford
1,1-difluoro-1-alkene 10. The benzenesulfonyl group is known to be a better
leaving group than a fluoride.
27(a)
Hence, we readily prepared
1,1-difluoro-1-alkenes 10 from the isolated substitution product 4 with t-BuOK in
THF at -20 ºC to ambient temperature. The deprotonation/ β-elimination reactions
proceeded smoothly (within 1h). Various 1,1-difluoro-1-alkenes were prepared in
good to excellent yields by this method using the previously prepared sulfone
compounds 4 (Table 2.3). Thus, the primary alkyl iodides were transformed into
1,1-difluoro-1-alkenes in two steps by a substitution-elimination sequence. The
advantage of this method is that the reactions are facile and straightforward, and
necessitate only safe and inexpensive reagents as well as convenient experimental
procedures.

38
Table 2.3 Preparation of 1,1-difluoro-1-alkenes 10 by deprotonation-elimination
reactions using 4 and t-BuOK in THF at temperatures ranging from -20 ºC to room
temperature.

RCH
2
CF
2
SO
2
Ph (4) yield (%)
a
Ph(CH
2
)
3
CF
2
SO
2
Ph 1 85
PhO(CH
2
)
3
CF
2
SO
2
Ph 7 88
a
Isolated yield.
Ph(CH
2
)
4
CF
2
SO
2
Ph 2 71
Ph(CH
2
)
5
CF
2
SO
2
Ph 3 82
Ph(CH
2
)
6
CF
2
SO
2
Ph 4
80
PhO(CH
2
)
4
CF
2
SO
2
Ph 8 87
entry
Ph
2
CH(CH
2
)
2
CF
2
SO
2
Ph 5
84
p-MeO-C
6
H
4
-
(CH
2
)
4
CF
2
SO
2
Ph 6
55
RCH=CF
2
(10)
Ph(CH
2
)
2
CH=CF
2
(10a)
Ph(CH
2
)
3
CH=CF
2
(10b)
Ph(CH
2
)
4
CH=CF
2
(10c)
Ph(CH
2
)
5
CH=CF
2
(10d)
Ph
2
CHCH
2
CH=CF
2
(10e)
p-MeO-C
6
H
4
-
(CH
2
)
3
CH=CF
2
(10f)
PhO(CH
2
)
2
CH=CF
2
(10g)
PhO(CH
2
)
3
CH=CF
2
(10h)

2.2.3 Facile preparation of difluoromethyl alkanes from 4
Reductive desulfonylation is widely used in organic synthesis to remove
arenesulfonyl groups after the desired transformations.
27(a)
After the
desulfonylation, arenesulfonyl groups are commonly replaced by a hydrogen atom.
Reductive desulfonylations of gem-difluorinated sulfones are scarce.
(Benzenesulfonyl)difluoromethyl carbinols have been reductively desulfonylated
into difluoromethyl carbinols in low yields, using sodium metal in ethanol.
23(a)

Similar poor yields were obtained, when we tried a Na/MeOH system as a
desulfonylating agent for the alkylated difluoromethyl sulfones 4. It soon became
apparent that under the reaction conditions, the in situ-generated strong base
MeONa will further complicate the reaction and thus decrease the desulfonylation

39
efficiency. Inspired by the early report that the clean desulfonylation reaction can
be obtained by applying a buffering agent to control the pH,
27(b), (c)
we added
sodium monohydrogenphosphate (Na
2
HPO
4
) in our desulfonylation reactions in
order to selectively produce difluoromethylated products (Scheme 2.8).
Sodium/mercury amalgam (5 wt.% Na in Hg) was used, and the reactions were
carried out at -20 ºC to 0 ºC for 0.5-1h. Various difluoromethyl compounds 11
were obtained from the corresponding alkylated difluoromethyl sulfones 4 in
excellent yields (Table 2.4). The reactions were highly selective, which simplified
the final purification process.
RCH
2
CF
2
SO
2
Ph
Na(Hg), MeOH, Na
2
HPO
4
-20
o
~ 0
o
C, 0.5~1 h
RCH
2
CF
2
H
411

Scheme 2.8 Preparation of difluoromethyl alkanes 11 by desulfonylation of 4

Table 2.4 Preparation of difluoromethylalkanes by desulfonylations of 4 using
Na(Hg)/MeOH ranging from -20 ºC to 0 ºC.

RCH
2
CF
2
SO
2
Ph (4) yield (%)
a
PhO(CH
2
)
3
CF
2
SO
2
Ph 6 91
a
Isolated yield.
Ph(CH
2
)
4
CF
2
SO
2
Ph 1 87
Ph(CH
2
)
5
CF
2
SO
2
Ph 2 90
Ph(CH
2
)
6
CF
2
SO
2
Ph 3
85
PhO(CH
2
)
4
CF
2
SO
2
Ph 7 88
entry
Ph
2
CH(CH
2
)
2
CF
2
SO
2
Ph 4
89
p-MeO-C
6
H
4
-
(CH
2
)
4
CF
2
SO
2
Ph 5
80
RCH
2
CF
2
H (11)
Ph(CH
2
)
4
CF
2
H (11a)
Ph(CH
2
)
5
CF
2
H (11b)
Ph(CH
2
)
6
CF
2
H (11c)
Ph
2
CH(CH
2
)
2
CF
2
H (11d)
p-MeO-C
6
H
4
-
(CH
2
)
4
CF
2
H (11e)
PhO(CH
2
)
3
CF
2
H (11f)
PhO(CH
2
)
4
CF
2
H (11g)

40
2.3 Conclusions
The unprecedented nucleophilic substitution reactions (S
N
2) of
(benzenesulfonyl)difluoromethide (in situ-generated from difluoromethyl phenyl
sulfone) with alkyl halides (especially alkyl iodides) have been completed
successfully, which demonstrates the first carbon-carbon bond formation between
a fluorinated carbanion and simple alkyl halides. The similar type of substitution
reactions with perfluoroalkyl iodides and elemental halogens has also been
studied. The new alkyl-substituted difluoromethyl sulfones are highly useful
compounds for their facile transformations into 1,1-difluoro-1-alkenes via
base-induced eliminations, and difluoromethylalkanes through reductive
desulfonylations. The new types of straightforward transformations from primary
alkyl iodides into 1,1-difluoro-1-alkenes and difluoromethylalkanes provide the
highly useful synthetic possibilities for many applications.

2.4 Experimental section
Materials and instrumentation. Unless otherwise mentioned, all other
chemicals were purchased from commercial sources. Potassium t-butoxide (95 %,
Aldrich) was used received. DMF was distilled over calcium hydride, and stored
over activated molecular sieve. Difluoromethyl phenyl sulphone (1) was prepared
using known procedures.
30
Some alkyl iodides were prepared from corresponding
alkyl bromide (using NaI in acetone) or alcohols.
31
Silica gel column

41
chromatography was used to isolate the products using 60-200 mesh silica gel
(from J. T. Baker), mostly using hexane-ethyl acetate (9:1) as eluent.
1
H,
13
C and
19
F NMR spectral were recorded on 500 MHz or 360 MHz NMR spectrometer.
1
H
NMR chemical shifts were determined relative to internal (CH
3
)
4
Si (TMS) at δ
0.0 or to the signal of a residual protonated solvent: CDCl
3
δ 7.26.
13
C NMR
chemical shifts were determined relative to internal TMS at δ 0.0 or to the
13
C
signal of solvent: CDCl
3
δ 77.0.
19
F NMR chemical shifts were determined
relative to internal CFCl
3
at δ 0.0. GC-MS data were recorded on GC-MS
spectrometer with a mass selective detector at 70 eV . High-resolution mass data of
low boiling compounds were recorded on a GC chromatograph with micromass
GCT (time of flight) mass spectrometer. Other high-resolution mass data were
recorded on a high-resolution mass spectrometer in the EI mode.
Typical procedure for nucleophilic substitution reactions of
difluoromethyl phenyl sulfone with alkyl iodides. Under an argon atmosphere,
into a Schlenk flask containing difluoromethyl phenyl sulfone (192 mg, 1 mmol)
and n-heptyl iodide (904 mg, 4 mmol) in DMF (4 mL) at –50
o
C, was added
dropwise via a syringe t-BuOK (224 mg, 2 mmol) in DMF (4 mL). The reaction
mixture was stirred at –50
o
C for 1 h, and the completion of the reaction was
monitored by
19
F NMR. The reaction was then quenched by adding 1N HCl
aqueous solution (5 mL) at –50
o
C, followed by warming to room temperature. A
saturated NaCl aqueous solution (10 mL) was added, and the mixture was

42
extracted with Et
2
O (15 mL x 3). The combined organic phase was dried over
MgSO
4
, filtered, and the solvent was removed in a rotary evaporator. The residue
was further purified by silica gel column chromatography (hexane: ethyl acetate =
9:1) to give 1,1-difluorooctyl phenyl sulfone (4a) (230 mg, 79% yield) as a
colorless oily liquid.
1
H NMR (500 MHz, CDCl
3
): δ 0.88 (t, J = 6.9 Hz, 3H), 1.28
(m, 8H), 1.64 (m, 2H), 2.33 (m, 2H), 7.60 (t, J = 8.3 Hz, 2H), 7.73 (t, J = 7.3 Hz,
1H), 7.99 (d, J = 7.9 Hz, 2H).
13
C NMR (125 MHz, CDCl
3
): δ 13.9; 20.7 (t, J =
3.4 Hz), 22.4, 28.7, 29.0, 29.1, 31.4, 124.6 (t, J = 286 Hz), 129.1, 130.6, 132.7,
135.1.
19
F NMR (470 MHz, CDCl
3
): δ -104.2 (t, J =19 Hz). GC-MS (EI, m/z):
291 (M
+
+1), 142, 77. HRMS (EI): m/z calcd for C
14
H
21
F
2
O
2
S (M
+
+H) 291.1230,
found 291.1222.
1,1-Difluorohexyl Phenyl Sulfone (4b): colorless liquid, yield: 80 %.
1
H
NMR (500 MHz, CDCl
3
): δ 0.90 (t, 3H), 1.37 (m, 4H), 1.62 (m, 2H), 2.30 (m,
2H), 7.60 (t, 2H), 7.78 (t, 1H), 8.00 (2, 2H).
13
C NMR (125 MHz, CDCl
3
): δ 13.7,
20.4, 22.2, 29.1 (t, J = 20.4 Hz), 31.2, 124.7 (t, J = 286 Hz), 129.2, 130.7, 132.5,
135.2.
19
F NMR (470 MHz, CDCl
3
): δ -104.6 (t, J = 19 Hz). GC-MS (EI, m/z):
262 (M
+
), 142, 77. HRMS (EI): m/z calcd for C
12
H
17
F
2
O
2
S (M
+
+H) 263.0917,
found 263.0904.
1,1-Difluoropentyl Phenyl Sulfone (4c): colorless liquid, yield: 84%.
1
H NMR
(500 MHz, CDCl
3
): δ 0.93 (t, J = 7.3 Hz), 1.42 (m, 2H), 1.62 (m, 2H), 2.32 (m,
2H), 7.60 (t, J = 7.3 Hz, 2H), 7.74 (t, J = 7.3 Hz, 1H), 7.97 (d, J = 7.9 Hz, 2H).

43
13
C NMR (125 MHz, CDCl
3
): δ 13.5, 22.3, 22.8 (t, J = 3.5 Hz), 28.9 (t, J = 20
Hz), 124.7 (t, J = 286 Hz), 129.2, 130.7, 132.7, 135.1.
19
F NMR (470 MHz,
CDCl
3
): δ -104.1 (t, J = 19 Hz). GC-MS (EI, m/z): 248 (M
+
), 142, 77. HRMS (EI):
m/z calcd for C
11
H
15
F
2
O
2
S (M
+
+H) 249.0761, found 249.0749.
1,1-Difluorobutyl Phenyl Sulfone (4d): colorless liquid, yield: 73%.
1
H NMR
(360 MHz, CDCl
3
): δ 0.98 (t, J = 7.2 Hz, 3H), 1.63 (m, 2H), 2.27 (m, 2H), 7.57 (t,
J = 7.8 Hz), 7.71 (t, J = 7.6 Hz, 1H), 7.95 (d, J = 7.7 Hz, 2H).
13
C NMR (90 MHz,
CDCl
3
): δ 13.6, 14.4 (t, J = 3.6 Hz), 30.9 (t, J = 20 Hz), 124.5 (t, J = 286 Hz),
129.2, 130.5, 132.4, 135.1.
19
F NMR (338 MHz, CDCl
3
): δ -104.1 (t, J = 20 Hz).
GC-MS (EI, m/z): 234 (M
+
), 142, 77. HRMS (EI): m/z calcd for C
10
H
12
F
2
O
2
S
(M
+
+H) 235.0604, found 235.0597.
1,1-Difluoropropyl Phenyl Sulfone (4e): colorless liquid, yield: 62%.
1
H
NMR (360 MHz, CDCl
3
): δ 1.15 (t, J = 7.2 Hz, 3H), 2.32 (m, 2H), 7.58 (t, J =7.7
Hz, 2H), 7.72 (t, J = 7.6 Hz, 1H), 7.95 (d, J = 7.8 Hz, 2H).
13
C NMR (90 MHz,
CDCl
3
): δ 5.0 (t, J = 4.9 Hz), 23.0 (t, J = 20.8 Hz), 124.6 (t, J = 285.4 Hz), 129.2,
130.5, 132.4, 135.2.
19
F NMR (338 MHz, CDCl
3
): δ -106.1 (t, J = 18 Hz).
GC-MS (EI, m/z): 220 (M
+
), 142, 77. HRMS (EI): m/z calcd for C
9
H
10
F
2
O
2
S (M
+
)
220.0342, found 220.0381.
1,1-Difluoroethyl Phenyl Sulfone (4f): colorless liquid, yield 42%.
1
H NMR
(500 MHz, CDCl
3
): δ 2.01 (t, J = 19 Hz, 3H), 7.59 (t, J = 7.9 Hz, 2H), 7.74 (t, J =
7.6 Hz, 1H), 7.97 (d, J = 7.9 Hz, 2H).
13
C NMR (125 MHz, CDCl
3
): δ 16.4 (t, J =

44
22 Hz), 124.0 (t, J = 283 Hz), 129.3, 130.7, 132.1, 135.3.
19
F NMR (470 MHz,
CDCl
3
): δ -97.5 (q, J = 19 Hz). GC-MS (EI, m/z): 206 (M
+
), 142, 77. HRMS (EI):
m/z calcd for C
8
H
8
F
2
O
2
S (M
+
) 206.0213, found 206.0212.
1,1-Difluoro-4-phenylbutyl Phenyl Sulfone (4g): colorless liquid, yield 71%.
1
H NMR (360 MHz, CDCl
3
): δ 2.01 (m, 2H), 2.39 (m, 2H), 2.74 (t, J = 7.5 Hz,
2H), 7.21 (m, 3H), 7.32 (t, J = 7.3 Hz, 2H), 7.62 (t, J = 7.6 Hz, 2H), 7.76 (t, J =
7.7 Hz, 1H), 8.00 (d, J = 7.9 Hz, 2H).
13
C NMR (90 MHz, CDCl
3
): δ 22.5 (t, J = 4
Hz), 28.6 (t, J = 20 Hz), 35.0; 124.5 (t, J = 286 Hz), 126.2, 128.3, 128.5, 129.2,
130.6, 132.3, 135.2, 140.5.
19
F NMR (338 MHz, CDCl
3
): δ -103.9 (t, J = 19 Hz).
MS (EI, m/z): 310 (M
+
), 165, 149, 104. HRMS (EI): m/z calcd for C
16
H
16
F
2
O
2
S
(M
+
) 310.0839, found 310.0829.
1,1-Difluoro-5-phenylpentyl Phenyl Sulfone (4h): colorless liquid, yield: 52
%.
1
H NMR (360 MHz, CDCl
3
): δ 1.73 (m, 4H), 2.38 (m, 2H), 2.67 (t, J = 7.3 Hz,
2H), 7.19 (m, 3H), 7.30 (t, J = 7.3 Hz, 2H), 7.62 (t, J = 7.9 Hz, 2H), 7.76 (t, J =
7.8 Hz, 1H), 7.99 (d, J = 7.8 Hz, 2H).
13
C NMR (90 MHz, CDCl
3
): δ 20.5 (t, J = 4
Hz), 29.0 (t, J = 20 Hz), 30.9, 35.4, 124.6 (t, J = 286 Hz), 125.9, 128.3, 128.4,
129.2, 130.7, 132.5, 135.2, 141.6.
19
F NMR (338 MHz, CDCl
3
): δ -104.1 (t, J =
18 Hz). HRMS (EI): m/z calcd for C
17
H
18
F
2
O
2
S (M
+
) 324.0996, found
324.1007.
1,1-Difluoro-6-phenylhexyl Phenyl Sulfone (4i): colorless thick liquid, yield:
59%.
1
H NMR (500 MHz, CDCl
3
): δ 1.46 (m 2H), 1.69 (m, 4H), 2.36 (m, 2H),

45
2.65 (t, J = 7.6 Hz, 2H), 7.21 (m, 3H), 7.31 (t, J = 7.4 Hz, 2H), 7.62 (t, J = 7.4 Hz,
2H), 7.76 (t, J = 7.5 Hz, 1H), 8.01 (d, J = 7.3 Hz, 2H).
13
C NMR (125 MHz,
CDCl
3
): δ 20.6 (t, J = 4 Hz), 28.6; 29.1 (t, J = 18 Hz), 30.9, 35.5, 124.6 (t, J = 286
Hz), 125.7, 128.2, 128.3, 129.2, 130.6, 132.4, 135.2, 142.1.
19
F NMR (470 MHz,
CDCl
3
): δ -104.1 (t, J = 18 Hz). HRMS (EI): m/z calcd for C
18
H
20
F
2
O
2
S (M
+
)
338.1152, found 338.1147.
1,1-Difluoro-7-phenylheptyl Phenyl Sulfone (4j): colorless thick liquid, yield:
50%.
1
H NMR (500 MHz, CDCl
3
): δ 1.41 (m, 4H), 1.66 (m, 4H), 2.34 (m, 2H),
2.62 (t, J = 7.3 Hz, 2H), 7.20 (m, 3H), 7.29 (t, J = 7.3 Hz, 2H), 7.62 (t, J = 7.5 Hz,
2H), 7.76 (t, J = 7.3 Hz, 1H), 8.00 (d, J = 7.5 Hz, 2H).
13
C NMR (125 MHz,
CDCl
3
): δ 20.7 (t, J = 4 Hz), 28.8, 29.0, 29.1 (t, J = 20 Hz), 31.1, 35.8, 124.6 (t, J
= 286 Hz), 125.6, 128.2, 128.3, 129.2, 130.7, 132.5, 135.2, 142.5.
19
F NMR (470
MHz, CDCl
3
): δ -104.1 (t, J = 19 Hz). HRMS (EI): m/z calcd for C
19
H
22
F
2
O
2
S
(M
+
) 352.1308, found 352.1298.
1,1-Difluoro-4,4-diphenylbutyl Phenyl Sulfone (4k): colorless oily liquid,
yield: 37%.
1
H NMR (500 MHz, CDCl
3
): δ 2.37 (m, 2H), 2.49 (m, 2H), 4.02 (t, J
= 7.3 Hz, 1H), 7.23~7.36 (m, 10 H), 7.60 (t, J = 7.4 Hz, 2H), 7.74 (t, J = 7.5 Hz,
1H), 8.00 (d, J = 7.4 Hz, 2H).
13
C NMR (125 MHz, CDCl
3
): δ 26.7, 28.2 (t, J =
20 Hz), 50.6, 124.5 (t, J = 286 Hz), 126.6, 127.6, 128.6, 129.2, 130.6, 132.3,
135.2, 143.3.
19
F NMR (470 MHz, CDCl
3
): δ -103.3 (t, J = 19 Hz). MS (EI,

46
m/z): 386 (M
+
). HRMS (EI): m/z calcd for C
22
H
20
F
2
O
2
S (M
+
) 386.1147, found
386.1148.
1,1-Difluoro-4-phenoxybutyl Phenyl Sulfone (4l): colorless oily liquid, yield:
71%.
1
H NMR (360 MHz, CDCl
3
): δ 2.17 (m, 2H), 2.61 (m, 2H), 4.04 (t, J = 5.9
Hz, 2H), 6.92 (d, J = 7.7 Hz, 2H), 7.00 (t, J = 7.3 Hz, 1H), 7.31 (t, J = 7.1 Hz, 2
H), 7.63 (t, J = 7.1 Hz, 2 H), 7.77 (t, J = 7.6 Hz, 1 H), 8.02 (d, J = 8.0 Hz, 2H).
13
C NMR (90 MHz, CDCl
3
): δ 21.2 (t, J = 3.7 Hz), 26.4, 66.1, 114.4, 120.9, 124.5
(t, J = 286 Hz), 129.3, 129.4, 130.7, 132.3, 135.3, 158.5.
19
F NMR (338 MHz,
CDCl
3
): δ -104.0 (t, J = 18 Hz). MS (EI, m/z): 326 (M
+
), 233, 185, 125. HRMS
(EI): m/z calcd for C
16
H
16
F
2
O
3
S (M
+
) 326.0788, found 326.0789.
1,1-Difluoro-5-phenoxypentyl Phenyl Sulfone (4m): colorless liquid, yield:
60%.
1
H NMR (360 MHz, CDCl
3
): δ 1.90 (m, 4H), 2.44 (m, 2H), 3.99 (t, J = 5.8
Hz, 2H) 6.85~6.98 (m, 3H), 7.29 (t, J = 7.5 Hz, 2H), 7.62 (t, J = 7.6 Hz, 2H), 7.77
(t, J = 7.6 Hz, 1H), 7.99 (d, J = 7.6 Hz, 2H).
13
C NMR (90 MHz, CDCl
3
): δ 17.8
(t, J = 3.6 Hz), 28.6, 28.9 (t, J = 20 Hz), 66.8, 114.3, 120.6, 124.4 (t, J = 286 Hz),
129.2, 129.3, 130.6, 132.3, 135.2, 158.7.
19
F NMR (338 MHz, CDCl
3
): δ -103.9 (t,
J = 18 Hz). HRMS (EI): m/z calcd for C
17
H
18
F
2
O
3
S (M
+
) 340.0945, found
340.0951.
Nucleophilic substitution reactions of difluoromethyl phenyl sulfone with
elemental iodine. Under an argon atmosphere, into a Schlenk flask containing
difluoromethyl phenyl sulfone (192 mg, 1 mmol) and elemental iodine (508 mg, 4

47
mmol) in DMF (4 mL) at –30
o
C, was added dropwise via a syringe t-BuOK (448
mg, 4 mmol) in DMF (4 mL). The reaction mixture was stirred at -30
o
C ~ -20
o
C
for 1 h, and the completion of the reaction was monitored by
19
F NMR. The
reaction mixture was then quenched by adding 1N HCl aqueous solution (5 mL)
at –50
o
C, followed by warming to room temperature. A saturated NaCl aqueous
solution (10 mL) was added, and the mixture was extracted with Et
2
O (15 mL x 3).
The combined organic phase was dried over MgSO
4
, filtered, and the solvent was
removed in a rotary evaporator. The residue was further purified by silica gel
column chromatography (hexane: ethyl acetate = 9:1) to give difluoroiodomethyl
phenyl sulfone (5) (294 mg, 92% yield) as a colorless solid, which readily turns to
red under light.
1
H NMR (500 MHz, CDCl
3
): δ 7.63 (t, J = 7.4 Hz, 2H), 7.79 (t, J
= 7.4 Hz, 1H), 7.99 (d, J = 7.5 Hz, 2H).
13
C NMR (125 MHz, CDCl
3
): δ 102.5 (t,
J = 355 Hz), 128.1, 129.7, 131.3, 136.1.
19
F NMR (470 MHz, CDCl
3
): δ -52.2.
MS (EI, m/z): 318 (M
+
), 177, 142, 127. HRMS (EI): m/z alcd for C
7
H
5
F
2
IO
2
S
(M
+
) 317.9023, found 317.9013.
Bromodifluoromethyl phenyl sulfone (6): light-sensitive colorless solid, yield:
38%.
1
H NMR (360 MHz, CDCl
3
): δ 7.67 (t, J = 7.7 Hz, 2H), 7.84 (t, J = 7.8 Hz,
1H), 8.04 (d, J = 7.8 Hz, 2H).
19
F NMR (338 MHz, CDCl
3
): δ -58.0. MS (EI, m/z):
272 [M(
81
Br)
+
], 156, 141, 111. HRMS (EI): m/z alcd for C
7
H
5
BrF
2
O
2
S (M
+
)
269.9162, found 269.9161.

48
Typical procedures for the preparation of 1,1-difluoro-1-alkenes (10)
from alkyl-substitued difluoromethyl sulfones (4): Under an argon atmosphere,
into a Schlenk flask containing 1,1-difluoro-4-phenylbutyl phenyl sulfone (4g)
(100 mg, 0.32 mmol) in THF (4 mL) at –20
0
C, was added dropwise via a syringe
t-BuOK (224 mg, 2 mmol) in DMF (4 mL). The reaction mixture was stirred at
–20
0
C ~ rt for 1 h, and the completion of the reaction was monitored by
19
F NMR
[δ -89.6 (d, J = 46.6 Hz, 1F), - 91.6 (dd, J = 46.6 Hz, 24.8 Hz, 1F)]. The
reaction mixture was then quenched by adding aqueous NaCl solution (10 mL),
followed by extraction with Et
2
O (15 mL x 3). The combined organic phase was
dried over anhydrous Na
2
SO
4
, filtered, and the solvent was removed. The crude
product was purified by a flash chromatography to give
1,1-difluoro-4-phenyl-1-butene (10a) (46 mg, 85 % yield) as a colorless liquid.
The characterization data is consistent with those reported earlier.
15(k)

1,1-Difluoro-5-phenyl-1-pentene (10b): colorless liquid, yield: 71%.
1
H NMR
(360 MHz, CDCl
3
): δ 1.70 (p, J = 7.6 Hz, 2H), 2.01 (qt, J = 7.5 Hz, 1.7 Hz, 2H),
2.62 (t, J =7.6 Hz, 2H), 4.15 (dtd, J = 25 Hz, 7.9 Hz, 2.7 Hz, 1H), 7.16~7.31 (m,
5H).
13
C NMR (90 MHz, CDCl
3
): δ 21.8, 31.1, 35.1, 77.7 (t, J = 21 Hz), 125.8,
128.3, 128.4, 142.0, 156.2 (t, J = 286 Hz).
19
F NMR (338 MHz, CDCl
3
): δ -89.7
(d, J = 46.6 Hz, 1F), -92.0 (dd, J = 46.6Hz, 25.1Hz, 1F). HRMS (EI): m/z calcd
for C
11
H
12
F
2
(M
+
) 182.0907, found 182.0909.

49
1,1-Difluoro-6-phenyl-1-hexene (10c): colorless liquid, yield: 82%.
1
H NMR
(360 MHz, CDCl
3
): δ 1.43 (m, 2H), 1.66 (m, 2H), 2.03 (m, 2H), 2.63 (t, J = 7.4
Hz, 2H), 4.14 (dtd, J = 25.5Hz; 7.8Hz, 2.5Hz, 1H), 7.18~7.34 (m, 5H).
13
C NMR
(90 MHz, CDCl
3
): δ 22.0, 29.0, 30.7, 35.5, 77.8 (t, J = 21 Hz), 125.7, 128.3,
128.4, 142.4, 156.3 (t, J = 286 Hz).
19
F NMR (338 MHz, CDCl
3
): δ -90.0(d, J =
50 Hz, 1F), -92.5 (dd, J = 50 Hz, 25 Hz, 1F). HRMS (EI): m/z calcd for
C
12
H
14
F
2
(M
+
) 196.1063, found 196.1061.
1,1-Difluoro-7-phenyl-1-heptene (10d): colorless liquid, yield: 80%.
1
H NMR
(360 MHz, CDCl
3
): δ 1.40 (m, 4H), 1.64 (m, 2H), 1.99 (m, 2H), 2.62 (t, J = 7.4
Hz, 2H), 4.13 (dtd, J = 25 Hz, 7.9 Hz, 3.0 Hz, 1H), 7.17~7.33 (m, 5H).
13
C NMR
(90 MHz, CDCl3): δ 22.1, 28.5, 29.3, 31.2, 35.9, 77.9 (t, J = 21 Hz), 125.6, 128.3,
128.4, 142.6, 156.3 (t, J = 286 Hz).
19
F NMR (338 MHz, CDCl3): δ -90.1(d, J =
50 Hz, 1F), -92.5 (dd, J = 50 Hz, 25 Hz, 1F).
1,1-Difluoro-4,4-diphenyl-1-butene (10e): colorless liquid, yield: 84%.
1
H
NMR (500 MHz, CDCl
3
): δ 2.76 (m, J = 7.7 Hz, 2H), 3.98 (t, J = 7.9 Hz, 1H),
4.10 (dtd, J = 25.4 Hz, 7.4 Hz, 2.6 Hz, 1H), 7.20~7.36 (m, 10 H).
13
C NMR (125
MHz, CDCl
3
): δ 28.5, 51.2, 76.6 (t, J = 20 Hz), 126.5, 127.8, 128.5, 143.7, 156.3
(t, J = 286 Hz).
19
F NMR (338 MHz, CDCl
3
): δ -88.8(d, J = 46 Hz, 1F), -90.7 (dd,
J = 46 Hz, 24 Hz, 1F). MS (EI, m/z): 244 [M
+
]. HRMS (EI): m/z calcd for
C
16
H
14
F
2
O (M
+
) 244.1052, found 244.1053.

50
1,1-Difluoro-5-(4'-methoxy)phenyl-1-pentene (10f): colorless liquid, yield:
55%.
1
H NMR (360 MHz, CDCl
3
): δ 1.67 (m, 2H), 1.99 (m, 2H), 2.57 (t, J = 7.4
Hz, 2H), 3.79 (s, 3H), 4.15 (dtd, J = 25 Hz, 7.8 Hz, 3.0 Hz, 1H), 6.83 (d, J = 8.6
Hz, 2H), 7.09 (d, J = 8.5 Hz, 2H).
13
C NMR (125 MHz, CDCl
3
): δ 14.1, 21.7,
34.2, 55.2, 77.7 (t, J = 21 Hz), 113.8, 129.3, 133.9, 156.3 (t, J = 286 Hz), 157.8.
19
F NMR (338 MHz, CDCl
3
): δ -90.0(d, J = 50 Hz, 1F), -92.3 (dd, J = 50Hz,
26Hz, 1F). HRMS (EI): m/z calcd for C
12
H
14
F
2
O

(M
+
) 212.1013, found 212.1001.
1,1-Difluoro-4-phenoxy-1-butene (10g): colorless liquid, yield: 88%.
1
H
NMR (500 MHz, CDCl
3
): δ 2.48 (m, 2H), 3.98 (t, J = 6.2 Hz, 2H), 4.35 (dtd, J =
25.4 Hz, 7.9 Hz, 2.4 Hz, 1H), 6.91 (d, J = 8.0 Hz, 2H), 6.97 (t, J = 7.5 Hz, 1H),
7.30 (t, J = 8.0 Hz)
13
C NMR (125 MHz, CDCl
3
): δ 22.8, 66.7, 74.7 (t, J = 22 Hz),
114.5, 120.9, 129.5, 156.8 (t, J = 287 Hz), 158.7.
19
F NMR (338 MHz, CDCl
3
): δ
-88.1 (d, J = 46 Hz, 1F), -90.5 (dd, J = 46 Hz, 26 Hz, 1F). MS (EI, m/z): 184 [M
+
].
HRMS (EI): m/z calcd. for C
10
H
10
F
2
O(M
+
) 184.0700, found 184.0702.
1,1-Difluoro-5-phenoxy-1-pentene (10h): colorless liquid, yield: 87 %.
1
H
NMR (500 MHz, CDCl
3
): δ 1.87 (m, 2H), 2.21 (m, 2H), 3.97 (t, J = 7.2 Hz, 2H),
4.21 (dtd, J = 25.4 Hz, 7.9 Hz, 2.4 Hz, 1H), 6.93 (m, 3H), 7.29 (t, J = 7.5 Hz, 2H).
13
C NMR (125 MHz, CDCl
3
): δ 19.0, 29.0 (t, J = 2.5 Hz), 66.6, 74.4 (t, J = 22
Hz), 114.5, 120.7, 129.4, 156.4 (t, J = 287 Hz), 159.0.
19
F NMR (338 MHz,
CDCl
3
): δ -89.2 (d, J = 46 Hz, 1F), -91.7 (dd, J = 46 Hz, 26 Hz, 1F). HRMS (EI):
m/z calcd. for C
11
H
12
F
2
O

(M
+
) 198.0856, found 198.0853.

51
Typical procedures for the preparation of difluoromethyl compounds (11)
by reductive desulfonylation of 4: Under an argon atmosphere, into a Schlenk
flask containing 1,1-difluoro-5-phenylpentyl phenyl sulfone (4h) (100 mg, 0.31
mmol), anhydrous Na
2
HPO
4
(308 mg, 2.2 mmol) in methanol (4 mL) at -20
0
C,
was added 5% Na/Hg amalgam beads (700 mg, ca.1.5 mmol Na). The reaction
mixture was stirred at -20
0
C ~ 0
0
C for 1 h, and the completion of the reaction
was monitored by
19
F NMR. The methanol solution was decanted out, and the
residual solids were washed with Et
2
O (5 mL x 3). The volatile solvents of the
combined solution were removed under vacuum, and the crude product was
purified by flash chromatography to give 1,1-difluoro-5-phenylpentane (11a)
(50 mg, 87% yield) as a colorless liquid.
1
H NMR (500 MHz, CDCl
3
): δ 1.51 (m,
2H), 1.70 (m, 2H), 1.86 (m, 2H), 2.64 (t, J = 7.7 Hz, 2H), 5.80 (tt, J = 57 Hz, 4.7
Hz, 1H), 7.19 (m, 3H), 7.30 (t, J = 7.6 Hz, 2H).
13
C NMR (125 MHz, CDCl
3
): δ
21.7 (t, J = 5.4 Hz), 30.8, 33.9 (t, J = 21 Hz), 117.3 (t, J = 239 Hz), 125.8, 128.3,
141.9.
19
F NMR (470 MHz, CDCl
3
): δ -116.2 (dt, J = 57 Hz, 18 Hz, 1F). HRMS
(EI): m/z calcd for C
11
H
14
F
2
(M
+
) 184.1064, found 184.1062.
1,1-Difluoro-6-phenylhexane (11b): colorless liquid, yield: 90%.
1
H NMR
(360 MHz, CDCl
3
): δ 1.40 (m, 2H), 1.49 (m, 2H), 1.66 (m, 2H), 1.82 (m, 2H),
2.63 (t, J = 7.6 Hz, 2H), 5.79 (tt, J = 57 Hz, 4.5 Hz, 1H), 7.20 (m, 3H), 7.29 (t, J =
7.6 Hz, 2H).
13
C NMR (90 MHz, CDCl
3
): δ 21.9 (t, J = 5.4 Hz), 28.6, 31.2, 34.0 (t,
J = 21 Hz), 35.7, 117.4 (t, J = 239 Hz), 125.7, 128.3, 128.4, 142.4.
19
F NMR (338

52
MHz, CDCl
3
): δ -116.4 (dt, J = 57 Hz, 18 Hz, 1F). HRMS (EI): m/z calcd for
C
12
H
16
F
2
(M
+
) 198.1220, found 198.1211.
1,1-Difluoro-7-phenylheptane (11c): colorless liquid, yield: 85%.
1
H NMR
(360 MHz, CDCl
3
): δ 1.37 (m, 4H), 1.44 (m, 2H), 1.63 (m, 2H), 1.81 (m, 2H),
2.61 (t, J = 7.5 Hz, 2H), 5.79 (tt, J = 57 Hz, 4.5 Hz, 1H), 7.19 (m, 3H), 7.26 (t, J =
7.5 Hz, 2H).
13
C NMR (90 MHz, CDCl
3
): δ 22.0 (t, J = 5.5 Hz), 28.9, 29.0, 31.2,
34.0 (t, J = 21 Hz), 35.8, 117.4 (t, J = 239 Hz), 125.6, 128.2, 128.4, 142.6.
19
F
NMR (338 MHz, CDCl
3
): δ -116.3 (dt, J = 57 Hz, 18 Hz, 1F). HRMS (EI): m/z
calcd for C
13
H
18
F
2
(M
+
) 212.1377, found 212.1372.
1,1-Difluoro-4,4-diphenylbutane (11d): colorless liquid, yield: 89%.
1
H NMR
(500 MHz, CDCl
3
): δ 1.80 (m, 2H), 2.23 (m, 2H), 3.94 (t, J = 7.4 Hz, 1H), 5.83 (tt,
J = 57 Hz, 4.7 Hz, 1H), 7.24 (m, 10H).
13
C NMR (125 MHz, CDCl
3
): δ 27.7, 32.7
(t, J = 21 Hz), 50.7, 117.1 (t, J = 239Hz), 126.6, 127.7, 128.6, 144.0.
19
F NMR
(470 MHz, CDCl
3
): δ -116.2 (dt, J = 57 Hz, 18 Hz, 1F). MS (EI, m/z): 246 [M
+
].
HRMS (EI): m/z calcd for C
16
H
16
F
2
(M
+
) 246.1215, found 246.1216.
1,1-Difluoro-5-(4'-methoxy)phenylpentane (11e): colorless liquid, yield: 80%.
1
H NMR (360 MHz, CDCl
3
): δ 1.48 (m, 2H), 1.65 (m, 2H), 1.83 (m, 2H), 2.58 (t,
J = 7.5 Hz, 2H), 3.79 (s, 3H), 5.79 (tt, J = 57 Hz, 4.5 Hz, 1H), 6.84 (d, J = 8.0 Hz,
2H), 7.08 (d, J = 8.0 Hz).
13
C NMR (90 MHz, CDCl
3
): δ 21.7 (t, J = 5.5 Hz), 31.1,
34.0 (t, J = 21 Hz), 34.7, 55.2, 113.8, 117.3 (t, J = 239 Hz), 129.2, 134.0, 157.8.

53
19
F NMR (338 MHz, CDCl
3
): δ -116.2 (dt, J = 57 Hz, 18 Hz, 1F). HRMS (EI):
m/z calcd for C
12
H
16
F
2
O(M
+
) 214.1169, found 214.1170.
1,1-Difluoro-4-phenoxybutane (11f): colorless liquid, yield: 91%.
1
H NMR
(500 MHz, CDCl
3
): δ 2.06 (m, 4H), 4.07 (t, J = 7.4 Hz, 2H), 5.94 (tt, J = 57 Hz,
4.7 Hz, 1H), 6.92 (d, J = 7.5 Hz, 2H), 6.98 (t, J = 7.4 Hz, 1H), 7.31 (t, J = 7.5 Hz,
2H).
13
C NMR (125 MHz, CDCl
3
): δ 22.1 (t, J = 5.9 Hz), 31.0 (t, J = 21 Hz), 66.6,
114.4, 117.1 (t, J = 239 Hz), 120.8, 129.5, 158.7.
19
F NMR (470 MHz, CDCl
3
): δ
-116.6 (dt, J = 57 Hz, 18 Hz, 1F). MS (EI, m/z): 186 [M
+
]. HRMS (EI): m/z calcd
for C
10
H
12
F
2
O (M
+
) 186.0856, found 186.0857.
1,1-Difluoro-5-phenoxypentane (11g): colorless liquid, yield: 88%.
1
H NMR
(500 MHz, CDCl
3
): δ 1.67 (m, 2H), 1.86 (m, 2H), 1.93 (m, 2H), 3.99 (t, J = 7.4
Hz, 2H), 5.85 (tt, J = 57 Hz, 4.7 Hz, 1H), 6.91 (d, J = 7.5 Hz, 2H), 6.96 (t, J = 7.4
Hz, 1H), 7.30 (t, J = 7.5 Hz, 2H).
13
C NMR (125 MHz, CDCl
3
): δ 19.0 (t, J = 5.9
Hz), 28.7, 33.8 (t, J = 21 Hz), 67.2, 114.4, 117.2 (t, J = 239 Hz), 120.7, 129.4,
158.9.
19
F NMR (470 MHz, CDCl
3
): δ -116.4 (dt, J = 57 Hz, 18 Hz, 1F). HRMS
(EI): m/z calcd for C
11
H
14
F
2
O (M
+
) 200.1013, found 200.1012.

54
2.5 Chapter 2 references

1. (a) Organofluorine Chemistry: Principles and Commercila Applications,
Banks, R. E.; Tatlow, J. C.; Smart, B. E., Eds. Plenum Press: New York,
1994. (b) McCarthy, J. Utility of Fluorine in Biologically Active Molecules,
ACS Fluorine Division Tutorial, 219th National ACS Meeting, San
Francisco, March 26, 2000. (c) Organofluorine compounds: Chemistry and
Applications, Hiyama, T., Eds. Springer: New York, 2000.

2. (a) Ichikawa, J.; Fukui, H.; Ishibashi, Y. J. Org. Chem. 2003, 68, 7800. (b)
Ichikawa, J.; Ishibashi, Y.; Fukui, H. Tetrahedron Lett. 2003, 44, 707. (c)
Ichikawa, J.; Wada, Y.; Fujiwara, M.; Sakoda, K. Synthesis 2002, 1917. (d)
Weintraub, P. M.; Holland, A. K.; Gates, C. A.; Moore, W. R.; Resvick, R. J.;
Bey, P.; Peet, N. P. Bioorg. Med. Chem. 2003, 11, 427. (e) Sasson, R.;
Hagooly, A.; Rozen, S. Org. Lett. 2003, 5, 769 and references cited therein.

3. Motherwell, W. B. Jr.; Tozer, M. J.; Ross, B. C. J. Chem. Soc., Chem. Comm.
1989, 1437.

4. (a) Moor, W. R.; Schatzman, G. L.; Jarvi, E. T.; Gross, R. S.; McCarthy, J. R.
J. Am. Chem. Soc. 1992, 114, 360. (b) Selective Fluorination in Organic and
Bioorganic Chemistry, ACS Symposium Series 456, Welch, J. T. Ed.
American Chemical Society: Washington, DC, 1991.

5. (a) Abe, T.; Tamai, R.; Tamaru, M.; Yano, H.; Takahashi, S.; Muramatsu, N.
WO 2003042153, 2003; Chem. Abstr. 2003, 138, 401741. (b) Abe, T.; Tamai,
R.; Ito, M.; Tamaru, M.; Yano, H.; Takahashi, S.; Muramatsu, N. WO
2003029211, 2003; Chem. Abstr. 2003, 138, 304304. (c) Fuji, K.; Hatano, Y.;
Tsutsumiuchi, K.; Nakahon, Y. JP 2000086636, 2000; Chem. Abstr. 2000,
132, 222532.

6. (a) Tozer, M. J.; Herpin, T. F. Tetrahedron 1996, 52, 8619. (b) Percy, J. M.
Contemp. Org. Synth. 1995, 2, 251.

7. (a) Yudin, A. K.; Prakash, G. K.S.; Deffieux, D.; Bradley, M.; Bau, R.; Olah,
G. A. J. Am. Chem. Soc. 1997, 119, 1572 and references cited therein. (b)
Erickson, J. A.; McLoughlin, J. I. J. Org. Chem. 1995, 60, 1626. (c)
Fluorine in Bioorganic Chemistry, Welch, J. T.; Eswarakrishnan, S. Eds.
Wiley: New York, 1991. (d) Modern Fluoroorganic Chemistry, Kirsch, P. Ed.
Wiley-VCH: Weinheim, 2004.

55

8. (a) Chen, Y .; Freskos, J. N.; Gasiecki, A. F.; Grapperhaus, M. L.; Hansen, D.
W., Jr.; Heintz, R. M.; Khanna, I. K.; Kolodziej, S. A.; Mantegani, S.; Massa,
M. A.; McDonald, J. J.; Mischke, D. A.; Nagy, M. A.; Perrone, E.; Schmidt,
M. A.; Spangler, D. P.; Talley, J. J.; Trivedi, M.; Wynn, T. A.; Becker, D. P.;
Rico, J. G. WO 2004000811, 2004; Chem. Abstr. 2004, 140, 59663. (b)
Parker, M. F.; McElhone, K. E.; Mate, R. A.; Bronson, J. J.; Gai, Y.;
Bergstrom, C. P.; Marcin, L. R.; Macor, J. E. WO 2003053912, 2003; Chem.
Abstr. 2003, 139, 85645.

9. (a) Kaneko, S.; Yamazaki, T.; Kitazume, T. J. Org. Chem. 1993, 58, 2302. (b)
Houlton, S. J.; Motherwell, W. B.; Ross, B. C.; Tozer, M. J.; Williams, D. J.;
Slawin, A. M. Z. Tetrahedron 1993, 49, 8087.

10. (a) Otaka, K.; Oohira, D.; Takaoka, D. WO 2004006677, 2004. (b) Markl,
M.; Schaper, W.; Ort, O.; Jakobi, H.; Braun, R.; Krautstrunk, G.; Sanft, U.;
Bonin, W.; Stark, H.; Pasenok, S.; Cabrera, I. WO 2000007998, 2000; Chem.
Abstr. 2000, 132, 166248.

11. Groure, W. F.; Leschinsky, K. L.; Wratten, S. J.; Chupp, J. P. J. Agric. Food.
Chem. 1991, 39, 981.

12. Kondou, T.; Matsui, S.; Miyazawa, K.; Takeuchi, H.; Kubo, Y .; Takeshita, F.;
Nakagawa, E. WO 9813324, 1998; Chem. Abstr. 1998, 128, 302171.

13. Fluorine-containing Molecules. Structure, Reactivity, Synthesis and
Applications, Liebman, J. F.; Greenberg, A.; Dolbier, W. R., Jr., Eds. VCH:
New York, 1998.

14. Rozov, L. A.; Huang, C.; Halpern, D. F.; Vernice, G. G. U.S. Patent
5,283,372, 1994; Halpern, D. F.; Robin, M. L., U.S. Patent 4,996,371, 1991.

56

15. (a) Burton, D. J.; Naae, D. G. J. Fluorine Chem. 1971, 1, 123. (b) Burton, D.
J.; Naae, D. G. Synth. Commun. 1973, 3, 197. (c) Ichikawa, J. J. Fluorine
Chem. 2000, 105, 257. (d) Matthews, D. P.; Miller, S. C.; Jarvi, E. T.; Sabol,
J. S. McCarthy, J. R. Tetrahedron Lett. 1993, 34, 3057 (e) Bennett, A. J.;
Percy, J. M.; Rock, M. H.; Synlett 1992, 483. (f) Percy, J. M. Tetrahedron
Lett. 1990, 31, 3931. (g) Tsukamoto, T.; Kitazume, T. Synlett. 1992, 977. (h)
Begue, J. –P; Bonnet-Delpon, D.; Rock, M. H. Tetrahedron Lett. 1995, 36,
5003. (i) Shi, G.; Huang, X.; Zhang, F. –J. Tetrahedron Lett. 1995, 36,
6305. (j) Begue, J. –P.; Bonnet-Delpon, D.; Rock, M. H. Tetrahedron Lett.
1994, 35, 6097. (k) Kim, K. –I.; McCarthy, J. R. Tetrahedron Lett. 1996, 37,
3223. (l) Brisdon, A. K.; Banger, K. K. J. Fluorine Chem. 1999, 100, 35. (m)
Coe, P. L. J. Fluorine Chem. 1999, 100, 45.

16. (a) Middleton, W. J. J. Org. Chem. 1975, 40, 574. (b) Olah, G. A.; Nojima,
M.; Kerekes, I. J. Am. Chem. Soc. 1974, 96, 925.

17. Martinez, G. A.; Barcina, O. J.; Rys, A. Z.; Subramanian, L. R. Tetrahedron
Lett. 1992, 33, 7787.

18. (a) Sondej, S. C.; Katzenellenbogen, J. A. J. Org. Chem. 1986, 51, 3508. (b)
Olah, G. A.; Chambers, R. D.; Prakash, G. K. S. Eds. Synthetic Fluorine
Chemistry, Wiley: New York, 1992.

19. Gonzales, J.; Foti, C. J.; Elsheimer, S. J. Org. Chem. 1991, 56, 4322.

20. (a) Hine, J.; Porter, J. J. J. Am. Chem. Soc. 1960, 82, 6178. (b) Langlois, B.
R. J. Fluorine Chem. 1988, 41, 247.

21. Houltona, J. S.; Motherwell, W. B.; Ross, B. C.; Ross, B. C.; Tozer, M. J.;
Williams, D. J.; Slawind, A. M. Z. Tetrahedron 1993, 49, 8087.

22. Hagiwara, T.; Fuchikami, T. Synlett 1995, 717.

23. (a) Stahly, G. P. J. Fluorine Chem. 1989, 43, 53. (b) Prakash, G. K. S.; Hu, J.;
Mathew, T.; Olah, G. A. Angew, Chem. Int. Ed. 2003, 42, 5216.

24. Prakash, G. K. S.; Hu, J.; Olah, G. A. J. Org. Chem. 2003, 68, 4457.

25. Advanced Organic Chemistry, 5th Ed., Smith, M. B.; March, J. Eds. Wiley:
New York, 2001.

57

26. Nucleophilic substitution reactions between CF
2
H- (generated in situ from
Et
3
SiCF
2
H and KF in DMF at 100 ºC) and simple alkyl halides have been
attempted by us with no success. The CuI-mediated coupling reaction
between iodobenzene and CF
2
H (generated similarly) did not work either.

27. (a) Sulfones in Organic Synthesis, Tetrahedron Organic Chemistry Series,
volumn 10, Baldwin, J. E.; Magnus, P. D. Eds. Pergamon: New York, 1993.
(b) Trost, B. M.; Chadiri, M. R. J. Am. Chem. Soc. 1984, 106, 7260. (c)
Trost, B. M. Bull. Chem. Soc. Jpn. 1988, 61, 107.

28. Wijekoon, W. M. K. P.; Wijaya, S. K.; Bhawalkar, J. D.; Prasad, P. N.;
Penner, T. L.; Armstrong, N. J.; Ezenyilimba, M. C.; Williams, D. J. J. Am.
Chem. Soc. 1996, 118, 4480.

29. (a) Toyota, A.; Ono, Y.; Chiba, J.; Sugihara, T.; Kaneko, C. Chem. Pharm.
Bull. 1996, 44, 703. (b) Chiba, J.; Sugihara, T.; Kaneko, C. Chem. Lett. 1995,
581.

30. (a) Hine, J.; Porter, J. J. J. Am. Chem. Soc. 1960, 82, 6178. (b) Stahly, G. P. J.
Fluorine Chem. 1989, 43, 53. (c) Langlois, B. R. J. Fluorine Chem. 1988,
41, 247.

31. (a) Fernandez, I.; Garcia, B.; Munoz, S.; Pedro, J. R.; de la Salud, R. Synlett
1993, 489. (b) Imamoto, T.; Matsumoto, T.; Kusumoto, T.; Yokoyama, M.,
Synthesis 1983, 460. (c) Kamal, A.; Ramesh, G.; Laxman, N. Synth.
Commun. 2001, 31, 827.

58
Chapter 3
Nucleophilic Reactions of Difluoromethyl Phenyl
Sulfone (PhSO
2
CF
2
H) with Carbonyl Compounds

3.1 Introduction
Incorporation of difluoromethyl group (CF
2
H) into small organic molecules
has attracted much interest since it plays critical roles in the bioactive molecules
as a lipophilic isostere of a hydroxy group (OH) or CH
2
OH group as well as a
hydrogen donor through hydrogen bonding.
1
However, few synthetic methods
have been available for this purpose.
2
Although nucleophilic trifluoromethylation
of carbonyl compounds are well-developed and widely used, especially with
(trifluoromethyl)trimethylsilane (TMS–CF
3
) developed by Prakash and Olah in
1989,
3
its analogous nucleophilic difluoromethylation is more challenging
regarding the generality and efficiency. This is mainly due to the fact that
Si–CF
2
H (bond order 0.436) is less polarized than the Si–CF
3
bond (bond order
0.220), indicating that the cleavage of former bond is much more difficult.
4

Fuchikami and co-workers have attempted the fluoride-induced
difluoromethylation of carbonyl compounds with difluoromethylsilane derivatives
in DMF, and found the reaction requiring high temperature (100
o
C) and giving
poor yields with ketones.
4
Stahly reported the difluoromethylation of aldehydes

59
with difluoromethyl phenyl sulfone, but the method is only limited to
non-enolizable aldehydes.
5
In 1997, our group reported the fluoride-induced
difluoromethylation of carbonyl compounds with Me
3
SiCF
2
SiMe
3
at room
temperature.
6
Although the reaction worked well with both enolizable and
non-enolizable aldehydes, it could not be applied to ketones.
6
Therefore, there is
still a lack of a general and efficient difluoromethylation method applicable to
both enolizable and non-enolizable aldehydes and ketones. As our continuing
effort, herein, we wish to disclose an efficient nucleophilic difluoromethylation of
both enolizable and non-enolizable aldehydes and ketones, using difluoromethyl
phenyl sulfone as a difluoromethyl anion (“CF
2
H
–
”) equivalent.

3.2 Results and discussion
Previously, our group has reported that difluoromethyl phenyl sulfone 1
7
can
act as a selective difluoromethylene dianion equivalent (“
–
CF
2
–
”) in the one-pot
stereoselective synthesis of anti-2,2-difluoropropane-1,3-diols,
8
a
difluoromethylidene equivalent (“=CF
2
”) in the synthesis of
1,1-difluoro-1-alkenes,
9
and a difluoromethyl anion equivalent (“CF
2
H
–
”) in the
synthesis of difluoromethylsilanes
10
and difluoromethylalkanes.
11
The chemistry
is mostly based on the selective deprotonation of the acidic CF
2
H proton of 1 with
a base (commonly tBuOK), to in situ generate a (benzenesulfonyl)difluoromethyl
anion (PhSO
2
CF
2
–
), and the latter species further reacts with electrophiles.
8,9,11

60
We attempted to apply a similar protocol in the difluoromethylation of carbonyl
compounds (see Scheme 3.1), i.e., to synthesize the
(benzenesulfonyl)difluoromethylated carbinols 3, followed by selective
desulfonylation to give difluoromethyl carbinols 4. However, when 1/tBuOK
reacted with benzaldehyde in DMF at –50
o
C ~ RT,
2,2-difluoro-1,3-diphenyl-1,3-propanediol was formed as a byproduct in
significant amounts (30~40 %), which decreased the product yield. Obviously,
here tBuOK also acts as a nucleophile to further activate the C–S bond cleavage
of the product 3.
8,12
Furthermore, the reactions of 1/tBuOK system with
enolizable aldehydes and ketones at –50
o
C ~ RT gave very poor yields of product
(10~30 %). It soon became apparent that the use of a proper base is crucial for
this reaction. The base has to satisfy the following two requirements: first, it
should be a reasonably strong base (for deprotonating 1 to generate PhSO
2
CF
2
–
)
but a weak nucleophile (unlike tBuOK), in order to avoid the C–S bond cleavage
during the reaction; second, the base should kinetically affect the deprotonation of
1 rather than the unwanted enolization of the carbonyl compounds at low
temperature. We have scanned a variety of bases including triethylamine, pyridine,
n-butyllithium, potassium hexamethyldisilazide and lithium hexamethyldisilazide
(LHMDS), and finally found that LHMDS
13
works the best. We have also noticed
that McCarthy
14
and Boger
15
have also applied LHMDS as a base in their
preparations of 1,1-difluoroalkenes from carbonyl compounds.

61

R
1
R
2
O
PhSO
2
CF
2
H (1), base
solvent
R
1
R
2
HO CF
2
SO
2
Ph
2
3
desulfonylation
R
1
R
2
HO CF
2
H
4

Scheme 3.1 Difluoromethylation of carbonyl compounds using 1.

3.2.1 Nucleophilic substitution reactions (S
N
2) of PhSO
2
CF
2
H and carbonyl
compounds.
A typical reaction was carried out as follows: LHMDS (2 equiv, dissolved in THF)
was slowly added into a mixture of 1 (1 equiv) and carbonyl compounds (2 equiv)
in THF-HMPA (10:1) at – 78
o
C, and the reaction mixture was kept at this
temperature and stirred for 1.5 ~ 8.0 h. The addition of hexamethylphosphoramide
(HMPA)
16
as a co-solvent was found to be helpful in shortening the reaction time
and enhancing the yields. A variety of structurally diverse carbonyl compounds
(both enolizable and non-enolizable aldehydes and ketones) have been used for
this reaction, and the results are summarized in Table 3.1. As shown in Table
3.1, the reaction works equally well with most aldehydes and ketones to give
(benzenesulfonyl)difluoromethyl carbinols 3 in high yields. It is remarkable that
with the enolizable substrates such as acetone (see Table 1, entry 5), the expected
product 3e was formed in 92 % yield. This indicates that at –78
o
C, both reaction
rates of deprotonation of 1 with LHMDS and nucleophilic addition of PhSO
2
CF
2
–

62
into carbonyl group are much faster than that of the unwanted enolization reaction.
When the same reaction was carried out at room temperature, much poorer yield
of product was obtained, indicating that the kinetic resolution plays a key role for
the success of the reaction at –78
o
C. Enolizable aldehydes showed more
sensitivity to LHMDS than the enolizable ketones, and relatively lower yields of
products were obtained (see entries 3 and 4). For the α,β-unsaturated aldehyde,
only 1,2-addition product 3b was observed (entry 2). In the case of
4-tert-butylcyclohexanone, both equatorial and axial addition products 3i and 3j
were isolated in 1:1.6 ratio (see entry 9). The reaction with benzophenone only
gave 61 % yield of product 3k (entry 10), probably due to the steric hinderance
between the PhSO
2
CF
2
–
anion and two phenyl rings of benzophenone. More
remarkably, the chemistry also works with complex molecules such as steroids
(see Table 3.1, entries 11 and 12). For 5 α-cholestan-3-one, both axial- and
equatorial-addition products 3l and 3m were obtained in 9:5 ratio (Table 3.1,
entry 11). A high diastereoselective addition reaction was observed with
pregnenolone acetate, to give the product 3n in 81 % yield with > 99 % de (Table
3.1, entry 12).

63
Table 3.1: Nucleophilic reaction of sulfone 1 (1.0 equiv) with carbonyl
compounds 2 (2.0 equiv) in the presence of LHMDS (2.0 equiv) in THF-HMPA
(10:1 v/v) at – 78
o
C.

Carbonyl compound 2 Product 3
Yield [%]
a
92
83
81
82
61
Entry
5
6
7
8
9
10
H
3
CCH
3
O
H
3
CCH
3
HO CF
2
SO
2
Ph
n-C
6
H
13
n-C
6
H
13
O
n-C
6
H
13
n-C
6
H
13
HO CF
2
SO
2
Ph
Ph CH
3
O
Ph CH
3
HO CF
2
SO
2
Ph
CF
2
SO
2
Ph
OH
O
OH
CF
2
SO
2
Ph
CF
2
SO
2
Ph
OH
33
53
86
Ph Ph
O
Ph Ph
HO CF
2
SO
2
Ph
83 1
Ph
H
CF
2
SO
2
Ph HO
2
Ph H
O
Ph
H
HO
CF
2
SO
2
Ph
84
3
H
O
H
OH
CF
2
SO
2
Ph
65
4
Ph
O
H
Ph
OH
H
CF
2
SO
2
Ph
53
Ph
H
O
(3a)
Reaction time (h)
2.0
2.0
2.0
2.0
1.5
1.5
1.5
3.0
1.5
(3b)
(3c)
(3d)
(3e)
(3f)
(3g)
O
(3h)
(3i)
(3j)
3.0
(3k)

64
HO
H
H
H
H
PhO
2
S
F
F
H
H
H
H
O
(3l, 3m)
8.0 85
b
Entry
11
Carbonyl compounds 2 Reaction time (h)
Product 3
Yield [%]
a
O
H
H H
H
3
C
OH
CF
2
SO
2
Ph
3n
O
O
H
H H
H
3
C
O
6.0 12
81
c
a
Isolated yields;
b
both axial addition product 3l and equitorial addition product 3m were obtained in 9:5 ratio;
c
only
one diasteromer was obatined with de >99 %.
O

3.2.2 Facile preparation of difluoromethyl compounds from 3.
Reductive desulfonylation is a widely used method in organic synthesis.
17

However, the reductive desulfonylation of gem-difluorinated sulfones are rare
(vide infra). Stahly has used Na/EtOH system to desulfonate
2,2-difluoro-1-(4-methylphenyl)-2-phenylsulfonylethanol in low yield (49 %).
5

Inspired by the earlier report,
18
we have found that Na(Hg)/MeOH/Na
2
HPO
4
is a
much better desulfonylating system for the gem-difluorinated sulfones.
[11]
In the
process of desulfonylation of above-obtained sulfones 3, sodium/mercury
amalgam (10 wt. % Na in Hg, 5 equiv) and Na
2
HPO
4
(5 equiv, used to control the

65
pH of the solution) in methanol were used, and the reaction was carried out at –
20 ~ – 10
o
C over a period of 1 ~ 3 h. The reactions were monitored by
19
F NMR
spectroscopy, and quantitative conversions were observed with high selectivity in
most cases. The results are summarized in Table 3.2. Various difluoromethyl
alcohols 4 were obtained in good to excellent yields. Both equatorial and axial
4-tert-butyl-1-difluoromethylcyclohexanols 4h/4i and 3-difluoromethyl-5 α-
cholestan-3-ols 4l/4k were obtained selectively in high yields (see entries 8, 9, 11
and 12). Interestingly, the reductive desulfonylation reaction condition was found
to be also effective for the deacetylation. As a result,
20-difluoromethylpregn-5-ene-3,20-diol 4m was obtained in one step from
20-(benzenesulfonyl)difluoromethylpregn-5-ene-3,20-diol 3-acetate 3n in 93 %
yield (Table 3.2, entry 13). It is worthwhile to mention that in most reactions as
shown in Table 3.2, simple standard work-up is sufficient to give difluoromethyl
products 4 in high purity.

66
Table 3.2: Reductive desulfonylation of carbinols 3 using Na(Hg) amalgam (10 wt.
% Na in Hg, 5 equiv) and Na
2
HPO
4
(5 equiv) in methanol at – 20 ~ – 10
o
C.

Carbinol 3 Product 4 Yield [%]
a
91
79
88
85
82
Entry
5
6
7
8
9
10
n-C
6
H
13
n-C
6
H
13
HO CF
2
H
Ph CH
3
HO CF
2
H
CF
2
H
OH
OH
CF
2
SO
2
Ph
CF
2
SO
2
Ph
OH
Ph Ph
HO CF
2
H
79 1
Ph
H
CF
2
H HO
2
Ph
H
HO
CF
2
H
84
3
H
OH
CF
2
H
76
4
Ph
OH
H
CF
2
H
86
(4a)
Reaction time (h)
1.0
1.5
2.0
2.0
2.0
1.5
2.0
2.0
2.0
(4b)
(4c)
(4d)
(4e)
(4f)
(4g)
2.0
(4j)
Ph
H
CF
2
SO
2
Ph HO
Ph
H
HO
CF
2
SO
2
Ph
H
OH
CF
2
SO
2
Ph
Ph
OH
H
CF
2
SO
2
Ph
n-C
6
H
13
n-C
6
H
13
HO CF
2
SO
2
Ph
Ph CH
3
HO CF
2
SO
2
Ph
CF
2
SO
2
Ph
OH
OH
CF
2
H
(4h)
CF
2
H
OH
(4i)
88
Ph Ph
HO CF
2
SO
2
Ph

67
HO
H
H
H
H
PhO
2
S
F
F
3.0 89
Entry
11
Carbinol 3 Reaction time (h)
Product 4
Yield [%]
a
HO
H
H H
H
3
C
OH
CF
2
H
(4m)
O
H
H H
H
3
C
OH
CF
2
SO
2
Ph
O
2.0 13
93
b
a
Isolated yields;
b
10 wt. % Na/Hg amagam (6 equivalent) was applied, and MeOH-THF (1:1) was used as the
solvent.
HO
H
H
H
H
H
F
F
HO
H
H
H
H
PhO
2
S
F
F
3.0
12
HO
H
H
H
H
H
F
F
(4k)
(4l)
90
b

3.3 Conclusions
In conclusion, a general and efficient nucleophilic difluoromethylation of
carbonyl compounds (both enolizable and non-enolizable aldehydes and ketones)
has been achieved by us using a nucleophilic
(benzenesulfonyl)difluoromethylation-reductive desulfonylation strategy under
mild conditions. Difluoromethyl phenyl sulfone acts as a difluoromethyl anion

68
(“CF
2
H
–
”) equivalent. This methodology requires only inexpensive reagents and
standard lab setups, and it promises to be a highly useful synthetic tool for many
potential applications.

3.4 Experimental section
Materials and instrumentation. Unless otherwise mentioned, all other
chemicals were purchased from commercial sources. THF was freshly distilled
over sodium. Difluoromethyl phenyl sulfone (1) was prepared using known
procedures.
5,7(a),7(b)
Silica gel column chromatography was used to isolate the
products using 60-200 mesh silica gel (from J. T. Baker), mostly using
hexane-ethyl acetate (9:1) as eluent.
1
H,
13
C and
19
F NMR spectra were recorded
on 500 MHz or 400 MHz NMR spectrometer.
1
H NMR chemical shifts were
determined relative to internal (CH
3
)
4
Si (TMS) at δ 0.0 or to the signal of a
residual proton of the solvent CDCl
3
δ 7.26.
13
C NMR chemical shifts were
determined relative to internal TMS at δ 0.0 or to the
13
C signal of solvent: CDCl
3

δ 77.0.
19
F NMR chemical shifts were determined relative to internal CFCl
3
at δ
0.0. GC-MS data were recorded on a GC-MS spectrometer with a mass selective
detector at 70 eV. High-resolution mass data were recorded on a high-resolution
mass spectrometer in the EI or CI mode.
Typical procedure for nucleophilic (benzenesulfonyl)difluoro-
methylation of Carbonyl Compounds: Under N
2
atmosphere, into a 50-mL

69
Schlenk flask containing carbonyl compounds (2 mmol) and PhSO
2
CF
2
H (1
mmol) in THF (5 mL)/HMPA (0.5 mL) at –78
o
C, was added dropwise a THF
solution (3 mL) of (TMS)
2
NLi (LHMDS, 2 mmol). The reaction mixture was then
stirred vigorously at –78
o
C for 1~8 h (see Table 1), followed by adding a
saturated NaCl water solution (10 mL) at this temperature. The solution mixture
was extracted with Et
2
O (20 mL x 3), and the combined organic phase was dried
over MgSO
4
. After the removal of volatile solvents under vacuum, the crude
product was further purified by silica gel column chromatography.
Typical procedure for reductive desulfonylation: Under N
2
atmosphere,
into a 50-mL Schlenk flask containing sulfone compound 3 (0.5 mmol) and
Na
2
HPO
4
(3 mmol) in 5 mL anhydrous methanol at –20
o
C, was added Na/Hg
amalgam (10 wt. % Na in Hg, net sodium content 3 mmol). The reaction mixture
was stirred at –20
o
C ~ 0
o
C for 1~3 h (see Table 2). The liquid phase was
decanted, and the solid residue was washed with Et
2
O. The solids were then
treated with elemental sulfur powder to destroy the mercury residue. The solvent
of combined organic phase was removed under vacuum, and 20 mL brine was
added, followed by extraction with Et
2
O brine thrice. The combined ether phase
was dried over MgSO
4
, and the ether was removed to give the product 4. In most
cases the obtained product was in high purity, and if necessary, they were further
purified by silica gel column chromatography.

70
Ph
H
HO
CF
2
SO
2
Ph
3a

2-Benzenesulfonyl-2,2-difluoro-1-phenylethanol (3a): yield 83 %, white solid.
1
H
NMR (CDCl
3
): δ 3.92 (d, J = 4.4 Hz, 1H), 5.60 (dd, J = 21 Hz, 2.3 Hz, 1H), 7.36
(m, 3H), 7.48 (m, 2H), 7.56 (t, J = 8 Hz, 2H), 7.70 (t, J = 8 Hz, 1H), 7.98 (d, J = 8
Hz, 2H).
19
F NMR (CDCl
3
): δ –106.4 (dd, J = 238 Hz, 3 Hz, 1F), –121.5 (dd, J =
238 Hz, 21 Hz, 1F). MS (EI, m/z): 298 (M
+
), 156, 140, 127, 107, 77. The data
are consistent with the previous report.
5

Ph
H
HO
CF
2
SO
2
Ph
3b

(E)-1-Benzenesulfonyl-1,1-difluoro-4-phenyl-3-buten-2-ol (3b): 84 % yield, white
solid.
1
H NMR (CDCl
3
): δ 3.07 (d, J = 5.5 Hz, 1H), 5.15 (m, 1H), 6.25 (dd, J =
15.8 Hz, 6.7 Hz, 1H), 6.89 (d, J = 16 Hz, 1H), 7.29~7.43 (m, 5H), 7.63(t, J = 8 Hz,
2H), 7.77 (t, J = 8 Hz, 1H), 8.00 (d, J = 8 Hz, 2H).
13
C NMR (CDCl
3
): δ 70.8
(dd, J = 23 Hz, 21 Hz), 120.3 (dd, J = 293 Hz, 290 Hz), 120.3 (t, J = 2.3 Hz),
126.9, 128.5, 128.6, 129.3, 130.6, 132.8, 135.5, 135.6, 136.4.
19
F NMR (CDCl
3
):
δ –107.0 (dd, J = 237 Hz, 6 Hz, 1F), –116.6 (dd, J = 237 Hz, 17 Hz, 1F). MS (EI,

71
m/z): 324 (M
+
), 207, 133, 115, 105, 77. HRMS (EI): m/z calcd for C
16
H
14
F
2
O
3
S
(M
+
) 324.0632, found 324.0642.

H
OH
CF
2
SO
2
Ph
3c

1-(Benzenesulfonyl)difluoromethylheptanol (3c): 65 % yield, colorless liquid.
1
H
NMR (CDCl
3
): δ 0.88 (t, J = 7 Hz, 3H), 1.20~1.85 (m, 10H), 2.69 (b, 1H), 4.43
(m, 1H), 7.63 (t, J = 8 Hz, 2H), 7.77 (t, J = 8 Hz, 1H), 8.00 (d, J = 8 Hz, 2H).
13
C NMR (CDCl
3
): δ 14.0, 22.5, 25.0, 28.8, 29.3 (t, J = 2 Hz), 31.6, 69.4 (dd, J =
25 Hz, 21 Hz), 121.3 (dd, J = 296 Hz, 292 Hz), 129.3, 130.6, 132.9, 135.5.
19
F
NMR (CDCl
3
): δ –108.1 (dd, J = 237 Hz, 6 Hz, 1F), –116.9 (dd, J = 237 Hz, 19
Hz, 1F). MS (EI, m/z): 306 (M
+
), 281, 271, 207, 141, 114, 77. HRMS (CI/NH
3
):
m/z calcd for C
14
H
20
F
2
O
3
S+NH
4
(MNH
4
+
) 324.1445, found 324.1439.

Ph
OH
H
CF
2
SO
2
Ph
3d

1-(Benzenesulfonyl)difluoromethyl-3-phenylpropanol (3d): 53 % yield, colorless
liquid.
1
H NMR (CDCl
3
): δ 2.09 (m, 2H), 2.77 (m, 1H), 2.97 (m, 1H), 3.05 (b,

72
1H), 4.45 (m, 1H), 7.22~7.34 (m, 5H), 7.62 (t, J = 8 Hz, 2H), 7.77 (t, J = 8 Hz,
1H), 8.00 (d, J = 8 Hz, 2H).
13
C NMR (CDCl
3
): δ 30.9 (b, 2C), 68.6 (dd, J = 24
Hz, 20 Hz), 121.2 (dd, J = 294 Hz, 292 Hz), 126.2, 128.4, 128.5, 129.3, 130.5,
132.7, 135.5, 140.5.
19
F NMR (CDCl
3
): δ –109.2 (dd, J = 238 Hz, 6 Hz, 1F),
–116.9 (dd, J = 238 Hz, 19 Hz, 1F). MS (EI, m/z): 326 (M
+
), 308, 167, 143, 104,
91, 77. HRMS (EI): m/z calcd for C
16
H
16
F
2
O
3
S (M
+
) 326.0788, found 326.0795.

H
3
CCH
3
HO CF
2
SO
2
Ph
3e

2-(Benzenesulfonyl)difluoromethyl-2-propanol (3e): 92 % yield, colorless liquid.
1
H NMR (CDCl
3
): δ 1.55 (s, 6H), 3.20 (b, 1H), 7.58 (t, J = 7.9 Hz, 2H), 7.72 (t, J
= 7.7 Hz, 1H), 7.96 (d, J = 7.8 Hz, 2H).
13
C NMR (CDCl
3
): δ 24.1 (t, J = 2.5
Hz), 74.1 (t, J = 21 Hz), 121.8 (t, J = 296 Hz), 129.2, 130.4, 133.6, 135.3.
19
F
NMR (CDCl
3
): δ –109.3 (s). MS (EI, m/z): 250 (M
+
), 235, 200, 141, 125, 94, 77.
MS: 250 (M
+
), 200, 125, 77. HRMS (EI): m/z calcd for C
10
H
12
F
2
O
3
S (M
+
)
250.0475, found 250.0467.

HO CF
2
SO
2
Ph
3f

73
7-(Benzenesulfonyl)difluoromethyl-7-tridecanol (3f): 83 % yield, colorless liquid.
1
H NMR (CDCl
3
): δ 0.88 (t, J = 6.7 Hz, 6H), 1.29~1.44 (m, 16H), 1.87 (m, 4H),
2.84 (b, 1H), 7.61 (t, J = 7.5 Hz, 2H), 7.75 (t, J = 7.5 Hz, 1H), 7.99 (d, J = 7.8 Hz,
2H).
13
C NMR (CDCl
3
): δ 14.0, 22.6, 22.7, 29.7, 31.6, 33.8, 78.2 (t, J = 19.5
Hz), 122.6 (t, J = 299 Hz), 129.2, 130.5, 134.0, 135.2.
19
F NMR (CDCl
3
): δ
–104.7 (s). MS (EI, m/z): 390 (M
+
), 199, 143, 125, 77, 69. HRMS (CI/NH
3
):
m/z calcd for C
20
H
32
F
2
O
3
S+NH
4
(MNH
4
+
) 408.2384, found 408.2392.

Ph CH
3
HO CF
2
SO
2
Ph
3g

1-Benzenesulfonyl-1,1-difluoro-2-phenyl-propan-2-ol (3g): 81 % yield, white
solid.
1
H NMR (CDCl
3
): δ 1.97 (t, J = 1.4 Hz, 3 H), 3.85 (b, 1H), 7.34 (m, 3H),
7.55 (m, 4H), 7.71 (tt, J = 7.6 Hz, 1.1 Hz, 1H), 7.87 (d, J = 8.0 Hz, 2H).
13
C
NMR (CDCl
3
): δ 24.8 (t, J = 2.5 Hz), 76.8 (t, J = 21 Hz), 120.8 (t, J = 299 Hz),
126.4, 128.1, 128.6, 129.2, 130.4, 133.7, 135.3, 138.7.
19
F NMR (CDCl
3
): δ
–105.2 (s). MS (EI, m/z): 312 (M
+
), 151, 121, 77. HRMS (EI): m/z calcd for
C
15
H
14
F
2
O
3
S (M
+
) 312.0632, found 312.0631.

74
CF
2
SO
2
Ph
OH
3h

1-(Benzenesulfonyl)difluoromethylcyclooctanol (3h): 82 % yield, colorless liquid.
1
H NMR (CDCl
3
): δ 1.41 (m, 4H), 1.67 (m, 8H), 2.10 (m, 2H), 2.92 (b, 1H), 7.58
(t, J = 8 Hz, 2H), 7.71 (t, J = 8 Hz, 1H), 7.96 (d, J = 8 Hz, 2H).
13
C NMR
(CDCl
3
): δ 21.1, 24.7, 27.6, 30.8, 78.7 (t, J = 20 Hz), 122.5 (t, J = 300 Hz), 129.1,
130.3, 133.9, 135.1.
19
F NMR (CDCl
3
): δ –106.2 (s). MS (EI, m/z): 318 (M
+
),
143, 127, 109, 77. HRMS (EI): m/z calcd for C
15
H
20
F
2
O
3
S (M
+
+ H) 319.1179,
found 319.1175.

OH
CF
2
SO
2
Ph
3i

cis-4-tert-Butyl-1-(benzenesulfonyl)difluoromethylcyclohexanol (3i): white solid.
1
H NMR (CDCl
3
): δ 0.87 (s, 9H), 1.47~2.15 (m, 9H), 2.71 (s, 1H), 7.61 (t, J = 8
Hz, 2H), 7.74 (t, J = 8 Hz, 1H), 8.00 (d, J = 8 Hz, 2H).
13
C NMR (CDCl
3
): δ
21.2, 27.4, 31.0 (t, J = 2.6 Hz), 32.3, 47.0, 75.3 (t, J = 20 Hz), 121.8 (t, J = 296
Hz), 129.2, 130.4, 133.9, 135.2.
19
F NMR (CDCl
3
): δ –110.4 (s). MS (EI, m/z):

75
346 (M
+
), 187, 171, 155, 143, 131, 125, 77. HRMS (EI): m/z calcd for
C
17
H
24
F
2
O
3
S (M
+
) 346.1414, found 346.1409.

CF
2
SO
2
Ph
OH
3j

trans-4-tert-Butyl-1-(benzenesulfonyl)difluoromethylcyclohexanol (3j): white
solid.
1
H NMR (CDCl
3
): δ 0.85 (s, 9H), 1.11~2.62 (m, 9H), 3.20 (s, 1H), 7.62 (t, J
= 8 Hz, 2H), 7.76 (t, J = 8 Hz, 1H), 8.00 (d, J = 8 Hz, 2H).
13
C NMR (CDCl
3
): δ
23.0 (t, J = 2.6 Hz), 27.5, 32.4, 34.6, 46.0, 74.3 (t, J = 20 Hz), 123.0 (t, J = 300
Hz), 129.2, 130.5, 133.7, 135.3.
19
F NMR (CDCl
3
): δ –102.3 (s). MS (EI, m/z):
346 (M
+
), 187, 171, 155, 143, 131, 125, 77. HRMS (EI): m/z calcd for
C
17
H
24
F
2
O
3
S (M
+
) 346.1414, found 346.1409.

Ph Ph
HO CF
2
SO
2
Ph
3k

2,2-Difluoro-2-benzenesulfonyl-1,1-diphenylethanol (3k): 61% yield, white solid.

1
H NMR (CDCl
3
): δ 4.46 (b, 1H), 7.34 (m, 6H), 7.56 (t, J = 8 Hz, 2H), 7.65 (m,
4H), 7.71 (t, J = 8 Hz, 1H), 7.88 (d, J = 8 Hz, 2H).
13
C NMR (CDCl
3
): δ 80.6 (t, J
= 20 Hz), 121.1 (t, J = 301 Hz), 127.4 (t, J = 2.5 Hz), 128.1, 128.6, 129.2, 130.2,

76
134.1, 135.2, 138.5.
19
F NMR (CDCl
3
): δ –98.3 (s). MS (EI, m/z): 374 (M
+
),
255, 183, 165, 105, 77. HRMS (EI): m/z calcd for C
20
H
16
F
2
O
3
S (M
+
) 374.0788,
found 374.0780.

HO
H
H
H
H
S
F
F
Ph
OO
3l

3-(Benzenesulfonyl)difluoromethyl-5 α-cholestan-3-ol (axial-addition isomer) (3l):
white solid.
1
H NMR (CDCl
3
): δ 0.64~2.50 (m, 43H), 3.21 (b, 1H), 7.62 (t, J = 8
Hz, 2H), 7.76 (t, J = 8 Hz, 1H), 7.99 (d, J = 8 Hz, 2H).
13
C NMR (CDCl
3
): δ
11.8, 12.0, 18.6, 21.1, 22.5, 22.8, 23.8, 24.2, 28.0, 28.2, 28.3, 30.2, 31.7, 34.9,
35.2, 35.4, 35.8, 36.1, 36.7, 39.5, 39.9, 41.7, 42.6, 54.0, 56.2, 56.4, 74.9 (t, J =
19.4 Hz), 123.0 (t, J = 300 Hz), 129.2, 130.5, 133.8, 135.3.
19
F NMR (CDCl
3
): δ
–102.1 (d, J = 240 Hz), –102.3 (d, J = 240 Hz). MS (EI, m/z): 578 (M
+
).
HRMS (EI): m/z calcd for C
34
H
52
F
2
O
3
S (M
+
) 578.3605, found 578.3622.

77
H
H
H
H
3m S
F
F
Ph
O
O
HO

3-(Benzenesulfonyl)difluoromethyl-5 α-cholestan-3-ol (equitorial-addition isomer)
(3m): white solid.
1
H NMR (CDCl
3
): 0.64~1.98 (m, 43H), 2.70 (b, 1H), 7.61 (t, J
= 8 Hz, 2H), 7.75 (t, J = 8 Hz, 1H), 7.98 (d, J = 8 Hz, 2H).
13
C NMR (CDCl
3
): δ
11.1, 12.1, 18.6, 20.9, 22.6, 22.8, 23.8, 24.2, 26.8, 28.0, 28.2, 31.9, 32.5, 33.3,
35.4, 35.8, 36.1, 39.5, 39.6, 39.9, 42.6, 53.8, 56.2, 56.4, 76.1 (t, J = 21 Hz), 121.6
(t, J = 297 Hz), 129.2, 130.5, 133.9, 135.3.
19
F NMR (CDCl
3
): δ –110 (s). MS
(EI, m/z): 578 (M
+
). HRMS (EI): m/z calcd for C
34
H
52
F
2
O
3
S (M
+
) 578.3605,
found 578.3600.

O
H
H H
H
3
C
OH
CF
2
SO
2
Ph
3n
O

78
20-(Benzenesulfonyl)difluoromethylpregn-5-ene-3,20-diol 3-acetate (3n): 81 %
yield, white solid.
1
H NMR (CDCl
3
): δ 0.87 (s, 3H), 1.00 (s, 3H), 1.80 (s, 3H),
2.01 (s, 3H), 0.88~2.31 (m, 22H), 2.74 (b, 1H), 4.58 (m, 1H), 5.35 (d, J = 5 Hz,
1H), 7.59 (t, J = 8 Hz, 2H), 7.73 (t, J = 8 Hz, 1H), 7.95 (d, J = 8 Hz, 2H).
13
C
NMR (CDCl
3
): δ 13.1, 19.2, 20.9, 21.4, 22.5, 22.6, 24.0, 27.6, 31.2, 31.5, 36.4,
36.8, 38.0, 39.8, 43.9, 49.6, 53.4, 56.0, 73.8, 78.3 (t, J = 20 Hz), 122.4, 122.5 (t, J
= 300 Hz), 129.1, 130.4, 134.0, 135.1, 139.5, 170.5.
19
F NMR (CDCl
3
): δ
–105.0 (s). MS (CI, m/z): 573 (MNa
+
). HRMS (CI, DCM/NBA/NaCl/PEG): m/z
calcd for C
34
H
52
F
2
O
3
SNa (MNa
+
) 573.2462, found 573.2472.

Ph
H
HO
CF
2
H
4a

2,2-Difluoro-1-phenylethanol (4a): 79 % yield, colorless liquid.
1
H NMR (CDCl
3
):
δ 3.15 (b, 1H), 4.78 (td, J = 10.2 Hz, 4.7 Hz, 1H), 5.76 (td, J = 55.6 Hz, 4.7 Hz,
1H), 7.41 (m, 5H).
13
C NMR (CDCl
3
): δ 73.5 (t, J = 24 Hz), 115.7 (t, J = 246
Hz), 127.1, 128.6, 128.9, 135.8 (t, J = 3.5 Hz).
19
F NMR (CDCl
3
): δ –127.7
(ddd, J = 284 Hz, 56 Hz, 9 Hz, 1F), –128.2 (ddd, J = 284 Hz, 57 Hz, 11 Hz, 1F).
MS (EI, m/z): 158 (M
+
), 107, 79, 77. The data are consistent with the previous
report.
19

79
H
HO
CF
2
H
4b

(E)-1-Benzenesulfonyl-1,1-difluoro-3-buten-2-ol (4b): 84 % yield, colorless liquid.
1
H NMR (CDCl
3
): δ 2.71 (b, 1H), 4.42 (m, 1H), 5.69 (td, J = 56 Hz, 4.6 Hz, 1H),
6.18 (dd, J = 16 Hz, 6.4 Hz, 1H), 6.76 (d, J = 16 Hz, 1H), 7.24~7.41 (m, 5H).
13
C NMR (CDCl
3
): δ 72.1 (t, J = 24.5 Hz), 115.4 (t, J = 245 Hz), 122.4 (t, J = 4
Hz), 126.7, 128.4, 128.6, 134.8, 135.7.
19
F NMR (CDCl
3
): δ –128.7 (ddd, J =
285 Hz, 56 Hz, 11 Hz, 1F), –129.6 (ddd, J = 285 Hz, 56 Hz, 10 Hz, 1F). MS
(EI, m/z): 184 (M
+
), 133, 115, 77. The data are consistent with the previous
reports.
20

H
HO
CF
2
H
4c

1-Difluoromethylheptanol (4c): 76 % yield, oily liquid.
1
H NMR (CDCl
3
): δ 0.88
(t, J = 7 Hz, 3H), 1.29 (m, 8H), 1.52 (m, 2H), 2.23 (br, 1H), 3.71 (m, 1H), 5.60 (td,
J = 56 Hz, 4 Hz, 1H).
13
C NMR (CDCl
3
): δ 14.0, 22.5, 24.8, 29.1, 30.0 (t, J =
3.3 Hz), 31.6, 71.1 (t, J = 23 Hz), 116.4 (t, J = 244 Hz).
19
F NMR (CDCl
3
): δ
–130.0 (ddd, J = 285 Hz, 56 Hz, 10 Hz, 1F), –130.4 (ddd, 285 Hz, 56 Hz, 11 Hz,

80
1F). MS (EI, m/z): 166 (M
+
), 115, 97, 70. The data are consistent with the
previous report.
21

H
HO
CF
2
H
4d

1,1-Difluoro-4-phenyl-2-butanol (4d): 86 % yield, colorless liquid.
1
H NMR
(CDCl
3
): δ 1.85 (m, 1H), 1.92 (m, 1H), 2.13 (b, 1H), 2.75 (m, 1H), 2.91 (m, 1H),
3.74 (m, 1H), 5.63 (td, J = 56 Hz; 4.2 Hz, 1H), 7.20~7.35 (m, 5H).
13
C NMR
(CDCl
3
): δ 30.9; 31.5 (t, J = 3.3 Hz), 70.2 (t, J = 23.5 Hz), 116.3 (t, J = 244 Hz),
126.2, 128.4, 128.5, 140.9.
19
F NMR (CDCl
3
): δ –130.0 (dd, J = 56 Hz, 11 Hz).
MS (EI, m/z): 186 (M
+
), 168, 117, 91, 77. The data are consistent with the
previous report.
19

HO CF
2
H
4e

7-difluoromethyl-7-tridecanol (4e): 91 % yield, oily liquid.
1
H NMR (CDCl
3
): δ
0.88 (t, J = 7 Hz, 6 H), 1.29 (m, 16H), 1.54 (m, 4H), 1.83 (b, 1H), 5.59 (t, J = 56
Hz).
13
C NMR (CDCl
3
): δ 14.0, 22.5, 22.6, 29.8, 31.7, 33.5 (t, J = 2.3 Hz), 74.2 (t,

81
J = 20 Hz), 117.6 (t, J = 248 Hz).
19
F NMR (CDCl
3
): δ –133.2 (d, J = 56 Hz).
MS (EI, m/z): 250 (M
+
), 199, 165, 127, 97, 69. HRMS (EI): m/z calcd for
C
14
H
28
F
2
O (M
+
) 250.2064, found 250.2062.

CH
3
HO
CF
2
H
4f

1,1-Difluoro-2-phenyl-2-ethanol (4f): 79 % yield, colorless liquid.
1
H NMR
(CDCl
3
): δ 1.67 (m, 3H), 2.47 (b, 1H), 5.73 (td, J = 56 Hz, 1.5 Hz, 1H), 7.34~7.57
(m, 5H).
13
C NMR (CDCl
3
): δ 22.2 (t, J = 2.6 Hz), 74.2 (t, J = 22 Hz), 116.9 (t,
J = 250 Hz), 125.7 (t, J = 1.4 Hz), 128.1, 128.4, 140.2 (t, J = 1.6 Hz).
19
F NMR
(CDCl
3
): δ –130.0 (dd, J =278 Hz, 56 Hz, 1F), –130.9 (dd, J = 278 Hz, 57 Hz, 1F).
MS (EI, m/z): 172 (M
+
), 121, 109, 77.
22

4g
OH
CF
2
H

1-Difluoromethylcyclooctanol (4g): 88 % yield, colorless liquid.
1
H NMR
(CDCl
3
): δ 1.39~1.87 (m, 15H), 5.49 (td, J = 56 Hz, 1.7 Hz, 1H).
13
C NMR
(CDCl
3
): δ 20.8, 24.4, 27.9, 30.0 (t, J = 2.0 Hz), 74.4 (t, J = 19.7 Hz), 118.3 (t, J =

82
248 Hz).
19
F NMR (CDCl
3
): δ –132.5 (d, J = 56 Hz). MS (EI, m/z): 178 (M
+
),
127, 109, 81, 67.

OH
CF
2
H
4h

cis-4-tert-Butyl-1-difluoromethylcyclohexanol (4h): 85 % yield, white solid.
1
H
NMR (CDCl
3
): δ 0.87 (s, 9H), 0.94~1.74 (m, 9H), 3.48 (s, 1H), 5.45 (t, J = 56.7
Hz, 1H).
13
C NMR (CDCl
3
): δ 21.1, 27.5, 30.3, 32.4, 47.6, 71.3 (t, J = 21 Hz),
118.0 (t, J = 247 Hz).
19
F NMR (CDCl
3
): δ –134.2 (d, J = 57 Hz). MS (EI, m/z):
206 (M
+
), 173, 155, 131, 117, 81.

CF
2
H
OH
4i

trans-4-tert-Butyl-1-difluoromethylcyclohexanol (4i): 88 % yield, white solid.
1
H
NMR (CDCl
3
): δ 0.86 (s, 9H), 1.11~2.09 (m, 10H), 5.83 (t, J = 56 Hz, 1H).
13
C
NMR (CDCl
3
): δ 23.4, 27.5, 32.3, 33.6, 46.8, 71.2 (t, J = 19.5 Hz), 116.2 (t, J =
245 Hz).
19
F NMR (CDCl
3
): δ –134.2 (d, J = 57 Hz).
19
F NMR (CDCl
3
): δ
–135.9 (d, J = 56 Hz). MS (EI, m/z): 206 (M
+
), 173, 155, 131, 117, 81.

83

HO CF
2
H
4j

2,2-Difluoro-1,1-diphenylethanol (4j): 82 % yield, sticky liquid.
1
H NMR
(CDCl
3
): δ 2.88 (b, 1H), 6.24 (t, J = 55 Hz, 1H), 7.33~7.50 (m, 10H).
13
C NMR
(CDCl
3
): δ 78.0 (t, J = 20 Hz), 116.8 (t, J = 250 Hz), 127.0 (t, J = 1.7 Hz), 128.2,
128.3, 140.4.
19
F NMR (CDCl
3
): δ –135.9 (d, J = 56 Hz).
19
F NMR (CDCl
3
): δ
–128.2 (d, J = 56 Hz). MS (EI, m/z): 234 (M
+
), 183, 165, 152, 105, 77. The data
are consistent with the previous report.
23

HO
H
H
H
H
H
F
F
4K

3-Difluoromethyl-5 α-cholestan-3-ol (axial-CF
2
H) (4k): 89 % yield, white solid.
1
H NMR (CDCl
3
): δ 0.65~1.98 (m, 44H), 5.84 (t, J = 56 Hz, 1H).
13
C NMR
(CDCl
3
): δ 11.8, 12.0, 18.6, 21.2, 22.5, 22.8, 23.8, 24.1, 28.0, 28.2, 28.5, 29.0,
31.8, 35.1, 35.4, 35.6, 35.8, 36.1, 39.5, 39.9, 42.5, 54.2, 56.2, 56.4, 71.8 (t, J = 18

84
Hz), 116.2 (t, J = 245 Hz).
19
F NMR (CDCl
3
): δ –135.8 (dd, J = 280 Hz, 54 Hz,
1F), –136.4 (dd, J = 280 Hz, 58 Hz, 1F). MS (EI, m/z): 438 (M
+
). HRMS (EI):
m/z calcd for C
28
H
48
F
2
O (M
+
) 438.3673, found 438.3673.

H
H
H
H
4l H
F
F
HO

3-Difluoromethyl-5 α-cholestan-3-ol (equitorial-CF
2
H) (4l): 90 % yield, white
solid.
1
H NMR (CDCl
3
): δ 0.65~1.99 (m, 44H), 5.43 (t, J = 56 Hz, 1H).
13
C
NMR (CDCl
3
): δ 11.1, 12.1, 18.6, 20.9, 22.6, 22.8, 23.8, 24.2, 25.9, 28.0, 28.2,
28.4, 31.9, 32.4, 32.7, 35.4, 35.8, 35.9, 36.1, 39.4, 39.5, 39.9, 42.5, 53.9, 56.2,
56.4, 72.1 (t, J = 20 Hz), 117.8 (t, J = 246 Hz).
19
F NMR (CDCl
3
): δ –134.1 (dd, J
= 279 Hz, 56 Hz, 1F), –134.7 (dd, J = 279 Hz; 57 Hz, 1F). MS (EI, m/z): 438
(M
+
). HRMS (EI): m/z calcd for C
28
H
48
F
2
O

(M
+
) 438.3673, found 438.3679.

85
HO
H
H H
H
3
C
OH
CF
2
H
4m

20-Difluoromethylpregn-5-ene-3,20-diol (4m): yield 93 %, white solid.
1
H NMR
(CDCl
3
): δ 0.87 (s, 3H), 1.00 (s, 3H), 1.36 (s, 3H), 0.87~2.32 (m, 22 H), 3.52 (m,
1H), 5.35 (b, 1H), 5.49 (t, J = 57 Hz, 1H).
13
C NMR (CDCl
3
): δ 13.3, 19.4, 20.9,
21.6, 23.9, 31.2, 31.6, 31.7, 36.4, 37.2, 39.8, 42.2, 43.1, 49.9, 52.81, 52.84, 56.4,
71.7, 74.8 (t, J = 20 Hz), 116.7 (dd, J = 250 Hz, 247 Hz), 121.5, 140.7.
19
F
NMR (CDCl
3
): δ –129.7 (dd, J = 280 Hz, 58 Hz), –137.4 (dd, J = 280 Hz, 59 Hz).
MS (EI, m/z): 368 (M
+
). HRMS (EI): m/z calcd for C
22
H
34
F
2
O (M
+
) 368.2527,
found 368.2520.

86
3.5 Chapter 3 references

1. (a) Biomedical Aspects of Organofluorine Chemistry, R. Filler, Y.
Kobayashi, Eds. Kodansha and Elsevier Biomedical: Amsterdam, 1983. (b)
Erickson, J. A.; McKoughlin, J. I. J. Org. Chem. 1995, 60, 1626. (c) Sasson,
R.; Hagooly, A.; Rozen, S. Org. Lett. 2003, 5, 769.

2. (a) Synthetic Fluorine Chemistry, Olah, G. A.; Chambers, R. R.; Prakash, G.
K. S. Eds. Wiley-Interscience: New York, 1992. (b) Modern Fluoroorganic
Chemistry, Kirsch, P. Ed. Wiley-VCH: Weinheim, 2004. (c) Organofluorine
Compounds, Chemistry and Application, Hiyama, T. Ed. Springer: New
York, 2000.

3. (a) Prakash, G. K. S.; Krishnamurti, R.; Olah, G. A. J. Am. Chem. Soc. 1989,
111, 393. (b) Krishnamurti, R.; Bellew, D. R.; Prakash, G. K. S. J. Org.
Chem. 1991, 56, 984. (c) Prakash, G. K. S.; Yudin, A. K. Chem. Rev. 1997,
97, 757.

4. Hagiwara, T.; Fuchikami, T. Synlett 1995, 717.

5. Stahly, G. P. J. Fluorine Chem. 1989, 43, 53.

6. Yudin, A. K.; Prakash, G. K. S.; Deffieux, D.; Bradley, M.; R. Bau; Olah, G.
A. J. Am. Chem. Soc. 1997, 119, 1572.

7. Difluoromethyl phenyl sulfone can be readily prepared from PhSNa and
CF
2
HCl followed by simple oxidation. See: (a) Hine, J.; Porter, J. J. J. Am.
Chem. Soc. 1960, 82, 6178. (b) Langlois, B. R. J. Fluorine Chem. 1988, 41,
247. (c) reference [4].

8. Prakash, G. K. S.; Hu, J.; Mathew, T.; Olah, G. A. Angew. Chem. 2003, 115,
5374; Angew. Chem. Int. Ed. 2003, 42, 5216.

9. Prakash, G. K. S.; Hu, J.; Wang, Y.; Olah, G. A. Angew. Chem. 2004, 116,
5315; Angew. Chem. Int. Ed. 2004, 43, 5203.

10. Prakash, G. K. S.; Hu, J.; Olah, G. A. J. Org. Chem. 2003, 68, 4457.

11. Prakash, G. K. S.; Hu, J.; Wang, Y .; Olah, G. A. Org. Lett. 2004, 6, 4315.

87
12. Prakash, G. K. S.; Hu, J.; Olah, G. A. Org. Lett. 2003, 5, 3253.

13. LHMDS (97% purity) was obtained from the commercial source and used
without further purification. For the previous use of LHMDS, see: Gray, M.;
Snieckus, V. in Encyclopedia of Reagents for Organic Synthesis, R. A.
Paquette, Ed.; Wiley: New York, 1995, p 3127.

14. Sabol, J. S.; McCarthy, J. R. Tetrahedron Lett. 1992, 33, 3101.

15. Boger, D. L.; Jenkins, T. J. J. Am. Chem. Soc. 1996, 118, 8860.

16. Dykstra, R. B. in Encyclopedia of Reagents for Organic Synthesis, R. A.
Paquette, Ed. Wiley: New York, 1995, p 2668.

17. Sulfones in Organic Synthesis, Tetrahedron Organic Chemistry Series,
volume 10, J. E. Baldwin, P. D. Magnus, Eds. Pergamon: New York, 1993.

18. Trost, B. M.; Arndt, H. C.; Strege, P. E.; Verhoeven, T. R. Tetrahedron Lett.
1976, 17, 3477.

19. Kaneko, S.; Yamazaki, T.; Tomoya, T. J. Org. Chem. 1993, 58, 2302.

20. (a) Hagiwara, T.; Fuchigami, T. Synlett 1995, 717. (b) Prakash, G. K. S.;
Mandal, M.; Schweizer, S.; Petasis, N. A.; Olah, G. A. J. Org. Chem. 2002,
67, 3718.

21. Katazume, T.; Asai, M.; Tsukamoto, T.; Yamazaki, T. J. Fluorine Chem.
1992, 56, 271.

22. Fuchigami, T.; Hagiwara, T. JP 06040974, 1994.

23. Patrick, T. B.; Canrell, G. L.; Inga, S. M. J. Org. Chem. 1980, 45, 1409.

88
Chapter 4
Nucleophilic Reactions of Difluoromethyl Phenyl
Sulfone (PhSO
2
CF
2
H) with Imines

4.1 Introduction
Synthesis of fluorinated amines or imines is important because of their
attractive properties in biological and medicinal chemistry.
1
The strong
electronegativity of fluorine can lower amine’s basicity and improve oral
absorption, thus promotes the bioavailability of a target drug.
2
Two classes of
gem-difluoro compounds have attracted much attention towards the endeavor,
they are β-hydroxy- α, α-difluoroalkyl imines
3
and difluoromethyl amines.
4

gem-Difluoromethylene group (-CF
2
-) is isosteric and isopolar to an ethereal
oxygen atom (-O-) and compounds containing -CF
2
- group can mimic the ether in
biological system.
5
CF
2
H functionality is isosteric and isopolar to a carbinol
(CH
2
OH) unit, which can increase the molecule’s lipophilicity.
1(a), 4(a)
These two
types of fluorinated compounds have been applied as anticancer agents,
3(a)
HIV-1
protease inhibitors,
3(b)
agrochemical fungicides
6
and so on.
7

The methods to prepare β-hydroxy- α,α-difluoroalkyl imines have not been
well explored. Only Uneyama et al. reported two methods for the preparation of

89
β-hydroxy- α,α-difluoroalkyl imines: Mg-promoted double silylation of
trifluoroacetimidoyl chloride followed by Lewis acid-catalyzed C-C bond
formation with carbonyl compounds
8
and the electrochemical reactions of
trifluoromethyl imines with aldehydes.
9
Dolbier et al. reported
10
the
tetrakis(dimethylamino)ethylene (TDAE) based electrochemical reduction of
2-(bromodifluoromethyl)benzoxazole and other bromodifluoromethyl
heterocyclic with carbonyl compound to give β, β-difluoro- α-heteroarylated
alcohols.
A number of examples for the preparation of α-difluoromethyl amines have
been documented in the literature,
11
including the use of difluoromethyl carbonyl
compounds or their imine derivatives as precursors. Recently, our group
reported
12
a convenient way to prepare difluoromethyl amines via trifluoromethyl
trimethylsilane (TMSCF
3
). Hu et al.
13
reported highly stereoselective and facile
synthesis of α-difluoromethyl amines from chiral sulfinylimines and
difluoromethyl phenyl sulfone (PhSO
2
CF
2
H). Pey and Schirlin
14
reported the
multistep synthesis of α-difluoromethyl amines from substituted malonate esters
and CHF
2
Cl followed by a Curtius rearrangement. However, the nucleophilic
reaction between aldimines (N-unactivated imines) and PhSO
2
CF
2
H has not been
studied before. Herein, we report the successful nucleophilic substitution of
difluoromethyl phenyl sulfone with aldimines, which allows us to accomplish the

90
facile and efficient synthesis of β-hydroxy- α,α-difluoroalkyl imines and
α-difluoromethyl amines. (Scheme 4.1)
PhSO
2
CF
2
H (1)
3
R
1
N
R
2
H
H CF
2
SO
2
Ph
N
R
2
HO
H
R
R
1
F
F
RCHO
R
1
N
R
2
H
H CF
2
H
R
1
CH=NR
2

Scheme 4.1 Preparation of β-hydroxy- α,α-difluoro imines and difluoromethyl
amines

4.2 Results and discussion
4.2.1 Nucleophilic substitution reactions of PhSO
2
CF
2
H and aldimines
Nucleophilic addition reactions between 1 and aldimines were carried out
according to the following procedure. Under an argon atmosphere, the lithium
hexamethyldisilazide (LHMDS) in THF was added dropwise to the mixture of 1
and aldimines in THF/HMPA solution at -78 ºC. The reaction conditions were
carefully optimized by using different reactant ratios, solvents and reaction time,
and we found that the best product yields were obtained with the following
reaction conditions: 2 equiv. of LHMDS, 1 equiv. of sulfone (1) and 1.2 equiv. of
aldimines (2) in THF/HMPA were stirred at -78 °C for 1 hour. A variety of
(benzenesulfonyl)difluoromethylated amines (3) were prepared in good to
excellent yields as shown in Table 4.1. However, the reactions of PhSO
2
CF
2
H
with 2j and 2k did not work most probably because of the steric effects.

91
Table 4.1 Preparation of substituted difluoromethyl sulfones 3 from 1 (1 equiv.),
aldimines 2 (1.2 equiv.), and LHMDS (2 equiv) in THF/HMPA at -78 ºC for 1
hour.

PhSO
2
CF
2
Br (4) p-Br-C
6
H
4
N
Ph
H
2 equiv. TDAE, lamp light
1 equiv. 2 equiv.
-30 ° C, 1 hr and r.t., overnight
DMF
p-Br-C
6
H
4
N
Ph
H
H CF
2
SO
2
Ph
60%
+

Yield [%]
84
95
99
95
90
94
81
85
50
Imine 2 Product 3
p-Br-C
6
H
4
N
Ph
H
p-Br-C
6
H
4
N
Ph
H
H CF
2
SO
2
Ph
p-Cl-C
6
H
4
N
Ph
H
p-Cl-C
6
H
4
N
Ph
H
H CF
2
SO
2
Ph
p-F-C
6
H
4
N
Ph
H
p-F-C
6
H
4
N
Ph
H
H CF
2
SO
2
Ph
p,o-Cl
2
-C
6
H
3
N
Ph
H
p,o-Cl
2
-C
6
H
3
N
Ph
H
H CF
2
SO
2
Ph
o-F-C
6
H
4
N
Ph
H
o-F-C
6
H
4
N
Ph
H
H CF
2
SO
2
Ph
p-Me-C
6
H
4
N
Ph
H
p-Me-C
6
H
4
N
Ph
H
H CF
2
SO
2
Ph
p-MeO-C
6
H
4
N
Ph
H
p-MeO-C
6
H
4
N
Ph
H
H CF
2
SO
2
Ph
Ph N
C
6
H
4
-OMe-p
H
Ph N
C
6
H
4
-OMe-p
H
H CF
2
SO
2
Ph
c-C
6
H
11
-C
6
H
4
N
Ph
H
c-C
6
H
11
-C
6
H
4
N
Ph
H
H CF
2
SO
2
Ph
t-Bu N
Ph
H
Ph N
Ph
Me
a
b
c
d
e
f
g
h
i
j
k
a
b
c
d
e
f
g
h
i
a
Isolated yield.

92
It is worthwhile to mention that the TDAE based electrochemical reduction of
bromodifluoromethyl phenyl sulfone (PhSO
2
CF
2
Br, 4) with aldimines also gave
(benzenesulfonyl)difluoromethylated amines 3 (Scheme 4.2). After 2 equiv. of
TDAE was added to the mixture of 1 equiv. of 4 and 2 equiv. of imine in DMF at
-30 ºC, the reaction solution was stirred at this temperature for 1 hr and then at
room temperature overnight, which produced
(benzenesulfonyl)difluoromethylated amines in 60% yield.

PhSO
2
CF
2
Br (4)+ Ph N
Ph
H
4-Br-
2 equiv. TDAE, lamp light
1 equiv. 2 equiv.
-30 ° C, 1 hr and r.t., overnight
DMF
Ph N
Ph
H
H CF
2
SO
2
Ph
4-Br-
60%

Scheme 4.2 Reaction of PhSO
2
CF
2
Br with imine

The resulting (benzensulfonyl)difluoromethyl amines (3) are very useful
intermediates, which can be further converted into β-hydroxy- α,α-difluoro imines
and difluoromethyl amines. It provides easy, efficient and highly selective ways to
introduce -CF
2
- and -CF
2
H group into bioactive compounds.

4.2.2 Preparation of β-hydroxy- α, α-difluoroalkyl imines from 3
Due to the high acidity of α-hydrogen atom adjacent to the difluoromethylene
group, fluorinated amines 3 can easily undergo deprotonation in the presence of

93
base to generate a new carbanion species 5 (Scheme 4.3). Intermediate 5 readily
undergoes β-elimination to eliminate the benzenesulfonyl group (rather than a
fluorine atom) to afford difluoroenamines 6 since the benzenesulfonyl group is a
better leaving group than the fluoride
15
. The excess base will further deprotonate
the hydrogen atom attached to nitrogen in difluoroenamines 6 to give an
azaallylanion synthon 7, which undergoes nucleophilic addition reactions with
aldehydes to provide β-hydroxy- α,α-difluoroalkyl imines 8. We attempted to
obtain the intermediate 6 by only adding base to DMF solution of 3, but failed. It
appears that the compound 6 is unstable in the basic environment and may
undergo further deprotonation or other side reactions.
t-BuOK
-50 C °
F
2
C
HN
R
1
R
2
t-BuOK
F
2
C
N
R
1
R
2
F
2
C
N
R
1
R
2 RCHO
3
R
1
N
R
2
H
H CF
2
SO
2
Ph
5 6
N
R
2
H
PhSO
2
R
1
F
F
N
R
2
HO
H
R
R
1
F
F
7 8
-50 C °

Scheme 4.3 Proposed mechanism for the reaction between fluorinated amines 3
and aldehydes

Nucleophilic addition reactions between 3 and aldehydes were carried out
according to the following procedure. Under an argon atmosphere, the t-BuOK in

94
DMF was added dropwise to the mixture of 3 and aldehydes in DMF solution at
-50 ºC. After careful modification of the reaction conditions, we found that 1
equiv of 3, 2 equiv. of aldehydes and 4 equiv. of t-BuOK in DMF at -50 ºC for 1
hr are beneficial for this reaction. Various β-hydroxy- α, α-difluoroalkyl imines 8
were obtained in good yields (Table 4.2).

Table 4.2 Preparation of β-hydroxy- α,α-difluoroalkyl imines 8 from 3 (1 equiv.),
aldehydes (2 equiv.), and t-BuOK (4 equiv) in DMF at -50 ºC for 1 hour.

Yield [%]
79
72
65
+
t-BuOK
-50 C, 1 hr °
N
R
2
HO
H
R
R
1
Amine 3 Product 8
3
R
1
N
R
2
H
H CF
2
SO
2
Ph
RCHO
F
F
Aldehyde
p-Br-C
6
H
4
-CHO
p-Br-C
6
H
4
-CHO
p-Br-C
6
H
4
-CHO
PhCHO
PhCH=CH-CHO
80
50
N
Ph
HO
H
p-Br-C
6
H
4
C
6
H
4
-Br-p
F
F
N
Ph
HO
H
p-Br-C
6
H
4
C
6
H
4
-Cl-p
F
F
N
Ph
HO
H
p-Br-C
6
H
4
C
6
H
4
-Me-p
F
F
N
Ph
HO
H
Ph
C
6
H
4
-F-p
F
F
N
Ph
HO
H
PhCH=CH
C
6
H
4
-F-p
F
F
p-Br-C
6
H
4
N
Ph
H
H CF
2
SO
2
Ph
p-Cl-C
6
H
4
N
Ph
H
H CF
2
SO
2
Ph
a
b
p-Me-C
6
H
4
N
Ph
H
H CF
2
SO
2
Ph
f
p-F-C
6
H
4
N
Ph
H
H CF
2
SO
2
Ph
c
p-F-C
6
H
4
N
Ph
H
H CF
2
SO
2
Ph
c
a
b
c
d
e
a
Isolated yield.

95
4,4’-Dichlorobenzophenone was also subjected to the nucleophilic reactions
with 3, but no desired product was formed due to the high steric hindrance of the
ketone.
4.2.3 Preparation of α-difluoromethyl amines from 3
Reductive desulfonylations of (benzenesulfonyl)difluoromethylated alcohols
and alkanes have been reported previously by our group by using sodium/mercury
amalgam as the reducing reagent
16
. Such reaction conditions are also suitable for
the desulfonylations of (benzenesulfonyl)difluoromethylated amines.

Table 4.3 Reductive desulfonylation of fluorinated amines 3 using Na(Hg)
amalgam (10 wt. % Na in Hg, 5 equiv) and Na
2
HPO
4
(5 equiv) in methanol at –20
o
C.

Na/Hg
MeOH,
-20 C, 1hr °
90
Yield [%] Amine (3)Product (9)
95
R
1
N
R
2
H
H CF
2
SO
2
Ph
R
1
N
R
2
H
H CF
2
H
p-Br-C
6
H
4
N
Ph
H
p-Br-C
6
H
4
N
Ph
H
H CF
2
H
p-Cl-C
6
H
4
N
Ph
H
p-Cl-C
6
H
4
N
Ph
H
H CF
2
H
a
b
a
b
9 3

96
The desulfonylations of 3 were carried out with excellent yields by adding 5
equivalents 10% Na(Hg) amalgam into the solution of 1 equivalent 3 and 5
equivalents Na
2
HPO
4
(buffering agent) in methanol at -20 to -10 ºC and
maintained at this temperature for 1 hour. The results are shown in Table 4.3.

4.3 Conclusions
The nucleophilic reactions of difluoromethyl phenyl sulfone with aldimines
in the presence of LHMDS were carried out with excellent yields. The resulting
difluoromethyl amines are very useful synthetic precursors for the facile
preparation of β-hydroxy- α,α-difluoroalkyl imines and α-difluoromethyl amines.
The methodology provides convenient and efficient ways to introduce
gem-difluoromethylene building block and difluoromethyl group into bioactive
organic compounds.

4.4 Experimental section
Materials and instrumentation. Unless otherwise mentioned, all other
chemicals were purchased from commercial sources. THF was freshly distilled
over sodium. Difluoromethyl phenyl sulfone (1) was prepared using known
procedures.
17
Imines were prepared by condensation reactions of corresponding
aldehydes and anilines. Silica gel column chromatography was used to isolate the
products using 60-200 mesh silica gel (from J. T. Baker).
1
H,
13
C and
19
F NMR

97
spectra were recorded on 500 MHz or 400 MHz NMR spectrometer.
1
H NMR
chemical shifts were determined relative to the signal of a residual proton of the
solvent CDCl
3
δ 7.26.
13
C NMR chemical shifts were determined relative to the
13
C signal of solvent CDCl
3
δ 77.0.
19
F NMR chemical shifts were determined
relative to internal CFCl
3
at δ 0.0. Mass data were recorded on a GC-MS
spectrometer with a mass selective detector at 70 eV. High-resolution mass data
were recorded on a high-resolution mass spectrometer in the FAB mode.
Typical procedure for nucleophilic substitution reactions of PhSO
2
CF
2
H
and aldimines. Under an argon atmosphere, into a 50-mL Schlenk flask
containing N-[(4-bromophenyl)methylene]-benzenamine 2a (312 mg, 1.2 mmol)
and PhSO
2
CF
2
H

(192mg, 1 mmol) in THF 5 mL and HMPA 0.5 mL at -78 °C was
added dropwise a THF solution (3 mL) of LHMDS (334mg, 2 mmol). The
reaction mixture was then stirred vigorously at –78 °C for 1 h, followed by
quenching with 30 mL cold brine upon warming to 0 °C. The solution mixture
was extracted with Et
2
O (25 mL x 3), and the combined organic phase was dried
over MgSO
4
. After the removal of volatile solvents under vacuum, the crude
product was further purified by silica gel column chromatography (9: 1 hexane:
ethyl acetate as eluent) to give N-[1-(4-bromophenyl)-
2,2-difluoro-2-(phenylsulfonyl)ethyl]aniline 3a (380 mg, 84%) as a pale yellow
solid.
1
H NMR (CDCl
3
): δ 4.76 (d, J= 7.4 Hz, 1H), 5.35 (ddd,
3
J
H, F
= 21.4 Hz,
3
J
H, F
= 5.8 Hz,
3
J
H, H
= 7.4 Hz, 1H), 6.60 (d, J = 7.8 Hz, 2H), 6.80 (t, J = 7.8 Hz,

98
1H), 7.16 (t, J = 7.8 Hz, 2H), 7.36 (d, J = 8.2 Hz, 2H), 7.50 (d, J = 8.2 Hz, 2H),
7.58 (t, J = 7.8 Hz, 2H), 7.74 (t, J = 7.8 Hz, 1H), 7.98 (d, J = 7.8 Hz, 2H).
13
C
NMR (CDCl
3
): δ 58.1 (dd, J = 25.6 Hz, 20.6 Hz), 114.0, 119.4, 120.9 (dd, J =
298.0 Hz, 289.5 Hz), 123.4, 129.4, 130.2, 130.7, 132.0, 132.7, 133.2, 135.6, 144.7.
19
F NMR (CDCl
3
): δ -101.5 (d, J = 239.2 Hz, 1F), -114.8 (dd, J = 239.2 Hz, 21.4
Hz, 1F). MS (EI, m/z): 452 (M
+
), 260, 185, 93, 75. HRMS (FAB): m/z calcd for
C
20
H
17
BrF
2
NO
2
S(M
+
) 452.0131, found 452.0122.
N-[1-(4-chlorophenyl)-2,2-difluoro-2-(phenylsulfonyl)ethyl]aniline (3b):
white solid.
1
H NMR (CDCl
3
): δ 4.77 (d, J = 7.2 Hz, 1H), 5.37 (ddd,
3
J
F, H
= 21.2
Hz,
3
J
F, H
= 5.6 Hz,
3
J
H, H
= 7.2 Hz, 1H), 6.60 (d, J = 7.8 Hz, 2H), 6.80 (t, J = 7.8
Hz, 1H), 7.17 (t, J = 7.8 Hz, 2H), 7.34 (d, J = 8.4 Hz, 2H), 7.43 (d, J = 8.4 Hz,
2H), 7.58 (t, J = 7.6 Hz, 2H), 7.74 (t, J = 7.6 Hz, 1H), 7.98 (d, J = 7.6 Hz, 2H).
13
C NMR (CDCl
3
): δ 58.0 (dd, J = 25.6 Hz, 19.2 Hz), 114.0, 119.4, 120.8 (dd, J =
296.7 Hz, 289.9 Hz), 128.9, 129.2, 129.3, 129.8, 130.6, 132.1, 133.2, 135.1, 135.4,
144.6.
19
F NMR (CDCl
3
): δ -101.4 (dd, J = 240.7 Hz, 5.6 Hz, 1F), -114.8 (dd, J =
240.7 Hz, 21.2 Hz, 1F). MS (EI, m/z): 408.2 (M
+
), 277, 216, 185, 93. HRMS
(FAB): m/z calcd for C
20
H
15
ClF
2
NO
2
S(M
+
) 407.0558, found 407.0561.
N-[1-(4-fluorophenyl)-2,2-difluoro-2-(phenylsulfonyl)ethyl]aniline (3c):
white solid.
1
H NMR (CDCl
3
): δ 4.76 (d, J = 7.4 Hz, 1H), 5.38 (ddd,
3
J
H, F
= 21.1
Hz,
3
J
F,H
= 5.7 Hz,
3
J
H, H
= 7.4 Hz, 1H), 6.61 (d, J = 7.8 Hz, 2H), 6.79 (t, J = 7.8
Hz, 1H), 7.06 (t,
3
J
H,H
,
3
J
F,H
= 8.5 Hz, 2H), 7.16 (t, J = 7.8 Hz, 2H), 7.40 (dd,
3
J
H,H

99
= 8.5 Hz,
4
J
F,H
= 5.7 Hz, 2H), 7.58 (t, J = 7.6 Hz, 2H), 7.74 (t, J = 7.6 Hz, 1H),
7.98 (d, J = 7.6 Hz, 2H).
13
C NMR (CDCl
3
): δ 57.9 (dd, J = 25.4 Hz, 19.5 Hz),
114.0, 115.8 (d,
2
J
F, C
= 21.9 Hz), 119.3, 120.9 (dd, J = 297.1 Hz, 290.3 Hz),
129.2, 129.3, 130.2 (d,
3
J
F, C
= 8.5 Hz), 130.6, 133.3, 135.4, 144.7, 163.1 (d,
1
J
F, C

= 248.1 Hz).
19
F NMR (CDCl
3
): δ -101.4 (dd, J = 240.6 Hz, 5.7 Hz, 1F), -112.9
(m, 1F), -114.9 (dd, J = 240.3 Hz, 21.1 Hz, 1F). MS (EI, m/z): 392.3 (M+1
+
), 277,
201, 185, 93. HRMS (FAB): m/z calcd for C
20
H
17
F
3
NO
2
S (M
+
) 392.0932, found
392.0928.
N-[1-(2,4-dichlorophenyl)-2,2-difluoro-2-(phenylsulfonyl)ethyl]aniline (3d):
white solid.
1
H NMR (CDCl
3
): δ 4.80 (d, J = 7.4 Hz, 1H), 5.95 (ddd,
3
J
H, F
= 23.0
Hz,
3
J
F,H
= 2.7 Hz,
3
J
H, H
= 7.4 Hz, 1H), 6.55 (d, J = 7.8 Hz, 2H), 6.79 (t, J = 7.8
Hz, 1H), 7.16 (t, J = 7.8 Hz, 2H), 7.23 (dd, J = 8.5 Hz, 2.0 Hz, 1H), 7.44 (d, J =
2.0 Hz, 1H), 7.49 (d, J = 8.5 Hz, 1H), 7.59 (t, J = 7.8 Hz, 2H), 7.76 (t, J = 7.8 Hz,
1H), 8.00 (t, J = 7.9 Hz, 2H).
13
C NMR (CDCl
3
): δ 54.0 (dd, J = 26.2 Hz, 18.1
Hz), 113.7, 119.5, 120.9 (dd, J = 295.5 Hz, 289.6 Hz), 127.8, 129.3, 129.4, 129.5,
130.3, 130.5, 130.6, 133.0, 135.4, 135.5, 135.6, 144.2.
19
F NMR (CDCl
3
): δ
-102.0 (d, J = 242.4 Hz, 1F), -116.5 (dd, J = 242.4 Hz, 23.0 Hz, 1F). MS (EI,
m/z): 442.2 (M+1
+
), 250, 185, 93. HRMS (FAB): m/z calcd for C
20
H
16
Cl
2
F
2
NO
2
S
(M
+
) 442.0247, found 442.0263.
N-[1-(2-fluorophenyl)-2,2-difluoro-2-(phenylsulfonyl)ethyl]aniline (3e): pale
yellow solid.
1
H NMR (CDCl
3
): δ 4.62 (d, J = 8.8 Hz, 1H), 5.80 (ddd,
3
J
F, H
=

100
22.4 Hz,
3
J
F,H
= 4.7 Hz,
3
J
H, H
= 8.8 Hz, 1H), 6.64 (d, J = 7.7 Hz, 2H), 6.78 (t, J =
7.7 Hz, 1H), 7.06~7.22 (m, 4H), 7.32 (m, 1H), 7.47 (t, J = 7.4 Hz, 1H), 7.57 (t, J
= 7.6 Hz, 2H), 7.73 (t, J = 7.6 Hz, 1H), 7.98 (t, J = 7.6 Hz, 2H).
13
C NMR
(CDCl
3
): δ 52.2 (ddd, J = 27.0 Hz, 19.1 Hz, 2.4 Hz), 113.9, 115.7 (d, J = 22.1 Hz),
119.5, 120.9 (d, J = 13.6 Hz), 121.2 (dd, J = 295.7 Hz, 291.0 Hz), 124.6 (d, J =
3.5 Hz), 129.2, 129.3, 129.6 (d, J = 3.5 Hz), 130.6, 130.8 (d, J = 8.5 Hz), 133.5,
135.3, 144.4, 161.2 (d, J = 248.6 Hz).
19
F NMR (CDCl
3
): δ -102.3 (ddd,
2
J
F, F
=
240.7 Hz,
5
J
F, F
= 11.6 Hz,
3
J
H, F
= 4.7 Hz, 1F), -114.9 (dd,
2
J
F,F
= 240.7 Hz,
3
J
H, F

= 22.4 Hz,
5
J
F, F
= 7.6 Hz 1F), -117.8 (m, 1F). MS (EI, m/z): 392.3 (M+1
+
), 200,
185, 93. HRMS (FAB): m/z calcd for C
20
H
17
F
3
NO
2
S (M
+
) 392.0932, found
392.0943.
N-[1-(4-methylphenyl)-2,2-difluoro-2-(phenylsulfonyl)ethyl]aniline (3f): pale
yellow solid.
1
H NMR (CDCl
3
): δ 2.35 (s, 3H), 4.72 (d, J = 7.6 Hz, 1H), 5.41
(ddd,
3
J
F, H
= 21.6 Hz,
3
J
F, H
= 5.1 Hz,
3
J
H, H
= 7.6 Hz, 1H), 6.67 (d, J = 7.3 Hz,
2H), 6.80 (t, J = 7.3 Hz, 1H), 7.19 (m, 4H), 7.39 (d, J = 7.0 Hz, 2H), 7.57 (t, J =
7.1 Hz, 2H), 7.72 (t, J = 7.1 Hz, 1H), 8.00 (d, J = 7.1 Hz, 2H).
13
C NMR (CDCl
3
):
δ 21.1, 58.1 (dd, J = 25.4 Hz, 18.9 Hz), 114.0, 119.0, 121.3 (dd, J = 295.9 Hz,
289.6 Hz), 128.3, 129.1, 129.2, 129.4, 130.4, 130.5, 133.5, 135.2, 138.9, 144.9.
19
F NMR (CDCl
3
): δ -101.5 (dd, J = 239.6 Hz, 5.1 Hz, 1F), -114.8 (dd, J = 239.6
Hz, 21.6 Hz, 1F). MS (EI, m/z): 388.3 (M+1
+
), 277, 185, 93. HRMS (FAB): m/z
calcd for C
21
H
20
F
2
NO
2
S (M
+
) 388.1183, found 388.1198.

101
N-[1-(4-methoxyphenyl)-2,2-difluoro-2-(phenylsulfonyl)ethyl]aniline (3g):
pale yellow solid.
1
H NMR (CDCl
3
): δ 3.77 (s, 3H), 4.68 (d, J = 7.6 Hz, 1H), 5.35
(ddd,
3
J
F, H
= 21.7 Hz,
3
J
F, H
= 5.7 Hz,
3
J
H, H
= 7.6 Hz, 1H), 6.63 (d, J = 7.5 Hz,
2H), 6.78 (t, J = 7.5 Hz, 1H), 6.89 (d, J = 8.2 Hz, 2H), 7.16 (t, J = 7.5 Hz, 2H),
7.39 (d, J = 8.2 Hz, 2H), 7.56 (t, J = 7.5 Hz, 2H), 7.72 (t, J = 7.5 Hz, 1H), 7.98 (d,
J = 7.5 Hz, 2H).
13
C NMR (CDCl
3
): δ 55.1, 57.9 (dd, J = 25.5 Hz, 18.8 Hz),
114.0, 114.1, 119.0, 121.2 (dd, J = 295.9 Hz, 289.2 Hz), 125.3, 129.1, 129.2,
129.6, 130.5, 133.6, 135.2, 144.9, 160.1.
19
F NMR (CDCl
3
): δ -101.5 (dd, J =
239.6 Hz, 5.7 Hz, 1F), -114.7 (dd, J = 239.6 Hz, 21.7 Hz, 1F). MS (EI, m/z):
404.3 (M+1
+
), 277, 185, 93. HRMS (FAB): m/z calcd for C
21
H
20
F
2
NO
3
S (M
+
)
404.1132, found 404.1128.
N-[1-phenyl-2,2-difluoro-2-(phenylsulfonyl)ethyl]-4-methoxyaniline (3f): pale
yellow solid.
1
H NMR (CDCl
3
): δ 3.70 (s, 3H), 4.43 (d, J = 7.8 Hz, 1H), 5.31
(ddd,
3
J
F, H
= 21.8 Hz,
3
J
F, H
= 5.3 Hz,
3
J
H, H
= 7.8 Hz, 1H), 6.60 (d, J = 8.9 Hz,
2H), 6.73 (d, J = 8.9 Hz, 2H), 7.35 (m, 3H), 7.45 (d, J = 6.5 Hz, 2H), 7.56 (t, J =
7.6 Hz, 2H), 7.71 (t, J = 7.6 Hz, 1H), 7.98 (d, J = 7.6 Hz, 2H).
13
C NMR (CDCl
3
):
δ 55.5, 59.4 (dd, J = 25.4 Hz, 18.7 Hz), 114.7, 115.7, 121.4 (dd, J = 296.0 Hz,
289.7 Hz), 128.4, 128.6, 129.0, 129.1, 130.5, 133.69, 133.72, 135.2, 138.8, 153.2.
19
F NMR (CDCl
3
): δ -100.9 (dd, J = 239.9 Hz, 5.3 Hz, 1F), -114.8 (dd, J = 239.9
Hz, 21.8 Hz, 1F). MS (EI, m/z): 404.3 (M+1
+
), 213, 185, 137. HRMS (FAB): m/z
calcd for C
21
H
19
F
2
NO
3
S (M
+
) 403.1054, found 403.1054.

102
N-[1-cyclohexyl-2,2-difluoro-2-(phenylsulfonyl)ethyl]aniline (3g): pale
yellow solid.
1
H NMR (CDCl
3
): δ 1.04~1.20 (m, 2H), 1.23~1.39 (m, 4H),
1.61~1.82 (m, 5H), 3.71 (d, J = 10.9 Hz, 1H), 4.40 (m, 1H), 6.60 (d, J = 8.9 Hz,
2H), 6.66 (d, J = 7.8 Hz, 2H), 6.76 (t, J = 7.8 Hz, 1H), 7.19 (t, J = 7.8 Hz, 2H),
7.51 (t, J = 7.8 Hz, 2H), 7.68 (t, J = 7.8 Hz, 1H), 7.88 (d, J = 7.8 Hz, 2H).
13
C
NMR (CDCl
3
): δ 25.8, 25.9, 26.2, 30.9, 39.2, 57.6 (dd, J = 22.4 Hz, 18.1 Hz),
113.4, 118.5, 123.5 (dd, J= 294.9 Hz, 293.5 Hz), 129.0, 129.2, 130.3, 134.0,
134.9, 146.6.
19
F NMR (CDCl
3
): δ -104.1 (dd, J = 236.3 Hz, 9.4 Hz, 1F), -114.8
(dd, J = 236.3 Hz, 19.0 Hz, 1F). MS (EI, m/z): 380.3 (M+1
+
), 277, 225, 185, 93.
HRMS (FAB): m/z calcd for C
20
H
24
F
2
NO
2
S (M
+
) 380.1496, found 380.1506.
Typical procedure for nucleophilic reactions of
(benzenesulfonyl)difluoromethylated amines 3 and aldehydes. Under an argon
atmosphere, into a 50-mL Schlenk flask containing
N-[1-(4-bromophenyl)-2,2-difluoro-2-(phenylsulfonyl)ethyl]aniline 3a (452 mg, 1
mmol) and 4-bromobenzylaldehyde

(370 mg, 2 mmol) in DMF 3 mL at -50 °C
was added dropwise a DMF solution (2 mL) of t-BuOK (224 mg, 2 mmol). The
reaction mixture was then stirred vigorously at –50 °C for 2 h, followed by
quenching with 30 mL cold brine upon warming to 0 °C. The solution mixture
was extracted with Et
2
O (25 mL x 3), and the combined organic phase was dried
over MgSO
4
. After the removal of volatile solvents under vacuum, the crude
product was further purified by silica gel column chromatography (9: 1 hexane:

103
ethyl acetate as eluent) to give 4-bromo- α-[1,1-difluoro-2-phenylimino]-
2-[4-bromophenyl]-benzenemethanol 8a (292 mg, 65%) as a pale yellow solid.
1
H
NMR (CDCl
3
): δ 4.48 (d, J = 4.3 Hz, 1H), 5.47 (dt,
3
J
H, F
= 19.7 Hz,
3
J
H, F
,
3
J
H, H

= 4.3 Hz, 1H), 6.71 (d, J = 7.8 Hz, 2H), 6.98 (d, J = 7.8 Hz, 2H), 7.09 (t, J = 7.8
Hz, 1H), 7.23 (t, J = 8.1 Hz, 2H), 7.38 (d, J = 8.1 Hz, 2H), 7.44 (d, J = 8.4 Hz,
2H), 7.55 (d, J = 8.4 Hz, 2H).
13
C NMR (CDCl
3
): δ 73.9 (dd, J = 29.3 Hz, 24.7
Hz), 115.8 (dd, J = 254.5 Hz, 248.7 Hz), 120.8, 122.9, 124.5, 125.7, 129.0, 129.8,
130.0, 130.3, 131.3, 131.6, 134.4, 146.4, 164.5 (t, J = 32.2 Hz).
19
F NMR (CDCl
3
):
δ -102.9 (d, J = 292.0 Hz, 1F), -113.9 (dd, J = 292.0 Hz, 19.7 Hz, 1F). MS (EI,
m/z): 496.3 (M+1
+
), 392, 277, 185, 93. HRMS (FAB): m/z calcd for
C
21
H
16
Br
2
F
2
NO (M
+
) 493.9567, found 493.9562.
4-Bromo- α-[1,1-difluoro-2-phenylimino]-2-[4-chlorophenyl]-benzenemethanol
(8b), pale yellow solid.
1
H NMR (CDCl
3
): δ 4.54 (d, J = 4.3 Hz, 1H), 5.47 (dt,
3
J
H,
F
= 18.0 Hz,
3
J
H, F
,
3
J
H, H
= 4.3 Hz, 1H), 6.71 (d, J = 8.0 Hz, 2H), 7.03~7.13 (m,
3H), 7.19~7.28 (m, 4H), 7.44 (d, J = 8.4 Hz, 2H), 7.54 (d, J = 8.4 Hz, 2H).
13
C
NMR (CDCl
3
): δ 73.9 (dd, J = 29.5 Hz, 24.6 Hz), 115.9 (dd, J = 254.5 Hz, 245.5
Hz), 120.8, 122.8, 125.6, 128.6, 129.0, 129.2, 130.0, 130.1, 131.3, 134.5, 136.1,
146.5, 164.5 (t, J = 32.2 Hz).
19
F NMR (CDCl
3
): δ -102.9 (d, J = 290.0 Hz, 1F),
-113.9 (dd, J= 290.0 Hz, 18.0 Hz, 1F). MS (EI, m/z): 452.4 (M+1
+
), 392, 277, 185.
HRMS (FAB): m/z calcd for C
21
H
16
BrClF
2
NO (M
+
) 450.0072, found 450.0093.

104
4-Bromo- α-[1,1-difluoro-2-phenylimino]-2-[4-methylphenyl]-benzenemethanol
(8c), pale yellow solid.
1
H NMR (CDCl
3
): δ 2.28 (s, 3H), 4.83 (d, J = 4.3 Hz, 1H),
5.46 (dt,
3
J
H, F
= 18.1 Hz,
3
J
H, F
,
3
J
H, H
= 4.3 Hz, 1H), 6.75 (d, J = 7.9 Hz, 2H),
7.00~7.10 (m, 5H), 7.22 (t, J = 8.1 Hz, 2H), 7.46 (d, J = 8.1 Hz, 2H), 7.54 (d, J =
8.1 Hz, 2H).
13
C NMR (CDCl
3
): δ 21.3, 74.1 (dd, J = 29.3 Hz, 24.7 Hz), 115.9
(dd, J = 254.9 Hz, 248.7 Hz), 120.9, 122.7, 125.3, 127.8, 128.7, 128.8, 128.9,
130.0, 131.2, 134.7, 140.1, 146.9, 165.8 (t, J = 32.0 Hz).
19
F NMR (CDCl
3
): δ
-102.7 (d, J = 290.7 Hz, 1F), -113.7 (dd, J = 290.7 Hz, 18.0 Hz, 1F). MS (EI,
m/z): 430.3 (M
+
), 246, 185, 93. HRMS (FAB): m/z calcd for C
22
H
19
BrF
2
NO (M
+
)
430.0618, found 430.0611.
α-[1,1-difluoro-2-phenylimino]-2-[4-fluorophenyl]-benzenemethanol (8d),
pale yellow solid.
1
H NMR (CDCl
3
): δ 4.46 (br. s, 1H), 5.50 (dd,
3
J
H, F
= 17.8 Hz,
3
J
H, F
= 4.0 Hz, 1H), 6.71 (d, J = 8.6 Hz, 2H), 6.90 (t, J = 8.6 Hz, 2H), 7.03~7.08
(m, 3H), 7.22 (t, J = 7.6 Hz, 2H), 7.38~7.45 (m, 3H), 7.57 (d, J = 7.6 Hz, 2H).
13
C
NMR (CDCl
3
): δ 74.6 (dd, J = 28.8 Hz, 24.9 Hz), 115.4 (d, J = 21.7 Hz), 116.2
(dd, J = 253.6 Hz, 248.7 Hz), 120.8, 125.4, 126.6, 128.1, 128.3, 128.7, 128.9,
131.0 (d, J = 8.5 Hz), 135.5, 146.8, 163.1 (d, J = 251.9), 164.9 (t, J = 31.7 Hz).
19
F NMR (CDCl
3
): δ -103.2 (dd, J = 287.0 Hz, 4.0 Hz, 1F), -109.9 (m, 1F), -113.0
(dd, J = 287.0 Hz, 17.8 Hz, 1F). MS (EI, m/z): 356.3 (M+1
+
), 281, 246, 185, 154,
137, 123. HRMS (FAB): m/z calcd for C
21
H
17
F
3
NO (M
+
) 356.1262, found
356.1272.

105
α-[1,1-difluoro-2-phenylimino]-2-[4-fluorophenyl]-styrylmethanol (8e), pale
yellow solid.
1
H NMR (CDCl
3
): δ 4.10 (d, J = 6.0 Hz, 1H), 5.05 (m, 1H), 6.42 (dd,
J = 15.6 Hz, 6.0 Hz, 1H), 6.70 (d, J = 7.6 Hz, 2H), 6.92 (d, J = 15.8 Hz, 1H), 6.96
(t, J = 8.0 Hz, 2H), 7.06 (t, J = 8.0 Hz, 1H), 7.17~7.24 (m, 4H), 7.29 (t, J = 7.5 Hz,
1H), 7.35 (t, J = 7.5 Hz, 2H), 7.45 (d, J = 7.5 Hz, 2H).
13
C NMR (CDCl
3
): δ 73.7
(t, J = 28.0 Hz), 115.6 (d, J = 21.9 Hz), 116.4 (dd, J = 252.4 Hz, 249.4 Hz), 120.8,
123.1 (t, J = 2.6 Hz), 125.4, 126.7, 126.8, 128.1, 128.6, 128.9, 131.1 (d, J = 8.5
Hz), 134.7, 136.2, 146.7, 163.2 (d, J = 251.3), 164.3 (dd, J = 33.0 Hz, 30.6 Hz).
19
F NMR (CDCl
3
): δ -103.8 (dd, J = 288.6 Hz, 6.0 Hz, 1F), -109.8 (m, 1F), -113.0
(dd, J = 288.6 Hz, 15.6 Hz, 1F).
Typical procedure for reductive desulfonylation of
(benzenesulfonyl)difluoromethylated amines 3. In a 50-mL Schlenk flask with
argon protection, N-[1-(4-bromophenyl)-2,2-difluoro-2-(phenylsulfonyl)ethyl]
aniline 3a (136 mg, 0.3 mmol) and Na
2
HPO
4
(298 mg, 2.1 mmol) in 5 mL
anhydrous methanol were added in. After the solution was cooled to -20 ºC,
Na/Hg amalgam (10 wt.% Na in Hg, 483 mg, 2.1 mmol) was added. The reaction
mixture was stirred at -20 to 0 ºC for 1 hr. Then the solution was diluted with 30
mL Et
2
O and the liquid was decanted from the solid. After evaporating the solvent
of the liquid phase by rotary evaporator, 30 mL saturated NaCl solution was
added, which was then extracted by Et
2
O three times. The combined ether
solution was dried over MgSO
4
and the solvent was removed to give pure product

106
N-(1-(4-bromophenyl)-2,2-difluoroethyl)aniline 9a (84 mg, 90% yield) as pale
yellow oil.
1
H NMR (CDCl
3
): δ 4.41 (br. s, 1H), 4.69 (m, 1H), 5.98 (td, J = 55.5
Hz, 2.9 Hz, 1H), 6.58 (d, J = 7.8 Hz, 2H), 6.77 (t, J = 7.8 Hz, 1H), 7.16 (t, J = 7.8
Hz, 2H), 7.32 (d, J = 8.2 Hz, 2H), 7.52 (d, J = 8.2 Hz, 2H).
13
C NMR (CDCl
3
): δ
59.7 (t, J = 22.1 Hz), 113.9, 115.2 (t, J = 247.6 Hz), 119.0, 122.6, 129.3, 129.4,
132.0, 134.3, 145.5.
19
F NMR (CDCl
3
): δ -126.3 (ddd, J = 281.3 Hz, 55.5 Hz,
13.3 Hz, 1F), -127.0 (ddd, J = 281.3 Hz, 55.5 Hz, 13.3 Hz, 1F). The data are
consistent with the previous report.
13
N-(1-(4-chlorophenyl)-2,2-difluoroethyl)aniline (9b), pale yellow oil.
1
H
NMR (CDCl
3
): δ 4.39 (br. s, 1H), 4.70 (m, 1H), 5.99 (td, J = 55.5 Hz, 2.9 Hz, 1H),
6.59 (d, J = 7.6 Hz, 2H), 6.77 (t, J = 7.6 Hz, 1H), 7.16 (t, J = 7.6 Hz, 2H), 7.37 (m,
4H).
13
C NMR (CDCl
3
): δ 59.6 (t, J = 22.2 Hz), 113.9, 115.3 (t, J = 246.8 Hz),
119.0, 129.0, 129.1, 129.3, 133.7, 134.5, 145.6.
19
F NMR (CDCl
3
): δ -126.3 (ddd,
J = 281.0 Hz, 55.5 Hz, 13.3 Hz, 1F), -127.0 (ddd, J = 281.0 Hz, 55.5 Hz, 13.3 Hz,
1F). The data are consistent with the previous report.
13

107
4.5 Chapter 4 references

1. (a) Kirsch, P. Modern Fluoroorganic Chemistry: Synthesis, Reactivity,
Application, Wiley-VCH: Weinheim, 2004. (b) Welch, J. T. The effects of
Selective Fluorination on Reactivity in Organic and Bioorganic Chemistry,
ACS Symposium Series 456, American Chemical Society: Washington, DC,
1991. (c) Ojima, I.; McCarthy, J. R.; Welch, J. T. Biomedical Frontiers of
Fluorine Chemistry, ACS: Washington DC, 1996.

2. (a) McCarthy, J. R. Fluorine in Drug Design: A Tutorial Review, 17
th
Winter
Fluorine Conference (St Pete Beach, Florida, USA), January 9-14, 2005. (b)
Rowley, M.; Hallett, D. J.; Goodacre, S.; Moyes, C.; Crawforth, J.; Sparey, T.
J.; Patel, S.; Marwood, R.; Patel, S.; Thomas, S.; Hitzel, L.; O’Connor, D.;
Szeto, N.; Castro, J. L.; Huston, P. H.; Macleod, A. M. J. Med. Chem. 2001,
44, 1603. (c) van Niel, M. B.; Collins, I.; Beer, M. S.; Broughton, H. B.;
Cheng, S. K. F.; Goodacre, S. C.; Heald, A.; Locker, K. L.; MacLeod, A. M.;
Morrison, D.; Moyes, C. R.; O’Connor, D.; Pike, A.; Rowley, M.; Russell,
M. G. N.; Sohal, B.; Stanton, J. A.; Thomas, S.; Verrier, H.; Watt, A. P.;
Castro, J. L. J. Med. Chem. 1999, 42, 2087.

3. (a) Chou, T. S.; Heath, P. C.; Patterson, L. E.; Poteet, L. M.; Lakin, R. E.;
Hunt, A. H. Synthesis, 1992, 6, 565. (b) Schirlin, D.; Baltzer, S.; Van
Dorsselaer, V.; Weber, F.; Weill, C.; Altenburger, J. M.; Neises, B.; Flynn,
G.; Remy, J. M.; Tarnus, C. Bioorg. & Med. Chem. Lett. 1993, 3, 253.

4. (a) Erickson, J. A.; McLoughlin, J. I. J. Org. Chem. 1995, 60, 1626. (b)
Moore, W. R.; Schatzman, G. L.; Jarvi, E. T.; Gross, R. S.; McCarthy, J. R. J.
Am. Chem. Soc. 1992, 114, 360.

5. Hiyama, T. Organofluorine Compounds: Chemistry and Applications,
Springer: New York, 1992.

6. Dunkel, R.; Elbe, H.; Greal, J. N.; Hartmann, B.; Gayer, H.; Seitz, T.;
Wachendorff-Neumann, U.; Dahmen, P.; Kuck, K. DE 102004041530, 2006.

7. Selnick, H. G.; Barrow, J. C.; Nantermet, P. G.; Williams, P. D.; Stauffer, K.
J.; Sanderson, P. E.; Rittle, K. E.; Morrissette, M. M.; Wiscount, C. M.; Tran,
L. O.; Lyle, T. A.; Staas, D. D. WO 2002050056 2002.

8. Kobayashi, T.; Nakagawa, T.; Amii, H.; Uneyama, K. Org. Lett. 2003, 5,
4297.

108

9. Uneyama, K.; Maeda, K.; Kato, T.; Katagiri, T. Novel Trends in
Electroorganic Synthesis [Papers presented at the international Symposium
on Electroorganic Synthesis], 3
rd
(Kurashiki, Japan), Sept. 24-27, 1997, 301.

10. Burkholder, C. R.; Dolbier, W. R. Jr.; Médebielle, M. J. of Fluorine Chem.
2001, 109, 39.

11. (a) Kaneko, S.; Yamazaki, T.; Kitazume, T.; J. Org. Chem. 1993, 58, 2302.
(b)Abe, H.; Amii, H.; Uneyama, K. Org. Lett. 2001, 3, 313. (c) Fustero, S.;
Navarro, A.; Pina, B.; Soler, J. G.; Bartolome, A.; Asensio, A.; Simon, A.;
Bravo, P.; Fronza, G.; V olonterio, A.; Zanda, M. Org. Lett. 2001, 3, 2621. (d)
Volonterio, A.; Vergani, B.; Crucianelli, M.; Zanda, M. J. Org. Chem. 1998,
63, 7236. (e) Funabiki, K.; Nagamori, M.; Goushi, S.; Matsui, M. Chem.
Commun. 2004, 1928.

12. Prakash, G. K. S.; Mogi, R.; Olah, G. A. Org. Lett. 2006, 8, 3589.

13. Li, Y. Hu, J. Angew. Chem. Int. Ed. 2005, 44, 5882.

14. Pey, P.; Schirlin, D. Tetrahedron Lett. 1978, 19, 5225.

15. Sulfones in Organic Synthesis, Tetrahedron Organic Chemistry Series,
volumn 10, Baldwin, J. E.; Magnus, P. D., Eds. Pergamon: New York, 1993.

16. (a) Prakash, G. K. S.; Hu, J.; Wang, Y.; Olah, G. A. Org. Lett. 2004, 6, 4315.
(b) Prakash, G. K. S.; Hu, J.; Wang, Y .; Olah, G. A. Eur. J. Org. Chem. 2005,
2218.

17. (a) Hine, J.; Porter, J. J. J. Am. Chem. Soc. 1960, 82, 6178. (b) Stahly, G. P. J.
Fluorine Chem. 1989, 43, 53. (c) Langlois, B. R. J. Fluorine Chem. 1988,
41, 247.

109
Chapter 5
Nucleophilic Reactions of Bromodifluoromethyl Phenyl
Sulfone (PhSO
2
CF
2
Br) with Aldehydes

5.1 Introduction
As discussed before, gem-difluorinated compounds, such as difluoromethyl
alcohols and 1,1 difluoro-1-alkenes, are highly useful for pharmaceutical or
agrochemical applications, since the difluoromethylene functionality (-CF
2
-) is
known to be an isostere and isopolar to an oxygen atom.
1
Difluoromethyl group
(CF
2
H) can act as both a lipophilic isostere of hydroxyl or hydroxymethyl group
and a hydrogen donor through hydrogen bonding,
2
while gem-difluorovinyl
functionality can act as a bioisostere for aldehydes and ketones
3
with a different
reaction path. Many functionalized difluoromethyl compounds and
1,1-difluoro-1-alkenes are used as enzyme inhibitors,
4
pesticides,
5
among others.
Moreover, 1,1-difluoro-1-alkenes can be further converted into different
fluorinated compounds and polymers.
6
Thus, the development of effective ways
for the preparation of these two classes of gem-difluorinated compounds is of
great significance. Recently, we have reported methods
7
using a difluoromethyl
phenyl sulfone as a synthon under highly basic conditions for this purpose.

110
Bromodifluoromethyl phenyl sulfone (PhSO
2
CF
2
Br) was first synthesized by
Burton and coworkers in 1981,
8
however, its synthetic application has scarcely
been explored. Recently, we have reported the use of bromodifluoromethyl phenyl
sulfone for the preparation of fluroalkylsilanes.
9
Tetrakis(dimethylamino)-
ethylene (TDAE), as an efficient reductant to generate substituted
difluoromethylated carbanions from halo-difluoromethyl precursors, has been
reported by Dolbier and coworkers.
10
However, the reaction between TDAE and
bromodifluoromethyl phenyl sulfone to generate (benzenesulfonyl)difluoromethyl
anion (PhSO
2
CF
2
-
), has not been reported yet. In this chapter, we describe the
efficient TDAE-mediated nucleophilic reactions between bromodifluoromethyl
phenyl sulfone (1) and aldehydes (2). The resulting
(benzensulfonyl)difluoromethyl alcohols (3) can be further transformed into
difluoromethyl alcohols (4) and 1,1-difluoro-1-alkenes (6) via reductive
desulfonylation and Julia olefination, respectively

(Scheme 5.1).
11

PhSO
2
CF
2
Br RCHO +
DMF
OH
R
H
CF
2
SO
2
Ph
OH
R
H
CF
2
H
RCH=CF
2
Me
2
NNMe
2
NMe
2
Me
2
N
+
TDAE
- 30
o
C ~ RT
Reductive
desulfonylation
Julia-Olefination
12
3
5
4

Scheme 5.1 Difluoromethylation of aldehydes using 1.

111
5.2 Results and discussion
5.2.1 Nucleophilic reactions between PhSO
2
CF
2
Br and aldehydes
Nucleophilic addition reactions between 1 and 2 were carried out according to
the following procedure. Under an argon atmosphere, the TDAE was added
dropwise to the mixture of 1 and 2 in DMF solution under 60W sun lamp
irradiation. The reaction conditions were carefully optimized by using different
reactant ratios, reaction temperatures and light intensities, and we found the best
product yields can be obtained with the following reaction conditions: 2.2 equiv.
of TDAE, 2.2 equiv. of sulfone (1) and 1.0 equiv. of aldehyde (2) in DMF were
stirred under the sun lamp at -30 °C for 1 hour and then at room temperature for 6
hours. A variety of (benzenesulfonyl)difluoromethylated alcohols (3) were
prepared in moderate to good yields as shown in Table 5.1. However, the
reactions of 1/TDAE system with ketones gave very poor yields of products
(10~30%) because of steric problems.

112
Table 5.1 Nucleophilic (benzenesulfonyl)difluoromethylation of aldehydes using
PhSO
2
CF
2
Br/TDAE in DMF at -30 °C ~ RT under sun-lamp irradiation.

Entry Aldehyde 2 Product 3 Yield
a
a
b
c
d
e
f
g
h
i
Ph H
O OH
CF
2
SO
2
Ph
Ph
H
74%
Ph H
O
Ph H
CF
2
SO
2
Ph
HO
40%
Ph H
O
Ph H
CF
2
SO
2
Ph
HO
53%
p-ClC
6
H
4
H
O
OH
CF
2
SO
2
Ph
p-ClC
6
H
4 H
65%
p-BrC
6
H
4
H
O
OH
CF
2
SO
2
Ph
p-BrC
6
H
4 H
55%
CHO
HO
CF
2
SO
2
Ph
H
70%
CHO
HO
CF
2
SO
2
Ph
H
82%
CHO
Cl
HO
CF
2
SO
2
Ph
H
Cl
57%
CHO
HO
CF
2
SO
2
Ph
H
80%
a
Isolated yields

113
The mechanism of this reaction is proposed in Scheme 5.2, which is similar to
the early reports.
10
Initially, an orange-red charge-transfer complex is formed
between 1 and TDAE. Then two electrons from TDAE is transferred to
bromodifluoromethyl phenyl sulfone to generate (benzenesulfonyl)difluoromethyl
anion (PhSO
2
CF
2
-
) and Br
-
. (Benzenesulfonyl)difluoromethyl anion undergoes
further addition to aldehydes to give (benzenesulfonyl)difluoromethyl alcohols 3.
Here the sun lamp irradiation is necessary for inducing the electron transfer from
TDAE to 1.
PhSO
2
CF
2
Br + TDAE
PhSO
2
CF
2

-
+ Br
-
+ TDAE
2+
PhSO
2
CF
2

-
+ RCHO
-
O

CF
2
SO
2
Ph
R
H
-
O

CF
2
SO
2
Ph
R
H
+ H
+
HO
CF
2
SO
2
Ph
R
H
sun lamp

Scheme 5.2. Mechanism of nucleophilic reaction of aldehydes with
PhSO
2
CF
2
Br/TDAE reagent

The resulting (benzenesulfonyl)difluoromethyl alcohols are very useful
intermediates, which can be further converted into various fluorinated materials.
12

Two types of reactions of the difluoromethyl alcohols were carried out to
demonstrate the utility of alcohols: the reductive desulfonylation to give
difluoromethyl compounds 4 and the Julia olefination to give
1,1-difluoro-1-alkenes 6. The results are outlined in Scheme 5.3.

114

HO
CF
2
SO
2
Ph
R
H
HO
CF
2
H
R
H
1. MsCl, Et
3
N, CH
2
Cl
2
2. 10% Na(Hg), Na
2
HPO
4
, MeOH
F
F
H
R
10% Na(Hg), Na
2
HPO
4
, MeOH
3
4
6

Scheme 5.3 Reductive desulfonylation and Julia olefination of 3.

5.2.2 Reductive desulfonylation of (benzenesulfonyl)difluoromethyl alcohols
3
Reductive desulfonylations of 3 were completed to give difluoromethyl
alcohols 4 in good yields by using 5 equiv. 10% Na(Hg) amalgam and 5 equiv. of
Na
2
HPO
4
in methanol at -20 ~ -10 °C over 1 hour. The results of desulfonylations
are shown in Table 5.2.

115
Table 5.2 Desulfonylation of (benzenesulfonyl)difluoromethyl alcohols 3 using
Na(Hg) amalgam

HO
CF
2
SO
2
Ph
R
H
+
10% Na(Hg)
7 eq. Na
2
HPO
4
MeOH
-20 C ~ -10 C
1 eq.
7 eq.
HO
CF
2
H
R
H
1 hr
° °
3
4

Entry Carbinol 3 Product 4
Yield [%]
a
a
b
c
OH
CF
2
SO
2
Ph
Ph
H
OH
CF
2
H
Ph
H
79
Ph H
CF
2
SO
2
Ph
HO
Ph H
CF
2
H
HO
84
Ph H
CF
2
SO
2
Ph
HO
Ph H
CF
2
H
HO
86
a
Isolated Yields

5.2.3 Julia-olefination of (benzenesulfonyl)difluoromethyl alcohols 3
Julia-type olefination of 3 were also successfully achieved to give
1,1-difluoro-1-alkenes 6 in good yields. First, the alcohols were converted into the
mesylates by using 2 equiv. of MsCl, 4 equiv. of Et
3
N, and catalytic amount of
4-dimethylaminopyridine (DMAP) in CH
2
Cl
2
at 0 °C over 2 hours. Then the
mesylates underwent the reductive elimination to give 1,1-difluoro-1-alkenes 5 by
treatment with 6 equiv. of 10% Na(Hg), 4 equiv. of Na
2
HPO
4
in CH
3
OH at -40 ~
0 °C for 1 hour. The Julia olefinations of (benzenesulfonyl)difluoromethyl

116
alcohols (3) are more difficult than that of the alcohols without fluorine atoms
because the high electronegativity of fluorine atoms in the carbanion intermediate
make it easier to undergo the protonation to form difluoromethyl compounds 4.
From the
19
F NMR spectrum of the reaction mixture, we can see that both the
1,1-difluoro-1-alkenes and the difluoromethyl alcohols are formed. Thus the
choice of the right leaving group becomes very important for the elimination of
these (benzenesulfonyl)difluoromethyl alcohol derivatives. We explored acetate
(Ac), tosylate (Ts), triflate, and mesylate groups as the protecting groups for the
alcohol, and found that the mesylates were the best for the further reductive
elimination to give 1,1-difluoro-1-alkenes 6. This suggests that neither the good
leaving groups such as the triflate (-OSO
2
CF
3
) and tosylate (-OSO
2
C
6
H
4
CH
3
) nor
the relatively stable leaving group such as acetate (OAc) were suitable for this
olefination protocol. This can be surmised by considering that reactive leaving
groups can be easily displaced before the desulfonylation step and making further
reductive elimination difficult, while the stable leaving group is difficult to be
removed in the reductive elimination of the carbanion intermediate, resulting in
the formation of difluoromethyl compounds. Considering the protonation
side-reaction, we also tried SmI
2
as the reducing agent
11
in the reductive
elimination step to avoid using the protic solvent MeOH, which is necessary in
Na(Hg) reduction. However, the result was not ideal and other undesired products
were formed rather than the expected alkenes. Finally, we optimized the

117
Julia-Olefination reaction of (benzenesulfonyl)difluoromethyl alcohols with the
OMs group as the leaving group and the Na(Hg) as the reducing reagent for the
elimination step. The results are listed in Table 5.3.
Table 5.3 Julia-Olefination reactions of (benzenesulfonyl)difluoromethyl
alcohols 3

HO
CF
2
SO
2
Ph
R
H
1 eq.
2 eq. MsCl
4 eq. Et
3
N, cat. DMAP
CH
2
Cl
2
, 0 C, 1 hr °
R
CF
2
SO
2
Ph
O
H
SO
2
CH
3 6 eq. 10% Na(Hg)
4 eq. Na
2
HPO
4
, MeOH
-40 C ~ 0 C, 1 hr ° °
F
F
H
R
3
6
1 eq.
5

Entry Carbinol 3
Yield [%]
a
RCH=CF
2
6
a
c
e
OH
CF
2
SO
2
Ph
Ph
H
PhCH=CF
2
Ph H
CF
2
SO
2
Ph
HO
Ph(CH
2
)
2
CH=CF
2
60
84
OH
CF
2
SO
2
Ph
p-BrC
6
H
4 H
p-BrC
6
H
4
CH=CF
2
70
a
Isolated Yields

5.3 Conclusions
The nucleophilic reactions of bromodifluoromethyl phenyl sulfone with
aldehydes in the presence of TDAE were completed successfully. The resulting
difluoromethyl alcohols are very useful intermediates, which can either undergo
reductive desulfonylation to give difluoromethyl alcohols or undergo
Julia-Olefination to give 1,1-difluoro-1-alkenes in good yields. The methodology

118
provides convenient and efficient ways to introduce the difluoromethyl group and
1,1-difluorovinyl functionality into the organic compounds.

5.4 Experimental section
Materials and instrumentation. Unless otherwise mentioned, all chemicals
were purchased from commercial sources. Bromodifluoromethyl phenyl sulfone 1
was prepared using known procedures.
8
CH
2
Cl
2
was distilled over calcium
hydride. Silica gel column chromatography was used to isolate the products using
60-200 mesh silica gel.
1
H,
13
C, and
19
F NMR spectra were recorded on either a
400 MHz or 360 MHz NMR spectrometer.
1
H NMR chemical shifts were
determined relative to the signal of a residual proton of solvent CDCl
3
δ 7.26 or
acetone-d
6
δ 2.04.
13
C NMR chemical shifts were determined relative to the
13
C
signal of solvent: CDCl
3
δ 77.0 or Acetone-d
6
δ 29.8.
19
F NMR chemical shifts
were determined relative to internal CFCl
3
at δ 0.0. High-resolution mass data of
low boiling compounds were recorded on a GC chromatograph with micromass
GCT (time of flight) mass spectrometer. Other high-resolution mass data were
recorded on a high-resolution mass spectrometer in the EI mode.
Typical procedure for nucleophilic reactions of 1 with aldehydes. Under
an argon atmosphere, bromodifluoromethyl phenyl sulfone 1 (600 mg, 2.2 mmol),
5 mL DMF, and benzaldehyde (106.1 mg, 1 mmol) were added into a dry Schlenk
flask and contents were cooled to -30 °C. After stirring the mixture for 15 min,

119
TDAE (440 mg, 2.2 mmol) was added in dropwise. Under the irradiation of sun
lamp, the reaction mixture was stirred at -30 °C for 1 hour and then at room
temperature for 6 hours. The completion of the reaction was monitored by
19
F
NMR. The resulting orange-red solution was filtered and the solid was washed
with 100 mL ether. After the ether layer was separated from the DMF layer, the
DMF layer was hydrolyzed with 50 mL brine and extracted by ether (20 mL × 3).
Then the combined ether layer was washed by brine five times and dried over
magnesium sulfate. After removing the solvent by a rotary evaporator, the crude
product was further purified by silica gel column chromatography (first hexane:
ethyl acetate = 7: 1, then hexane: ethyl acetate = 1: 1) to give pure
2-Benzenesulfonyl-2, 2-difluoro-1-phenylethanol (3a) (221 mg, 74% yield) as a
colorless crystal.
1
H NMR (CDCl
3
): δ 3.92 (d, J = 4.4 Hz, 1H), 5.60 (dd, J = 21
Hz, 3.0 Hz, 1H), 7.36 (m, 3H), 7.48 (m, 2H), 7.56 (t, J = 8 Hz, 2H), 7.70 (t, J = 8
Hz, 1H), 7.98 (d, J = 8 Hz, 2H).
19
F NMR (CDCl
3
): δ –104.4 (dd, J = 238 Hz, 3
Hz, 1F), –119.9 (dd, J = 238 Hz, 21 Hz, 1F). MS (EI, m/z): 298 (M
+
), 156, 140,
127, 107, 77. The data are consistent with the previous report.
12

(E)-1-Benzenesulfonyl-1,1-difluoro-4-phenyl-3-buten-2-ol (3b): 40% yield,
white solid.
1
H NMR (CDCl
3
): δ 3.07 (d, J = 5.5 Hz, 1H), 5.15 (m, 1H), 6.25
(dd, J = 15.8 Hz, 6.7 Hz, 1H), 6.89 (d, J = 15.8 Hz, 1H), 7.29~7.43 (m, 5H),
7.63(t, J = 8 Hz, 2H), 7.77 (t, J = 8 Hz, 1H), 8.00 (d, J = 8 Hz, 2H).
13
C NMR
(CDCl
3
): δ 70.8 (dd, J = 23 Hz, 21 Hz), 120.3 (dd, J = 293 Hz, 290 Hz), 120.3 (t,

120
J = 2.3 Hz), 126.9, 128.5, 128.6, 129.3, 130.6, 132.8, 135.5, 135.6, 136.4.
19
F
NMR (CDCl
3
): δ –107.0 (dd, J = 237 Hz, 6 Hz, 1F), –116.6 (dd, J = 237 Hz, 17
Hz, 1F). MS (EI, m/z): 324 (M
+
), 207, 133, 115, 105, 77. HRMS (EI): m/z calcd
for C
16
H
14
F
2
O
3
S (M
+
) 324.0632, found 324.0642.
1-(Benzenesulfonyl)difluoromethyl-3-phenylpropanol (3c): 53% yield,
colorless liquid.
1
H NMR (CDCl
3
): δ 2.09 (m, 2H), 2.77 (m, 1H), 2.97 (m, 1H),
3.05 (b, 1H), 4.45 (m, 1H), 7.22~7.34 (m, 5H), 7.62 (t, J = 8 Hz, 2H), 7.77 (t, J =
8 Hz, 1H), 8.00 (d, J = 8 Hz, 2H).
13
C NMR (CDCl
3
): δ 30.9 (b, 2C), 68.6 (dd, J =
24 Hz, 20 Hz), 121.2 (dd, J = 294 Hz, 292 Hz), 126.2, 128.4, 128.5, 129.3, 130.5,
132.7, 135.5, 140.5.
19
F NMR (CDCl
3
): δ –109.2 (dd, J = 238 Hz, 6 Hz, 1F),
–116.9 (dd, J = 238 Hz, 19 Hz, 1F). MS (EI, m/z): 326 (M
+
), 308, 167, 143, 104,
91, 77. HRMS (EI): m/z calcd for C
16
H
16
F
2
O
3
S (M
+
) 326.0788, found 326.0795.
4-Chloro-[difluoro(phenylsulfonyl)methyl]-benzenemethanol (3d): 65% yield,
white solid.
1
H NMR (CDCl
3
): δ 3.46 (s, 1H); 5.57 (dd, J = 21 Hz, 2.3Hz, 1H),
7.35 (d, J = 8.4 Hz, 2H), 7.42 (d, J = 8.4 Hz, 2H), 7.62 (t, J = 8.1 Hz, 2H), 7.78 (t,
J = 8.1 Hz, 1H), 7.99 (d, J = 8.1 Hz, 2H).
13
C NMR (CDCl
3
): δ 70.6 (dd, J = 26
Hz, 20 Hz), 119.8 (dd, J = 299 Hz, 290 Hz), 128.6, 129.38, 129.41, 130.6, 131.9,
132.3, 135.5, 135.7.
19
F NMR (CDCl
3
): δ -104.6 (d, J = 241 Hz, 1F), -119.8 (dd, J
= 241 Hz, 21 Hz, 1F). MS (EI, m/z): 332 (M
+
), 143, 141, 77.
4-Bromo-[difluoro(phenylsulfonyl)methyl]-benzenemethanol (3e): 55% yield,
light yellow solid.
1
H NMR (CDCl
3
): δ 3.57 (s, 1H), 5.55 (dd, J = 21 Hz, 2.3 Hz,

121
1H), 7.35 (d, J = 8.4 Hz, 2H), 7.51 (d, J = 8.4 Hz, 2H), 7.62 (t, J = 8.2 Hz, 2H),
7.77 (t, J = 8.2 Hz, 1H), 7.99 (d, J = 8.2 Hz, 2H).
13
C NMR (CDCl
3
): δ 70.6 (dd, J
= 26 Hz, 20 Hz), 119.8 (dd, J = 300 Hz, 290 Hz), 123.7, 129.4, 129.7, 130.6,
131.6, 135.7.
19
F NMR (CDCl
3
): δ -104.6 (d, J = 236 Hz, 1F), -119.7 (dd, J = 236
Hz, 21 Hz, 1F). MS (EI, m/z): 376 (M
+
), 306, 235, 218, 185, 157, 136, 125, 106,
94. HRMS (EI): m/z calcd for C
14
H
11
O
3
SF
2
Br (M
+
) 375.9580, found 375.9577.
α-[(Benzenesulfonyl)difluoromethyl]-1-naphthalenemethanol (3f): 70% yield,
white solid.
1
H NMR (CDCl
3
): δ 3.72 (d, J = 4.2 Hz, 1H), 5.77 (ddd, J = 21.6 Hz,
4.2 Hz, 2.9 Hz, 1H), 7.48-7.60 (m, 5H), 7.71 (t, J = 7.4 Hz, 1H), 7.81-7.87 (m,
3H), 7.95-8.03 (m, 3H).
13
C NMR (CDCl
3
): δ 71.3 (dd, J = 26.4 Hz, 19.7 Hz),
120.3 (dd, J = 299 Hz, 290 Hz), 124.9, 126.3, 126.7, 127.6, 128.0, 128.18, 128.21,
129.3, 130.6, 131.0, 132.6, 132.8, 133.7, 135.5.
19
F NMR (CDCl
3
): δ -104.0 (d, J
= 239 Hz, 1F), -119.2 (dd, J = 239 Hz, 21.6 Hz, 1F). MS (EI, m/z): 348 (M
+
), 157,
129, 77.
α-[(Benzenesulfonyl)difluoromethyl]-9-anthracenemethanol (3g): 82% yield,
yellow solid.
1
H NMR (CDCl
3
): δ 3.63 (d, J = 4.2 Hz, 1H), 7.33 (dd, J = 26.9 Hz,
4.2 Hz, 1H), 7.4-9.1 (m, 14H).
13
C NMR (CDCl
3
): δ 67.8 (dd, J = 28.4 Hz, 20.0
Hz), 121.5 (dd, J = 305 Hz, 289 Hz), 122.6, 123.8, 124.8, 125.0, 126.0, 127.3,
128.9, 129.4, 130.67, 130.75, 132.3, 135.7.
19
F NMR (CDCl
3
): δ -101.9 (d, J =
237 Hz, 1F), -113.6 (ddd, J = 237 Hz, 26.9 Hz, 4.2 Hz, 1F). MS (EI, m/z): 398
(M
+
), 207, 179, 178, 77.

122
α-[(Benzenesulfonyl)difluoromethyl]-10-chloro-9-anthracenemethanol (3h):
57% yield, yellow solid.
1
H NMR (CDCl
3
): δ 3.69 (d, J = 4.3 Hz, 1H), 7.35 (dd, J
= 26.6 Hz, 4.3 Hz, 1H), 7.4-9.1 (m, 13H).
13
C NMR (CDCl
3
): δ 67.7 (dd, J = 27.9
Hz, 19.6 Hz), 121.3 (dd, J = 305 Hz, 289 Hz), 122.9, 123.7, 125.2, 126.0, 126.2,
126.5, 127.5, 129.4, 130.8, 132.0, 132.7, 135.8.
19
F NMR (CDCl
3
): δ -101.8 (d, J
= 237 Hz, 1F), -113.3 (ddd, J = 237 Hz, 26.6 Hz, 4.3 Hz, 1F). MS (EI, m/z): 432
(M
+
), 243, 241, 240, 212, 178, 176, 77.
α-[(Benzenesulfonyl)difluoromethyl]-1-Pyrenemethanol (3i): 80% yield,
yellow solid.
1
H NMR (CD
3
COCD
3
): δ 6.18 (d, J = 6.2 Hz 1H), 6.80 (ddd, J =
21.7 Hz, 6.2 Hz, 3.4 Hz, 1H), 7.71 (t, J = 8.0 Hz, 2H), 7.84 (t, J = 7.6 Hz, 1H),
8.0~8.4 (m, 11H).
13
C NMR (CD
3
COCD
3
): δ 67.9 (dd, J = 27.9 Hz, 19.6 Hz),
122.8 (dd, J = 299 Hz, 287 Hz), 123.5, 125.1, 125.2, 125.6, 126.3, 126.6, 127.1,
127.3, 128.2, 128.9, 129.0, 130.00, 130.05, 130.2, 131.3, 131.4, 132.1, 132.6,
135.4, 136.2.
19
F NMR (CD
3
COCD
3
): δ -102.7 (d, J = 239 Hz, 1F), -116.6 (dd, J
= 239 Hz, 21.7 Hz, 1F). MS (EI, m/z): 422 (M
+
), 231, 203, 202, 77.
Typical procedure for reductive desulfonylation. In a 50-mL Schlenk flask
with argon protection, 2-benzenesulfonyl-2, 2-difluoro-1-phenylethanol (3a) (150
mg, 0.5 mmol) and Na
2
HPO
4
(497 mg, 3.5 mmol) in 10 mL anhydrous methanol
were added in. After the solution was cooled to -20 °C, Na/Hg amalgam (10 wt.
% Na in Hg, 805 mg, 3.5 mmol) was added. The reaction mixture was stirred at
-20 °C ~ 0 °C for 1.5 h. Then the solution was diluted with Et
2
O and the liquid

123
was decanted from the solid. After removing the solvent of the liquid phase by
rotary evaporator, 30 mL saturated NaCl solution was added, which was then
extracted by Et
2
O three times. The combined ether solution was dried with
MgSO
4
and the solvent was removed to give pure product
2,2-difluoro-1-phenylethanol (4a) (62 mg, 79% yield) as a white solid.
1
H NMR
(CDCl
3
): δ 2.44 (b, 1H), 4.82 (td, J = 10.5 Hz, 4.8 Hz, 1H), 5.77 (td, J = 56.4 Hz,
4.8 Hz, 1H), 7.41 (m, 5H).
13
C NMR (CDCl
3
): δ 73.6 (t, J = 20.0 Hz), 115.8 (t, J
= 245.9 Hz), 127.1, 128.6, 129.0, 135.8 (t, J = 3.7 Hz).
19
F NMR (CDCl
3
): δ
-127.8 (ddd, 284.8 Hz, 56.4 Hz, 10.5 Hz, 1F), -128.3 (ddd, 284.8 Hz, 56.4 Hz,
10.5 Hz, 1F). MS (EI, m/z): 158 (M
+
), 107, 79, 77. The data are consistent with
the previous report.
13

1-Benzenesulfonyl-1,1-difluoro-3-buten-2-ol (4b): 84% yield, colorless liquid.
1
H NMR (CDCl
3
): δ 2.71 (b, 1H), 4.42 (m, 1H), 5.69 (td, J= 56 Hz, 4.6 Hz, 1H),
6.18 (dd, J = 16 Hz, 6.4 Hz, 1H), 6.76 (d, J = 16 Hz, 1H), 7.24~7.41 (m, 5H).
13
C
NMR (CDCl
3
): δ 72.1 (t, J = 24.5 Hz), 115.4 (t, J = 245 Hz), 122.4 (t, J = 4 Hz),
126.7, 128.4, 128.6, 134.8, 135.7.
19
F NMR (CDCl
3
): δ -128.7 (ddd, J = 285 Hz,
56 Hz, 11 Hz, 1F), -129.6 (ddd, J = 285 Hz, 56 Hz, 11 Hz, 1F). MS (EI, m/z): 184
(M
+
), 133, 115, 77. The data are consistent with the previous report.
14

1,1-Difluoro-4-phenyl-2-butanol (4c): 86% yield, colorless liquid.
1
H NMR
(CDCl
3
): δ 1.85 (m, 1H), 1.92 (m, 1H), 2.13 (b, 1H), 2.75 (m, 1H), 2.91 (m, 1H),
3.74 (m, 1H), 5.63 (td, J = 56 Hz, 4.2 Hz, 1H), 7.20~7.35 (m, 5H).
13
C NMR

124
(CDCl
3
): δ 30.9, 31.5 (t, J = 3.3 Hz), 70.2 (t, J = 23.5 Hz), 116.3 (t, J = 244 Hz),
126.2, 128.4, 128.5, 140.9.
19
F NMR (CDCl
3
): δ -130.0 (dd, J = 56 Hz, 11 Hz).
MS (EI, m/z): 186 (M
+
), 168, 117, 91, 77. The data are consistent with the
previous report.
13

Typical procedure for Julia-olefination of 3. A solution of 3a (150 mg,
0.5 mmol) and 4-dimethylaminopyridine (DMAP) (catalytic amount) in 5 mL
CH
2
Cl
2
under Ar was cooled to 0 °C and treated with Et
3
N (0.28 mL, 2 mmol).
After stirring for 20 min, methanesulfonyl chloride (0.08 mL, 1 mmol) was added
dropwise and the reaction mixture was stirred at 0 °C for 2 hr. The reaction
mixture was quenched by buffer solution and extracted with EtOAc (3 × 25 mL).
The combined organic solution was washed by brine (2 × 25 mL) and dried over
MgSO
4
. After removing the solvent, the crude product was purified by column
chromatography (9: 1 hexane: EtOAc) to give mesylate 5a 169 mg, 90% yield.
1
H
NMR (CDCl
3
): δ 3.06 (s, 3H), 6.26 (dd, J = 16.5 Hz, 6.7 Hz, 1H), 7.44 (m, 3H),
7.53 (d, J = 7.8 Hz, 2H), 7.61 (t, J = 7.8 Hz, 2H), 7.76 (t, J = 7.8 Hz, 1H), 7.97 (d,
J = 7.8 Hz, 2H).
19
F NMR (CDCl
3
): δ -105.5 (dd, J = 243.0 Hz, 6.7 Hz, 1F),
-113.2 (dd, J = 243 Hz, 16.5 Hz, 1F). MS (EI, m/z): 376.1 (M
+
), 185, 140, 107, 77.
The mesylate 5a (100mg, 0.27 mmol) in anhydrous MeOH (5 mL) was cooled to
-40 °C and treated with Na
2
HPO
4
(151 mg, 1.06 mmol) and 10% Na(Hg) (368 mg,
1.60 mmol). After stiring for 1 hr at -20 °C, the reaction mixture was diluted with
30 mL EtOAc and decanted from the solid Hg residue. The organic solution was

125
washed by brine 30 mL and the brine was extracted with EtOAc (3 × 25 mL). The
combined organic solution was dried over MgSO
4
, condensed by reduced
pressure and purified by column chromatography (20: 1 Hexane: EtOAc) to give
2,2-difluoroethenylbenzene (6a) 22 mg, 60% yield as colorless liquid.
19
F NMR
(CDCl
3
): δ -82.9 (dd, J = 33 Hz, 27.4 Hz, 1F), -84.8 (d, J = 33 Hz, 1F). The
characterization data is consistent with those reported earlier.
15

Mesylate (5c): 87% yield, white solid.
1
H NMR (CDCl
3
): δ 3.20 (s, 3H), 5.46
(m, 1H), 7.29 (m, 3H), 7.37 (t, J = 7 Hz, 2H), 7.68 (t, J = 8 Hz, 2H), 7.85 (t, J = 8
Hz, 1H), 8.01 (d, J = 8 Hz, 2H).
13
C NMR (CDCl
3
): δ 30.7, 31.1, 39.1, 76.2 (dd, J
= 26.0 Hz, 20.4 Hz), 119.5 (dd, J = 286.0 Hz, 283.2 Hz), 126.4, 128.5, 128.6,
129.5, 130.7, 132.2, 135.9, 139.6.
19
F NMR (CDCl
3
): δ -107.2 (d, J = 243 Hz, 1F);
-110.0 (d, J = 243 Hz, 1F).
Mesylate (5e): 86% yield, light yellow solid.
1
H NMR (CDCl
3
): δ 3.14 (s,
3H), 6.22 (dd, J = 16.2 Hz, 6.8 Hz, 1H), 7.41 (d, J = 8.3 Hz, 2H), 7.57 (d, J = 8.3
Hz, 2H), 7.62 (t, J = 7.5 Hz, 2H), 7.78 (t, J = 7.5 Hz, 1H), 7.96 (d, J = 7.5 Hz, 2H).
19
F NMR (CDCl
3
): δ -105.6 (d, J = 243 Hz, 1F), -113.3 (d, J = 243 Hz, 1F).
(4,4-Difluoro-3-butenyl)-benzene (6c): 84% yield, colorless liquid.
19
F NMR
(CDCl
3
): δ -89.6 (d, J = 49 Hz, 1F), -91.6 (dd, J = 49 Hz, 28 Hz, 1F). The
characterization data is consistent with those reported earlier.
16

126
1-Bromo-4-(2,2-difluoroethenyl)-benzene (6e): 70% yield, colorless liquid.
19
F NMR (CDCl
3
): δ -81.7 (dd, J = 30.1 Hz, 26.2 Hz, 1F), -83.6 (d, J = 30.1 Hz,
1F). The characterization data is consistent with those reported earlier.
17

127
5.5 Chapter 5 references

1. Filler, R.; Kobayashi, Y. Biomedical Aspects of Organofluorine Chemistry,
Kodansha and Elsevier Biomedical: Amsterdam, 1983.

2. (a) Erickson, J. A.; McLoughlin, J. I. J. Org. Chem. 1995, 60, 1626. (b)
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Modern Fluoroorganic Chemistry: Synthesis, Reactivity, Application,
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3. Motherwell, W. B. Jr.; Tozer, M. J.; Ross, B. C. J. Chem. Soc., Chem. Comm.
1989, 19, 1437.

4. (a) Chen, Y.; Freskos, J. N.; Gasiecki, A. F.; Grapperhaus, M. L.; Hansen, D.
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J. Org. Chem. 2004, 69, 4203. (e) McCarthy, J. R. Utility of Fluorine in
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of Selective Fluorination on Reactivity in Organic and Bioorganic Chemistry,
ACS Symposium Series 456, American Chemical Society, Washington, DC
1991.

5. (a) Otaka, K.; Oohira, D.; Takaoka, D. WO 2004006677, 2004. (b) Markl,
M.; Schaper, W.; Ort, O.; Jakobi, H.; Braun, R.; Krautstrunk, G.; Sanft, U.;
Bonin, W.; Stark, H.; Pasenok, S.; Cabrera, I. WO 2000007998, 2000
[Chem. Abstr. 2000, 132, 166248]. (c) Abe, T.; Tamai, R.; Tamaru, M.; Yano,
H.; Takahashi, S.; Muramatsu, N. WO 2003042153, 2003 [Chem. Abstr.
2003, 138, 401741]. (d) Abe, T.; Tamai, R.; Ito, M.; Tamaru, M.; Yano, H.;
Takahashi, S.; Muramatsu, N. WO 2003029211, 2003 [Chem. Abstr. 2003,
138, 304304]. (e) Fuji, K.; Hatano, Y.; Tsutsumiuchi, K.; Nakahon, Y. JP
2000086636, 2000 [Chem. Abstr. 2000, 132, 222532].

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6. Liebman, J. F.; Greenberg, A.; Dolbier, W. R. Jr. Fluorine-containing
Molecules: Structure, Reactivity, Synthesis and Applications, VCH: New
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7. (a) Prakash, G. K. S.; Hu, J.; Wang, Y.; Olah, G. A. Org. Lett. 2004, 6, 4315
and the references therein; (b) Prakash, G. K. S.; Hu, J.; Wang, Y.; Olah, G.
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2218 and the references therein.

8. Burton, D. J.; Wiemers, D. M. J. Fluorine Chem. 1981, 18, 573.

9. Prakash, G. K. S.; Hu, J.; Olah, G. A. J. Org. Chem. 2003, 68, 4457.

10. (a) A їt-Mohand, S.; Takechi, N.; Médebielle, M.; Dolbier, W R. Jr. Org. Lett.
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Tetrahedron Lett. 1997, 38, 821. (d) Burkholder, C.; Dolbier, W. R. Jr.;
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W. R. Jr.; Médebielle, M. J. Fluorine Chem. 2001, 109, 39.

11. (a) Otaka, K.; Oohira, D.; Takaoka, D. WO 2004006677, 2004. (b) Markl,
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129
Chapter 6
Fluoride-Induced Nucleophilic Reactions of
[Difluoro(phenylthio)methyl]trimethylsilane
(TMSCF
2
SPh) with Carbonyl Compounds

6.1 Introduction
Recently, the selective introduction of difluoro(arylthio)methyl or
difluoro(heteroarylthio)methyl group (ArSCF
2
) into organic molecules has been
found to be attractive, since these compounds have potential biological
applications such as anti-HIV-1 reverse transcriptase inhibitors and other
agrochemical intermediates.
1
The currently known methods to construct the
ArSCF
2
moiety are based on the S
RN
1 reactions between an aryl- or
heteroarylthiolate (ArSNa) and a halodifluoromethyl-containing compounds
(halo= Br, Cl).
1
To our best knowledge, there is no synthetic method available so
far for the direct introduction of a difluoro(arylthio)methyl (ArSCF
2
) building
block into organic molecules.
In 1989, Prakash and co-workers developed the first general and efficient
nucleophilic trifluoromethylation method using (trifluoromethyl)trimethylsilane
(TMS–CF
3
).
2
With a similar protocol, fluoride-induced nucleophilic
chlorodifluoromethylation with TMS–CF
2
Cl, (trimethylsilyl)difluoromethylation

130
with TMSCF
2
TMS, and perfluorovinylation with TMSCF
2
CF
2
TMS have been
previously developed in our laboratory.
3
Herein, we would like to disclose
another nucleophilic fluoroalkylation methodology in this category, using
[difluoro(phenylthio)methyl]trimethylsilane (TMS–CF
2
SPh) as the nucleophilic
(phenylthio)difluoromethylating reagent.

6.2 Results and discussion
[Difluoro(phenylthio)methyl]trimethylsilane (TMS–CF
2
SPh) was prepared for
the first time as a high-boiling and reasonably stable liquid (bp 86~87
o
C/4
mmHg), using the Barbier coupling reaction of bromodifluoromethyl phenyl
sulfide (1), magnesium metal and chlorotrimethylsilane (TMSCl) in 85% isolated
yield (Scheme 1).
4
Since compound 1 can be readily prepared from
dibromodifluoromethane (Halon 1202) and sodium benzenethiolate,
5

TMS–CF
2
SPh is an inexpensive chemical and can have wide synthetic potential.

Scheme 6.1 Preparation of TMS–CF
2
SPh.

The reaction conditions for the fluoride-induced nucleophilic
(phenylthio)difluoromethylation reaction (Scheme 6.2) is similar to that of
trifluoromethylation with TMS–CF
3
.
2(a),2(b)
Catalytic amount (10 mol %) of
Et
2
O
PhSCF
2
Br
Me
3
SiCl, Mg
DMF
TMS CF
2
Br
2
+ PhSNa
1
dibenzo-18-crown-6
CF
2
SPh
85 %

131
tetrabutylammonium triphenyldifluorosilicate (TBAT) was used as the anhydrous
fluoride source. The results are summarized in Table 6.1.

R
1
R
2
O
TMS-CF
2
SPh, TBAT (10 mol %)
THF, 0
o
C to RT
R
1
CF
2
SPh
OSiMe
3
R
2
TBAF, THF
or H
3
O
+
R
1
CF
2
SPh
OH
R
2
4
2
3

Scheme 6.2 Nucleophilic (phenylthio)difluoromethylation with TMS–CF
2
SPh.

132
Table 6.1. Nucleophilic (phenylthio)difluoromethylation of carbonyl compounds
with TMS–CF
2
SPh (after desilylation).

CF
2
SPh
OH
H
85
CF
2
SPh
OH
H
87
CF
2
SPh
OH
CH
3
82
HO CF
2
SPh
86
CF
2
SPh
OH
H
91
CF
2
SPh
OH
H
Cl
CF
2
SPh
OH
H
Br
HO CF
2
SPh
77
72
81
H
O
H
O
H
O
Cl
H
O
Br
H
O
O
CH
3
O
O
1
2
3
4
5
6
7
8
Entry Carbonyl compounds 2 Product 4 Yield (%)
a
4a
4b
4c
4d
4e
4f
4g
4h
a
Isolated yield.

133
As shown in Table 6.1, various aldehydes and ketones were
(phenylthio)difluoromethylated in good to excellent yields with this method.
Enolizable carbonyl compounds behave similarly as non-enolizable ones, with
slightly lower yields (see entries 7 and 8). In the case of α,β-unsaturated carbonyl
compounds, only 1,2-addition product was obtained (entry 5).
This new type of (phenylthio)difluoromethylation method was also applied to
other systems such as disulfides and esters. For example, when excess potassium
tert-butoxide was used as the promoter, diphenyl disulfide (5) reacted with
TMS–CF
2
SPh to give product 6 in 85 % yield (Scheme 6.3, eq. 1). The reaction
between methyl benzoate

SS
THF, 0
o
C, 2 h
SCF
2
SPh
85 %
OCH
3
O
TMS-CF
2
SPh, TBAT (cat.)
- 78
o
C to rt
OMe
OSiMe
3
CF
2
SPh
H
3
O
+
CF
2
SPh
O
28~41 %
TMS-CF
2
SPh, t-BuOK
56
(1)
8
7
(2)

Scheme 6.3 (Phenylthio)difluoromethylation of diphenyl disulfide and methyl
benzoate

134

(7) and TMS–CF
2
SPh was attempted several times using different solvents from
–78
o
C to room temperature, and the ketone product 8 was produced in 28~41 %
conversions (Scheme 6.3, eq. 2).
The above obtained (phenylthio)difluoromethyl carbinols 4 can also be further
transformed into difluoromethyl carbinols 10, using simple oxidation and
reductive desulfonylation procedure (Scheme 6.4). As previously discussed,
difluoromethyl alcohols are highly useful compounds for many applications.
6

RCF
2
SPh
OH
H
H
2
O
2
, HOAc
RCF
2
SO
2
Ph
OH
H
MeOH
RCF
2
H
OH
H
Na/Hg, Na
2
HPO
4
- 20
o
C ~ 0
o
C
R = Ph, 49 % (10a)
R = 2-naphthyl, 53 % (10b)
4
9
10
For two steps:

Scheme 6.4 Preparation of difluoromethyl alcohols (10) from 4.

Concerning the mechanism of this fluoride-induced
(phenylthio)difluoromethylation of carbonyl compounds (both aldehydes and
ketones), we propose that a pentacovalent silicon anion species 11 is formed from
TMS–CF
2
SPh and TBAT (Scheme 5). Species 11 acts as a real
(phenylthio)difluoromethylating agent, transferring the PhSCF
2
–
moiety into the
carbonyl compound 2 to give alkoxide 12. Alkoxide 12 can further act as an

135
initiator for TMS–CF
2
SPh to form another pentacovalent silicon species 13 as a
(phenylthio)difluoromethylating agent, thus giving the silylated carbinol product
3 from TMS–CF
2
SPh and carbonyl compounds 2 in a catalytic cycle (Scheme
6.5). In principle, the reaction is a fluoride induced autocatalytic process, and such
a mechanism has been previously proposed by us in the case of TMS–CF
3
.
2(a)

TMS-CF
2
SPh
"F
-
"
TBAT
Ph
3
SiF
Si
F
H
3
C
H
3
C
CF
2
SPh
CH
3
R
1
R
2
O
Me
3
SiF
R
1
R
2
PhSF
2
C O
Si
O
H
3
C
H
3
C
CF
2
SPh
CH
3
R
2
PhSF
2
C
R
1
TMS-CF
2
SPh
R
1
R
2
O
R
1
R
2
PhSF
2
C OSiMe
3 TBAF or H
3
O
+
R
1
R
2
PhSF
2
C OH
4
3
11
12
13
2
2

Scheme 6.5 Proposed mechanism of the (phenylthio)difluoromethylation of
carbonyl compounds with TMS–CF
2
SPh.

6.3 Conclusions
In conclusion, a fluoride-induced nucleophilic (phenylthio)difluoro-
methylation method using TMS–CF
2
SPh has been achieved. This new
methodology efficiently transfers PhSCF
2
group into both enolizable and
non-enolizable aldehydes and ketones to give the corresponding
(phenylthio)difluoromethylated carbinols in good to excellent yields.
Diphenyldisulfide can also be (phenylthio)difluoromethylated into PhSCF
2
SPh in

136
high yield. The reaction with methyl benzoate, however, gives only low yield of
(phenylthio)difluoromethyl phenyl ketone. The above-obtained
PhSCF
2
-containing alcohols can be further transformed into difluoromethyl
alcohols using oxidation-desulfonylation procedure. This nucleophilic
fluoroalkylation chemistry can also be extended to other
(arylthio)dilfuoromethylation, (heteroarylthio)difluoromethylation and
(alkylthio)difluoromethylation using corresponding TMS–CF
2
SR reagents, which
are still under investigation in our laboratory.

6.4 Experimental section
Materials and instrumentation. Unless otherwise mentioned, all reagents
were purchased from commercial sources. TMS–CF
2
SPh was prepared according
to our previous procedures.
4
THF was distilled under nitrogen over
sodium/benzophenone ketyl prior to use. Toluene was distilled over sodium.
Column chromatography was carried out using silca gel (60-200 mesh).
1
H,
13
C,
19
F NMR spectra were recorded on Bruker AMX 500 and Varian
Mercury-400 NMR spectrometers. (CH
3
)
4
Si (TMS) was used as an internal
standard for
1
H and
13
C NMR, CFCl
3
was used as internal standard for
19
F NMR.
For some cases, CDCl
3
was used as the internal standard for
1
H NMR (7.26 ppm)
and
13
C NMR (77 ppm). Mass spectra were obtained on a Hewlett Packard 5890
Gas Chromatograph equipped with a Hewlett Packard 5971 Mass Selective

137
Detector at 70 eV. HRMS data were recorded on a VG 7070 high-resolution mass
spectrometer. The purity of the isolated products (usually > 97 % pure) was
examined by GC-MS and
1
H,
13
C,
19
F NMR spectroscopy.
Typical procedures for the nucleophilic (phenylthio)difluoromethylation
with TMS–CF
2
SPh, Under an argon atmosphere, into a Schlenk flask containing
benzaldehyde (106 mg, 1.0 mmol) and TMS–CF
2
SPh (278 mg, 1.2 mmol) in dry
THF (5 mL) at 0
o
C, was added dropwise a THF solution (3 mL) of TBAT (54 mg,
0.1 mmol). Then the reaction mixture was stirred at 0
o
C for 1 h, followed by
stirring at room temperature overnight. A wet THF solution (10 mL, containing 10
% of water) of TBAF ٠3H
2
O (315 mg, 1 mmol) was then added and the whole
mixture was stirred for another 30 min. The THF solvent was removed under
vacuum, and the residue was purified by silica gel column chromatography
(hexane:ethyl acetate (v/v) = 9:1, then 7:1) to give the
2,2-difluoro-2-phenylthio-1-phenylethanol (4a) as a colorless liquid, yield: 226
mg (85 %).
2,2-Difluoro-2-phenylthio-1-phenylethanol (4a): colorless liquid, 85 % yield.
1
H NMR (CDCl
3
): δ 2.71 (d, J = 4 Hz, 1H), 4.92 (m, 1H), 7.21~7.51 (m, 10H).
13
C NMR (CDCl
3
): δ 76.0 (t, J = 28 Hz), 125.7 (t, J = 2.6 Hz), 127.7, 128.3, 128.8
(t, J = 285 Hz), 128.9, 129.0, 129.8, 135.2, 136.4.
19
F NMR (CDCl
3
): δ –81.7 (dd,
J = 210 Hz, 8.2 Hz, 1F), –85.2 (dd, J = 210 Hz, 12 Hz, 1F). MS: 266 (M
+
), 160,
107, 77. HRMS (EI): m/z calcd for C
14
H
12
F
2
OS (M
+
) 266.0577, found 266.0575.

138
2,2-Difluoro-2-phenylthio-1-(2-naphthyl)ethanol (4b): pale yellow solid, 87 %
yield.
1
H NMR (CDCl
3
): δ 3.01 (d, J = 3.5 Hz, 1H), 5.20 (m, 1H), 7.28~8.00 (m,
12H).
13
C NMR (CDCl
3
): δ 76.0 (t, J = 27 Hz), 124.9 (t, J = 1.4 Hz), 125.8 (t,

J =
2.3 Hz), 126.2, 126.5, 127.5, 127.6, 128.0, 128.2, 129.0, 129.0 (t, J = 264 Hz),
129.8, 132.6, 132.8, 133.5, 136.4.
19
F NMR (CDCl
3
): δ –81.3 (dd, J = 210 Hz, 8
Hz, 1F); –84.6 (dd, J = 210 Hz, 12 Hz, 1F). MS: 316 (M
+
), 187, 157, 129, 77.
HRMS (EI): m/z calcd for C
18
H
14
F
2
OS (M
+
) 316.0733, found 316.0730.
2,2-Difluoro-2-phenylthio-1-(4’-chlorophenyl)ethanol (4c): white solid, 72%
yield.
1
H NMR (CDCl
3
): δ 3.08 (d, J = 4.2 Hz, 1H), 4.97 (m, 1H), 7.35~7.60 (m,
9H).
13
C NMR (CDCl
3
): δ 75.4 (t, J = 27.3 Hz), 125.5 (t, J = 2.2 Hz), 128.5, 128.7
(t, J = 285 Hz), 129.1, 129.2, 130.0, 133.6, 135.0, 136.4.
19
F NMR (CDCl
3
): δ
–81.4 (dd, J = 210 Hz, 7.2 Hz, 1F), –85.2 (dd, J = 210 Hz, 11.5 Hz, 1F). HRMS
(EI): m/z calcd for C
14
H
11
ClF
2
OS (M
+
) 300.0187, found 300.0179.
2,2-Difluoro-2-phenylthio-1-(4’-bromophenyl)ethanol (4d): pale yellow solid,
81 % yield.
1
H NMR (CDCl
3
): δ 2.84 (d, J = 4 Hz, 1H), 4.96 (m, 1H), 7.35~7.60
(m, 9 H).
13
C NMR (CDCl
3
): δ 75.5 (t, J = 27.3 Hz), 123.3, 125.4, 128.6 (t, J =
285 Hz), 129.1, 129.4, 130.0, 131.5, 134.0, 136.4.
19
F NMR (CDCl
3
): δ –81.6 (dd,
J = 211 Hz, 7.3 Hz, 1F); –85.7 (dd, J = 211 Hz, 11.4 Hz, 1F). HRMS (EI): m/z
calcd for C
14
H
11
BrF
2
OS (M
+
) 343.9682, found 343.9681.
1,1-Difluoro-1-phenylthio-4-phenyl-but-3-en-2-ol (4e): pale yellow liquid, 91
% yield.
1
H NMR (CDCl
3
): δ 3.13 (d, J = 5.4 Hz, 1H), 4.59 (m, 1H), 6.26 (dd, J =

139
16.1 Hz, 6.3 Hz, 1H), 6.77 (d, J = 16 Hz, 1H), 7.31 (m, 8H), 7.60 (d, J = 7.8 Hz,
2H).
13
C NMR (CDCl
3
): δ 75.0 (t, J

= 27 Hz), 122.4, 125.7 (t, J = 2.5 Hz), 126.8,
128.3, 128.5, 128.9 (t, J = 285 Hz), 129.0, 129.8, 135.1, 135.7, 136.4.
19
F NMR
(CDCl
3
): δ –83.0 (dd, J = 207.6 Hz, 9.2 Hz, 1F), –84.8 (dd, J = 207.8 Hz, 8.9 Hz,
1F). HRMS (EI): m/z calcd for C
16
H
14
F
2
OS (M
+
) 292.0733, found 292.0728.
2,2-Difluoro-2-phenylthio-1,1-diphenylethanol (4f): white solid, 86 % yield.
1
H NMR (CDCl
3
): δ 3.16 (b, 1H), 7.29~7.62 (m, 15H).
13
C NMR (CDCl
3
): δ 81.5
(t, J = 24 Hz), 126.2 (t, J = 2 Hz), 127.7 (t, J = 2 Hz), 127.9, 128.2, 128.9, 129.7,
131.1 (t, J = 293 Hz), 136.6, 140.2.
19
F NMR (CDCl
3
): δ –77.9 (s). MS: 342 (M
+
),
213, 183, 165, 105, 77. HRMS (EI): m/z calcd for C
20
H
16
F
2
OS (M
+
) 342.0890,
found 342.0899.
2,2-Difluoro-2-phenylthio-1-methyl-1-phenylethanol (4g): colorless liquid, 82
% yield.
1
H NMR (CDCl
3
): δ 1.83 (s, 3H), 2.64 (b, 1H), 7.32~7.68 (m, 10H).
13
C
NMR (CDCl
3
): δ 24.5 (t, J = 2.4 Hz), 77.9 (t, J = 24.4 Hz), 126.1 (t, J = 2.2 Hz),
126.3, 128.1, 128.2, 128.8, 129.6, 131.0 (t, J = 290 Hz), 136.5, 140.0.
19
F NMR
(CDCl
3
): δ –82.1 (d, J = 204.5 Hz, 1F), –84.9 (d, J = 204.5 Hz, 1F). HRMS (EI):
m/z calcd for C
15
H
14
F
2
OS (M
+
) 280.0733, found 280.0727.
1-Difluoro(phenylthio)methylcyclohexanol (4h): colorless liquid, 77 % yield.
1
H NMR (CDCl
3
): δ 1.19~1.88 (m, 11H), 7.34~7.63 (m, 5H).
13
C NMR (CDCl
3
):
δ 20.8, 25.3, 31.0 (t, J = 2.2 Hz), 75.9 (t, J = 23.3 Hz), 126.2 (t, J = 2.4 Hz), 128.9,

140
129.6, 132.1, 136.7.
19
F NMR (CDCl
3
): δ –87.6 (s). HRMS (EI): m/z calcd for
C
13
H
16
F
2
OS (M
+
) 258.0890, found 258.0894.
Nucleophilic (phenylthio)difluoromethylation of diphenyl disulfide. Under
an argon atmosphere, into a Schlenk flask containing diphenyl disulfide (218 mg,
1.0 mmol) and TMS–CF
2
SPh (464 mg, 2.0 mmol) in dry THF (7 mL) at 0
o
C, was
added dropwise a THF solution (3 mL) of t-BuOK (336 mg, 3.0 mmol). Then the
reaction mixture was stirred at 0
o
C to room temperature for 2 h, followed by
quenching with saturated NaCl aqueous solution (10 mL). The mixture was
extracted with ether (15 mL x 3), and the combined organic phase was dried over
MgSO
4
. After the removal of volatile solvents, the residue was further purified by
silica gel column chromatography (using hexane as eluent) to give PhSCF
2
SPh (6)
as a colorless liquid, yield: 227 mg (85 %).
1
H NMR (CDCl
3
): δ 7.33 (tt, J = 7.3
Hz, 2.0 Hz, 4H), 7.39 (tt, J = 7.3 Hz, 2.0 Hz, 2 H), 7.58 (d, J = 8.0 Hz, 4H).
13
C
NMR (CDCl
3
): δ 127.2 (t, J = 14 Hz), 129.1, 130.2, 132.3 (t, J = 315 Hz), 136.1.
19
F NMR (CDCl
3
): δ –49.5 (s). MS: 268 (M
+
), 159, 109, 77.
Preparation of difluoromethylated alcohols (10) from
(phenylthio)difluoromethylated alcohols (4). Compound 4a (or 4b) (1 equiv)
was oxidized with 30 % aqueous H
2
O
2
(4 equiv) in acetic acid at 50
o
C overnight.
After a standard workup, the neutralized crude product 9a (or 9b) was added into
a mixture of Na(Hg) amalgam (5 wt % Na in Hg, 5 equiv) and MeOH at –20
o
C,
and the mixture was stirred at –20
o
C to room temperature for 1 h. The liquid

141
phase was decanted, and the solid residue was washed with ether for 3 times.
After solvent removal of the combined organic phase, the residue was purified by
silica gel column chromatography (hexane/ethyl acetate (v/v) = 5:1) to give
product 10a (or 10b) in 49 % and 53 % yield, respectively. The characterization
data of 10a are consistent with the previous report
7
[10]. For product 10b:
1
H
NMR (CDCl
3
): δ 2.99 (b, 1H), 4.98 (m, 1H), 5.86 (td, J = 56 Hz, 4.7 Hz, 1H),
7.50 (m, 3H), 7.87 (m, 4H).
13
C NMR (CDCl
3
): δ 73.7 (t, J = 24.6 Hz), 115.8 (t, J
= 246 Hz), 124.3, 126.4, 126.5, 126.6, 127.7, 128.1, 128.4, 133.0, 133.2 (t, J = 3.5
Hz), 133.5 (aryl).
19
F NMR (CDCl
3
): δ –127.4 (ddd, J = 284 Hz, 56 Hz, 9 Hz, 1F),
–128.0 (ddd, J = 284 Hz, 56 Hz, 10 Hz, 1F). MS: 208 (M
+
).

142
6.5 Chapter 6 references

1. (a) Burkholder, C. R.; Dolbier, W. R. Jr.; Medebielle, M. J. Fluorine Chem.
2000, 102, 369. (b) Burkholder, C.; Dolbier, W. R. Jr.; Medebielle, M.;
Ait-Mohand, S. Tetrahedron Lett. 2001, 42, 3459.

2. (a) Prakash, G. K. S.; Krishnamurti, R.; Olah, G. A. J. Am. Chem. Soc. 1989,
111, 393. (b) Krishnamurti, R.; Bellew, D. R.; Prakash, G. K. S. J. Org.
Chem. 1991, 56, 984. (c) Prakash, G. K. S.; Yudin, A. K. Chem. Rev. 1997,
97, 757. (d) Prakash, G. K. S.; Mandal, M. J. Fluorine Chem. 2001, 112, 123.
(e) Prakash, G. K. S.; Hu, J. “New Fluoroalkylation Chemistry”, in
Fluorinated Synthons (V. Soloshonok, Ed.), ACS Symposium Series, 2005,
in press.

3. Yudin, A. K.; Prakash, G. K. S.; Deffieux; D.; Bradley, M.; Bau, R.; Olah,
G. A. J. Am. Chem. Soc. 1997, 119, 1572.

4. Prakash, G. K. S.; Hu, J.; Olah, G. A. J. Org. Chem. 2003, 68, 4457.

5. Li, X.-Y.; Jiang, X.; Gong, Y.; Pan, H. HuaXue XueBao 1985, 43, 260.
6. Kirsch, P. Modern Fluoroorganic Chemistry: Synthesis, Reactivity,
Applications, Wiley-VCH: Weinheim, 2004.

7. Kaneko, S.; Yamazaki, T.; Katazume, T. J. Org. Chem. 1993, 58, 2302.

143
Chapter 7
Nucleophilic Perfluoroalkylation of Imines, Aldehydes,
Ketones and Alkyl Iodides with Perfluoroalkyl
Sulfones

7.1 Introduction
Fluorine-containing compounds are widely used in biological and material
fields.
1
Due to the small size and high electronegativity, fluorine can impact
unique chemical and biological properties to an organic molecule, including
stability, high lipophilicity and bioavailability. Its high lipophilicity can favorably
change the transport and absorption rates of drugs in vivo.
2
In the past two
decades, introducing fluorine into organic compounds has attracted much
attention. There are many reports on the development of trifluoromethylation
methods, including nucleophilic,
3
electrophilic,
4
radical
5
and organometallic
6

trifluoromethylations. The most common trifluoromethylation reagent,
(trifluoromethyl)trimethylsilane (TMSCF
3
), which has been developed by Prakash
et al., has been widely used under mild reaction conditions.
3(b), 3(d), 7
Methods to
add pentafluoroethyl group into organic compounds are limited. Our group
previously reported the use of (pentafluoroethyl)trimethylsilane as
pentafluoroethide equivalent.
8
Recently, Dolbier and coworkers
9
reported the use

144
of C
2
F
5
I with tetrakis(dimethylamino)ethylene (TDAE) in the nucleophilic
perfluoroalkylation reactions of aldehydes, ketones, imines, disulfides and
diselenides. Other methods include C
2
F
5
I/CH
3
Li system, which was originally
developed by Gassman et al.,
10
and ultrasound-promoted C
2
F
5
X (X = Br, I)/Zn
system which was developed by Kitazume et al.
11
The limitation of these methods
is that only carbonyl compounds can be pentafluoroethylated. Herein, we wish to
introduce a new and powerful pentafluoroethylation reagent, pentafluoroethyl
phenyl sulfone 1, which can be applied to the pentafluoroethylation of imines,
aldehydes, ketones and alkyl halides efficiently in the presence of t-BuOK.
Besides pentafluoroethyl phenyl sulfone 1, trifluoromethyl phenyl sulfone 2
has also been developed as a trifluoromethylation reagent by our group and its
efficient trifluoromethylation of nonenolizable carbonyl compounds and
disulfides in the presence of t-BuOK has been reported previously.
11
However,
trifluoromethylation of imines by 2 was not pursued at that time. In this paper,
we’ll also demonstrate the successful trifluoromethylation of imines by using
trifluoromethyl phenyl sulfone 2. The chemistry of perfluoroalkylations by 1 or 2
is based on the attack of nucleophile alkoxide on the sulfur center of 1 or 2 to
generate a pentafluoroethyl anion (CF
3
CF
2
-
) or trifluoromethyl anion (CF
3
-
)
(Scheme 7.1) in situ.

145
S
O
O
R
F
S
O
-
O
R
F
OR
"R
F
-
"
R
F
= CF
2
CF
3
, CF
3
OR
1 or 2

Scheme 7.1 Mechanistic Consideration

Noticeably, when a homochiral sulfinylimine was used as a substrate in the
perfluoroalkylation reactions, high diastereoselectivity was achieved. The chiral
sulfonamide can be further converted into fluorinated amines in enantiomerically
pure form,
7
which provides an effective and highly stereoselective method for the
preparation of perfluoroalkylated amines.
Trifluoromethyl phenyl sulfone is commercially available. Pentafluoroethyl
phenyl sulfone was obtained from the reaction of potassium
pentafluoropropionate (CF
3
CF
2
COOK) and diaryldisulfide
13
followed by the
oxidation with hydrogen peroxide (Scheme 7.2)
PhSSPh + CF
3
CF
2
COOK
145 °C
PhSCF
2
CF
3
H
2
O
2
/AcOH
PhSO
2
CF
2
CF
3
70% 80%
DMF, 5h
reflux overnight

Scheme 7.2 Synthesis of PhSO
2
CF
2
CF
3

146
7.2 Results and discussion
7.2.1 Nucleophilic addition reactions between PhSO
2
CF
2
CF
3
and imines
Nucleophilic addition reactions between PhSO
2
CF
2
CF
3
and imines were
carried out by carefully optimizing the reaction conditions. The reaction was
typically performed under argon atmosphere by slowly adding a base into a
solution of PhSO
2
CF
2
CF
3
and the imine. The reaction condition optimization data
are presented in Table 7.1.

Table 7.1 Modification of reaction condition for the introduction of CF
3
CF
2

group into imines
+
base
solvent
13 4
R
1
H
N
R
2
R
1
H
N
H
CF
2
CF
3
R
2
PhSO
2
CF
2
CF
3

imine 3
(equiv.)
1
(equiv.)
base
(equiv.)
solvent temperature
( C)
time
(h)
yield
(%)
3a (2.0)
3a (1.0)
3a (1.0)
1.0
1.5
1.5
1.5 3a (1.0)
t-BuOK (2.0)
t-BuOK (6.0)
t-BuOK (6.0)
t-BuOK (4.5)
DMF -30 ~ rt 1.5 34
b
DMF -65 1.5 69
a
DMF -55 1.5 -
THF -78 1.5 99
a
a
Isolated Yield;
b
Yields were estimated by
19
F NMR.
°

We tried different solvents, reaction temperatures, reactant ratios to increase
the yields. Previous study
11
demonstrated that DMF as a solvent and t-BuOK as a

147
base were the best choice for trifluoromethylation reaction based on PhSO
2
CF
3
.
Therefore, we initially applied similar reaction conditions for the
pentafluorination reaction. However, the yield was low and there were some
unreacted PhSO
2
CF
2
CF
3
and imine left. By modifying the reaction conditions, we
found that low temperatures and excess of PhSO
2
CF
2
CF
3
and t-BuOK favored the
reaction. In order to lower temperature to -75 °C, we used THF as solvent instead
of DMF, which greatly enhanced the yield (99%). An excess of t-BuOK was
necessary as it removes the moisture from the solvent and reagents, thus
preventing the hydrolysis of CF
3
CF
2
-
to form CF
3
CF
2
H. After carefully modifying
the reaction conditions, we obtained good yields ( 60~99%) by the following
protocol: under an argon atmosphere, 4.5 equivalent of t-BuOK in THF was
added dropwise to the solution of 1.5 equivalent of PhSO
2
CF
2
CF
3
and 1
equivalent of imine in THF between -75 °C and -70 °C. Then the reaction mixture
was stirred at that temperature for 1.5 hours. The results are summarized in Table
7.2. A variety of structurally diverse imines were used to react with PhSO
2
CF
2
CF
3

in the presence of t-BuOK to provide the corresponding pentafluoroethylated
amines in moderate to excellent yields. Even the imines bearing α hydrogen atom
were found to be reactive to PhSO
2
CF
2
CF
3
in t-BuOK. Remarkably, the chiral
sulfinylimine 3k, when subjected to this reaction, gave high diastereoselectivity
(d.r.= 97: 3).

148
Table 7.2 Reaction of PhSO
2
CF
2
CF
3
1 (1.5 equiv.) with imines 3 (1.0 equiv.) and
t-BuOK (4.5 equiv.) in THF between -75 °C and -70 °C for 1.5 hrs.

Imines 3
Yield [%]
a
(R
s
, S)/(R
s
, R)
b
N
Ph
H
Br
N
Ph
H
Cl
N
Ph
H
F
N
Ph
H
Me
N
Ph
H
MeO
N
Ph
H
Cl
N
Ph
H
Cl
F
N
Ph
H
N
Ph
H
Bu
S
N
O
t
H
Br
N
H
Ph
CF
2
CF
3
Br
N
H
Ph
CF
2
CF
3
Cl
N
H
Ph
CF
2
CF
3
F
N
H
Ph
CF
2
CF
3
Me
N
H
Ph
CF
2
CF
3
MeO
N
H
Ph
CF
2
CF
3
Cl
Cl
N
H
Ph
CF
2
CF
3
F
N
H
Ph
CF
2
CF
3
N
H
Ph
CF
2
CF
3
Bu
S
N
H
O
t
Br
CF
2
CF
3
99
99
96
88
82
96
88
57
50
57 97: 03
a
Isolated yields.
b
Diatereomeric ratios were determined by
19
F NMR spectroscopy of the crude reaction mixture
Product 4
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j

149
7.2.2 Nucleophilic reactions between PhSO
2
CF
2
CF
3
and carbonyl compounds
PhSO
2
CF
2
CF
3
based pentafluoroethylation of aldehydes and ketones (Table
7.3) were also very successful. In this case, we applied similar reaction conditions
as the pentafluoroethylation of imines and good yields of pentafluoroethyl
carbinols were realized. Our studies showed that both nonenolizable and
enolizable aldehydes worked in this reaction but enolizable aldehydes gave lower
yields due to concomitant enolization. The work-up procedure of this reaction is
quite simple. After ether extraction and aqueous washing, byproducts, tert-butyl
alcohol and benzenesulfonic acid derivatives can be removed. Recrystallization
provides pentafluoroethyl alcohols in high purity.

150
Table 7.3 Pentafluoroethylation of carbonyl compounds by using PhSO
2
CF
2
CF
3

PhSO
2
CF
2
CF
3
+
4.5 equiv t-BuOK / THF
-75 ~ -70°C, 90min
1.5 equiv.
1 equiv.
R
1
O
R
1
R
2
CF
2
CF
3
R
2
HO
1
5
6

Carbonyl Compound 5 Product 6 Yield [%]
Br
Me
O
Cl Cl
O
OMe MeO
O
NO
2
H
O
H
O
H
O
H
O
H
O
O
CF
2
CF
3
OH
CF
2
CF
3
OH
CF
2
CF
3
OH
Br
Me
CF
2
CF
3
OH
CF
2
CF
3
OH
Cl Cl
HO CF
2
CF
3
OMe MeO
HO CF
2
CF
3
HO CF
2
CF
3
NO
2
OH
CF
2
CF
3
91
a
85
a
84
a
89
a
66
b
93
a
99
a
67
a
99
a
a
Isolated yields.
b
Yield were determined by
1
H NMR of reaction crude.
5a
5b
5c
5d
5e
5f
5g
5h
5i
6a
6b
6c
6d
6e
6f
6g
6h
6i

151
7.2.3 Nucleophilic reactions between PhSO
2
CF
2
CF
3
and alkyl iodide
To our knowledge, methods for direct pentafluoroethylation of alkyl halides
are rare. Kabayashi reported the trifluoromethylation of n-decyl iodide with
pre-prepared CF
3
Cu/HMPA in 48% yield.
14
Chambers et al. discovered sodium
perfluoroalkane carboxylates as a source for perfluoroalkylation of aromatic
halides and alkyl iodides.
15
Chen et al. reported the trifluoromethylation of
aliphatic halides by methyl chlorodifluoroacetate in the presence of potassium
fluoride, copper iodide and cadmium iodide at 120 °C in HMPA.
16
However, all
these methods involve oxidative addition-reductive elimination protocol. Herein,
we have developed the nucleophilic pentafluoroethylation of alkyl iodides and 1.
The results are summarized in Table 7.4.

Table 7.4 Pentafluoroethylation of Alkyl Iodides (1 equiv) by using 1 (1.5 equiv)
in the presence of t-BuOK (4.5 equiv) in THF at -75 °C.

Alkyl Iodide 7 Product 8 Yield (%)
Ph(CH
2
)
4
I 7a Ph(CH
2
)
4
CF
2
CF
3
45
a
PhO(CH
2
)
3
I 7b PhO(CH
2
)
3
CF
2
CF
3
50
b
a
isolated yield.
b
Determined by
19
F NMR using PhOCF
3
as an internal standard.
8a
8b

7.2.4 Nucleophilic reactions between PhSO
2
CF
3
and imines
As was reported before,
12
PhSO
2
CF
3
/t-BuOK trifluoromethylation of
carbonyl compounds and disulfides are quite convenient and efficient. Now we

152
have found that PhSO
2
CF
3
/t-BuOK based trifluoromethylation of imines also
works well. In this case, the use of DMF as solvent gave cleaner products with
higher yields than THF, which indicates that CF
3
-
is more stabilized in DMF than
in THF. The optimized reaction conditions were (PhSO
2
CF
3
/imine/t-BuOK = 1.5:
1: 4.5, -70 °C -60 °C, 90 min, DMF) and the results are summarized in Table 7.5.

Table 7.5 Trifluoromethylation of Imines by using PhSO
2
CF
3

PhSO
2
CF
3
+
4.5 equiv. t-BuOK / DMF
-70 ~ -60°C, 90min
1.5 equiv. 1.0 equiv.
R
1
N
R
2
H
R
1
N
H
R
2
CF
3
2 3 9

Imine 3 Yield [%]
a
(R
s
, S)/(R
s
, R)
b
N
Ph
H
Br
N
H
Ph
CF
3
Br
N
Ph
H
Cl
N
H
Ph
CF
3
Cl
N
Ph
H
F
N
H
Ph
CF
3
F
Cl
Cl
Bu
S
N
O
t
H
Bu
S
N
H
O
t
CF
3
Ph
Ph Ph
Ph
H
91
72
59
68 98: 2
3f
3a
3c
3k
Product 7
9f
9a
9c
9k
a
Isolated yields;
b
Diatereomeric ratios were determined by
19
F NMR spectroscopy of the crude reaction mixture

Gernerally the imines having bulky groups on the C=N carbon gave much
better results. After carefully examining the
19
F NMR spectrum of the reaction

153
mixture, side products were found to increase when the substituted group on the
imine becomes smaller. Also, by using chiral sulfinylimine, trifluoromethyl
sulfinamide with high diastereoselectivity was realized. The resulting
trifluoromethyl sulfinamide can be hydrolyzed to obtain the corresponding amine
salts with high enantiomeric purity, following our group’s previously published
procedure.
7

7.3 Conclusions
In summary, a new and powerful method was developed for the preparation
of pentafluoroethyl amines, pentafluoroethyl carbinols, pentafluoroethylalkanes
and trifluoromethyl amines by using PhSO
2
CF
2
CF
3
or PhSO
2
CF
3
as the
perfluoroalkyl sources. High stereoselective perfluoroalkylation was also
achieved in the case of sulfinylimines.

7.4 Experimental section
Materials and instrumentation. Unless otherwise mentioned, all other
chemicals were purchased from commercial sources. Potassium tert-butoxide
(95%, Aldrich) was used as received. DMF was distilled over calcium hydride and
stored over activated molecular sieve. THF was freshly distilled over sodium.
PhSO
2
CF
2
CF
3
was prepared from potassium pentafluoropropionate
(CF
3
CF
2
COOK)
13
followed by oxidation with H
2
O
2
(described in next paragraph).

154
Imines were prepared by condensation reactions of corresponding aldehydes and
anilines. PhSO
2
CF
3
3(c)
and N-(tert-butanesulfinyl)imines
17
were prepared using a
known procedure. Silica gel column chromatography was used to isolate the
products using 60-200 mesh silica gel (from J. T. Baker).
1
H,
13
C and
19
F NMR
spectra were recorded on 500 MHz or 400 MHz NMR spectrometer.
1
H NMR
chemical shifts were determined relative to the signal of a residual proton of
CDCl
3
δ 7.26.
13
C NMR chemical shifts were determined relative to the
13
C signal
of solvent CDCl
3
δ 77.0.
19
F NMR chemical shifts were determined relative to
internal CFCl
3
at δ 0.0. Mass data were recorded on a GC-MS spectrometer with a
mass selective detector at 70 eV. High-resolution mass data were recorded on a
high-resolution mass spectrometer in the FAB mode.
The preparation of PhSO
2
CF
2
CF
3
. To a solution of CF
3
CF
2
COOK (2.38 g,
11.8 mmol) in anhydrous DMF (25 mL) was added diaryl difulfide (2.18 g, 10
mmol) at room temperature under an argon atmosphere. The reaction solution was
then heated to 140 ºC over 5 hours. At the end of the reaction, the product
PhSCF
2
CF
3
in DMF was obtained through the reduced pressure distillation (40
torr). The product solution was poured into brine and extracted with ether (25
mL×3). The combined organic fractions were rinsed with water and then dried
over MgSO
4
. After the removal of volatile solvents under vacuum, 1.5 g of crude
product PhSCF
2
CF
3
(b.p. 53 ºC at 28 mmHg) was obtained.
19
F NMR (CDCl
3
): δ
–83 (s, 3F), -92 (s, 2F). The crude product PhSCF
2
CF
3
(1.5 g, 6.5 mmol) was

155
transferred to a round bottom flask with 35% H
2
O
2
(2.5 g, 26 mmol) in 10 mL
acetic acid. The reaction solution was kept under reflux at 90 ºC overnight till all
of PhSCF
2
CF
3
was converted into PhSO
2
CF
2
CF
3
. Saturated NaCl solution (30 mL)
was added into the reaction mixture and dichloromethane was used to extract the
solution (25 mL × 3). The combined organic extract was then washed by aqueous
solution of 10% Na
2
SO
3
(25 mL × 2), 10% NaHCO
3
(25 mL × 3) and brine (25
mL × 1) subsequently. After drying over MgSO
4
and removal of the solvent on a
rotary evaporator, the crude product was further purified by silica gel column
chromatography (9: 1 hexane: ethyl acetate as eluent) to give PhSO
2
CF
2
CF
3
as
colorless liquid 1.1 g.
1
H NMR (CDCl
3
): δ 7.68 (t, J = 7.8 Hz, 2H), 7.85 (t, J =
7.8 Hz, 1H), 8.04 (d, J = 7.8 Hz, 2H).
19
F NMR (CDCl
3
): δ –78.3 (s, 3F), -116.6
(s, 2F).
Typical procedure for nucleophilic pentafluoroethylation of imines with
PhSO
2
CF
2
CF
3
. Under an argon atmosphere, into a 50-mL Schlenk flask
containing N-[(4-bromophenyl)methylene]-benzeneamine 3a (169 mg, 0.65 mmol)
and PhSO
2
CF
2
CF
3
(260mg, 1 mmol) in THF 5 mL at -75 °C was added dropwise
a THF solution (4 mL) of t-BuOK (336mg, 3 mmol). The reaction mixture was
then stirred vigorously between –75 ~ -70 °C for 1.5 hrs, followed by quenching
with 30 mL 2% HCl aqueous solution at the same temperature. The solution
mixture was extracted with Et
2
O (25 mL x 3), and the combined organic phase
was rinsed with saturated NaHCO
3
solution, NaCl solution and water

156
subsequently and then dried over MgSO
4
. After the removal of volatile solvents
under vacuum, the crude product was further purified by silica gel column
chromatography (10: 1 hexane: ethyl acetate as eluent) to give
N-(1-(4-bromophenyl)-3,3,3,2,2,-pentafluoropropyl)aniline 4a (245 mg, 99%) as
a pale yellow solid.
1
H NMR (CDCl
3
): δ 4.41 (br, s, 1H), 5.05 (m, 1H), 6.66 (d, J
= 7.8 Hz, 2H), 6.84 (t, J = 7.8 Hz, 1H), 7.21 (t, J = 7.8 Hz, 2H), 7.34 (d, J = 8.3
Hz, 2H), 7.56 (d, J = 8.3 Hz, 2H).
13
C NMR (CDCl
3
): δ 58.1 (dd, J = 25.7 Hz,
20.5 Hz), 113.9 (tq, J = 258.2 Hz, 36.2 Hz), 114.0, 119.19 (qt, J = 288.1 Hz, 36.2
Hz), 119.20, 128.1, 129.3, 129.5, 130.4, 139.0, 145.1.
19
F NMR (CDCl
3
): δ –81.5
(s, 3F), -118.6 (dd, J = 275 Hz, 8.3 Hz, 1F), -126.3 (dd, J = 275 Hz, 18.4 Hz, 1F).
MS (EI, m/z): 379 (M
+
), 259, 179, 77. HRMS (FAB): m/z calcd for C
15
H
11
BrF
5
N
(M
+
) 378.9995, found 378.9998.
N-(1-(4-chlorophenyl)-3,3,3,2,2,-pentafluoropropyl)aniline (4b): white solid.
1
H NMR (CDCl
3
): δ 4.38 (d, J = 8.9 Hz, 1H), 5.04 (m, 1H), 6.63 (d, J = 7.9 Hz,
2H), 6.81 (t, J = 7.9 Hz, 1H), 7.19 (t, J = 7.9 Hz, 2H), 7.39 (s, 4H).
13
C NMR
(CDCl
3
): δ 57.9 (dd, J = 26.0 Hz, 20.9 Hz), 113.7 (tq, J = 258.5 Hz, 36.2 Hz),
114.0, 119.1 (qt, J = 287.2 Hz, 36.2 Hz), 119.6, 129.1, 129.4, 129.6, 131.9, 135.2,
144.6.
19
F NMR (CDCl
3
): δ –81.5 (s, 3F), -118.1 (dd, J = 276 Hz, 7.8 Hz, 1F),
-126.3 (dd, J = 276 Hz, 18.8 Hz, 1F). MS (EI, m/z): 336 (M
+
), 215. HRMS (FAB):
m/z calcd for C
15
H
11
ClF
5
N (M
+
) 335.0500, found 335.0507.

157
N-(1-(4-fluorophenyl)-3,3,3,2,2,-pentafluoropropyl)aniline (4c): white solid.
1
H NMR (CDCl
3
): δ 4.39 (d, J = 7.8 Hz, 1H), 5.06 (m, 1H), 6.65 (d, J = 7.7 Hz,
2H), 6.82 (t, J = 7.7 Hz, 1H), 7.11 (m, 2H), 7.20 (t, J = 7.7 Hz, 2H), 7.44 (m, 2H).
13
C NMR (CDCl
3
): δ 57.7 (dd, J = 26.1 Hz, 20.7 Hz), 113.8 (tq, J = 256.9 Hz,
36.0 Hz), 114.0, 115.9 (d, J = 21.5 Hz), 119.1 (qt, J = 286.7 Hz, 36.0 Hz), 119.5,
129.2, 129.4, 130.0 (d, J = 8.4 Hz), 144.7, 163.1 (d, J = 247.7 Hz).
19
F NMR
(CDCl
3
): δ –81.5 (s, 3F), -112.8 (m, 1F), -118.3 (dd, J = 276 Hz, 8.7 Hz, 1F),
-126.3 (dd, J = 276 Hz, 18.4 Hz, 1F). MS (EI, m/z): 319 (M
+
), 199, 77. HRMS
(FAB): m/z calcd for C
15
H
11
F
6
N (M
+
) 319.0796, found 319.0830.
N-(1-(4-methylphenyl)-3,3,3,2,2,-pentafluoropropyl)aniline (4d): pale yellow
solid.
1
H NMR (CDCl
3
): δ 2.36 (s, 3H), 4.37 (br, s, 1H), 5.01 (m, 1H), 6.66 (d, J
= 7.7 Hz, 2H), 6.78 (t, J = 7.7 Hz, 1H), 7.15~7.24 (m, 4H), 7.33 (d, J = 8.0 Hz,
2H).
13
C NMR (CDCl
3
): δ 21.1, 58.1 (dd, J = 25.9 Hz, 20.7 Hz), 113.9 (tq, J =
258.0 Hz, 35.7 Hz), 114.0, 119.1 (qt, J = 287.8 Hz, 35.7 Hz), 119.2, 128.1, 129.3,
129.5, 130.4, 139.0, 145.1.
19
F NMR (CDCl
3
): δ –81.5 (s, 3F), -118.6 (dd, J =
274.9 Hz, 8.4 Hz, 1F), -126.3 (dd, J = 274.9 Hz, 18.0 Hz, 1F). MS (EI, m/z): 315
(M
+
), 194, 103, 77. HRMS (FAB): m/z calcd for C
16
H
14
F
5
N (M
+
) 315.1046, found
315.1060.
N-(1-(4-methoxyphenyl)-3,3,3,2,2,-pentafluoropropyl)aniline (4e): pale
yellow solid.
1
H NMR (CDCl
3
): δ 3.81 (s, 3H), 4.37 (br, s, 1H), 5.02 (m, 1H),
6.67 (d, J = 7.8 Hz, 2H), 6.80 (t, J = 7.8 Hz, 1H), 6.94 (d, J = 8.9 Hz, 2H), 7.19 (t,

158
J = 7.8 Hz, 2H), 7.38 (d, J = 8.9 Hz, 2H).
13
C NMR (CDCl
3
): δ 55.2, 57.8 (dd, J
= 25.7 Hz, 20.7 Hz), 113.9 (tq, J = 257.6 Hz, 35.7 Hz), 114.0, 114.2, 119.1 (qt, J
= 286.8 Hz, 35.7 Hz), 119.2, 125.2, 129.3, 129.4, 145.1, 160.1.
19
F NMR (CDCl
3
):
δ –81.5 (s, 3F), -118.8 (dd, J = 274.9 Hz, 8.6 Hz, 1F), -126.3 (dd, J = 274.9 Hz,
18.1 Hz, 1F). MS (EI, m/z): 331 (M
+
), 238, 212. HRMS (FAB): m/z calcd for
C
16
H
14
F
5
NO (M
+
) 331.0996, found 331.0999.
N-(1-(2,4-dichlorophenyl)-3,3,3,2,2,-pentafluoropropyl)aniline (4f): white
solid.
1
H NMR (CDCl
3
): δ 4.47 (br, s, 1H), 5.78 (m, 1H), 6.65 (d, J = 7.8 Hz, 2H),
6.84 (t, J = 7.8 Hz, 1H), 7.22 (d, J = 7.8 Hz, 2H), 7.30 (dd, J = 8.6 Hz, 2.1 Hz,
1H), 7.45 (d, J = 8.6 Hz, 1H), 7.50 (d, J = 2.1 Hz, 1H).
13
C NMR (CDCl
3
): δ 53.3
(dd, J = 27.2 Hz, 20.0 Hz), 113.6 (tq, J = 258.6 Hz, 36.2 Hz), 113.8, 119.0 (qt, J
= 286.8 Hz, 36.2 Hz), 119.7, 127.9, 129.5, 129.7, 129.8, 130.3, 135.7, 144.2.
19
F
NMR (CDCl
3
): δ –82.2 (s, 3F), -117.7 (dd, J = 278.6 Hz, 4.2 Hz, 1F), -128.4 (dd,
J = 274.9 Hz, 21.1 Hz, 1F). MS (EI, m/z): 369 (M
+
), 249, 76. HRMS (FAB): m/z
calcd for C
15
H
10
Cl
2
F
5
N (M
+
) 369.0110, found 369.0107.
N-(1-(2-fluorophenyl)-3,3,3,2,2,-pentafluoropropyl)aniline (4g): pale yellow
oil.
1
H NMR (CDCl3): δ 4.46 (br, s, 1H), 5.54 (m, 1H), 6.71 (d, J = 7.8 Hz, 2H),
6.82 (t, J = 7.8 Hz, 1H), 7.11~7.25 (m, 4H), 7.33~7.40 (m, 1H), 7.46 (t, J = 7.5
Hz, 1H),
13
C NMR (CDCl
3
): δ 51.5 (ddd, J = 26.8 Hz, 20.7 Hz, 3.1 Hz), 113.82
(tq, J = 258.4 Hz, 35.2 Hz), 113.83, 115.8 (d, J = 22.2 Hz), 119.1 (qt, J = 286.8
Hz, 35.2 Hz), 119.5, 120.8 (d, J = 13.8 Hz), 124.7 (d, J = 3.8 Hz), 129.1 (d, J =

159
3.1 Hz), 129.5, 130.9 (d, J = 7.4 Hz), 144.6, 161.2 (d, J = 246.9 Hz).
19
F NMR
(CDCl
3
): δ –82.0 (s, 3F), -118.3 (m, 1F), -118.8 (ddd, J = 275.0 Hz, 9.6 Hz, 7.6
Hz, 1F), -126.9 (ddd, J = 275.0 Hz, 19.4 Hz, 6.0 Hz, 1F). MS (EI, m/z): 319 (M
+
),
200, 77. HRMS (FAB): m/z calcd for C
15
H
11
F
6
N (M
+
) 319.0796, found 319.0805.
N-(1-cyclohexyl-3,3,3,2,2,-pentafluoropropyl)aniline (4h): pale yellow oil.
1
H
NMR (CDCl3): δ 1.06~1.36 (m, 5H), 1.62~2.04 (m, 6H), 3.75 (br, s, 1H), 3.97 (m,
1H), 6.65 (d, J = 7.8 Hz, 2H), 6.76 (t, J = 7.8 Hz, 1H), 7.19 (d, J = 7.8 Hz, 2H).
13
C NMR (CDCl
3
): δ 25.8, 24.9, 26.2, 26.8, 31.0, 38.5, 57.3 (dd, J = 24.5 Hz,
19.5 Hz), 113.0, 115.3 (tq, J = 259.0 Hz, 35.8 Hz), 118.4, 119.2 (qt, J = 288.2 Hz,
35.8 Hz), 129.4, 146.9.
19
F NMR (CDCl
3
): δ -82.7 (s, 3F), -118.5 (dd, J = 274.1
Hz, 7.8 Hz, 1F), -123.9 Hz (dd, J = 274.1 Hz, 21.8 Hz, 1F). MS (EI, m/z): 307
(M
+
), 223, 187, 105. HRMS (FAB): m/z calcd for C
15
H
18
F
5
N (M
+
) 307.1359,
found 307.1348.
N-(1-(tert-Butyl)-3,3,3,2,2,-pentafluoropropyl)aniline (4i): pale yellow oil.
1
H
NMR (CDCl
3
): δ 1.13 (s, 9H), 3.78 (d, J = 10.8 Hz, 1H), 3.88 (dd, J = 26.3 Hz,
10.8 Hz, 1H), 6.62 (d, J = 8.0 Hz, 2H), 6.75 (t, J = 8.0 Hz, 1H), 7.20 (t, J = 8.0
Hz, 2H).
13
C NMR (CDCl
3
): δ 27.6 (dd, J = 4.2 Hz, 2.3 Hz), 37.2 (d, J = 2.3 Hz),
59.0 (dd, J = 24.5 Hz, 20.3 Hz), 112.6, 116.4 (tq, J = 262.2 Hz, 35.0 Hz), 118.1,
119.0 (qt, J = 288.3 Hz, 35.0 Hz), 129.4, 146.6.
19
F NMR (CDCl
3
): δ -82.7 (s, 3F),
-112.1 (d, J = 272.6 Hz, 1F), -127.2 (dd, J = 272.6 Hz, 26.3 Hz, 1F). MS (EI,

160
m/z): 281 (M
+
), 223, 57. HRMS (FAB): m/z calcd for C
13
H
16
F
5
N (M
+
) 281.1230,
found 281.1198.
N-(p-Bromophenyl-3,3,3,2,2-pentafluoropropyl)-t-butanesulfinamide (4j):
white solid.
1
H NMR (CDCl
3
): δ 1.24 (s, 9H), 3.67 (d, J = 8.5 Hz, 1H), 4.82 (ddd,
J = 15.5 Hz, 11.4 Hz, 8.5 Hz, 1H), 7.27 (d, J = 8.2 Hz, 2H), 7.55 (d, J = 8.2 Hz,
2H).
13
C NMR (CDCl
3
): δ 22.2, 57.2, 60.0 (dd, J = 24.7 Hz, 21.3 Hz), 113.4 (tq, J
= 259.0 Hz, 36.0 Hz), 118.8 (qt, J = 287.1 Hz, 36.0 Hz), 124.0, 129.8, 132.3,
132.4.
19
F NMR (CDCl
3
): δ -81.1 (s, 3F), -121.0 (dd, J = 275.1 Hz, 11.4 Hz, 1F),
-122.9 (dd, J = 275.1 Hz, 15.5 Hz, 1F). HRMS [FAB, (M+1
+
)]: m/z calcd for
C
13
H
16
BrF
5
NOS 408.0056, found 408.0063.
Typical procedure for the nucleophilic pentafluoroethylation of carbonyl
compounds with PhSO
2
CF
2
CF
3
. Under an argon atmosphere, into a 50-mL
Schlenk flask containing benzaldehyde (69 mg, 0.65 mmol) and PhSO
2
CF
2
CF
3

(260mg, 1 mmol) in THF 5 mL at -75 °C was added dropwise a THF solution (4
mL) of t-BuOK (336mg, 3 mmol). The reaction mixture was then stirred
vigorously between –75 ~ -70 °C for 1.5 hrs, followed by quenching with 30 mL
2% HCl aqueous solution at the same temperature. The solution mixture was
extracted with Et
2
O (25 mL x 3), and the combined organic phase was rinsed with
saturated NaHCO
3
solution, NaCl solution and water subsequently and then dried
over MgSO
4
. After the removal of volatile solvents under vacuum, the crude
product was further purified by recrystallization with 2 mL hexane at -50 °C to

161
give α-(pentafluoroethyl)-benzenemethanol 6a (133 mg, 91%) as a pale yellow
solid.
1
H NMR (CDCl
3
): δ 2.65 (br, 1H), 5.12 (dd,
3
J
H, F
= 16.9 Hz,
3
J
H, F
= 7.5
Hz, 1H), 7.41~7.51 (m, 5H).
13
C NMR (CDCl
3
): δ 72.0 (dd, J = 27.9 Hz, 22.6 Hz),
113.0 (tq, J = 258.1 Hz, 36.1 Hz), 119.1 (qt, J = 286.7 Hz, 36.1 Hz), 127.8, 128.6,
129.7, 133.9.
19
F NMR (CDCl
3
): δ –81.8 (s, 3F), -122.5 (dd, J = 277.0 Hz, 7.5 Hz,
1F), -129.8 (dd, J = 277.0 Hz, 16.9 Hz, 1F).
4-Bromo- α-(pentafluoroethyl)-benzenemethanol (6b): white solid.
1
H NMR
(CDCl
3
): δ 2.78 (br, 1H), 5.09 (dd,
3
J
H, F
= 15.7 Hz,
3
J
H, F
= 7.5 Hz, 1H), 7.33 (d, J
= 8.3 Hz, 2H), 7.55 (d, J = 8.3 Hz, 2H).
13
C NMR (CDCl
3
): δ 71.4 (dd, J = 27.9
Hz, 22.9 Hz), 112.7 (tq, J = 258.5 Hz, 36.3 Hz), 118.9 (qt, J = 286.3 Hz, 36.3 Hz),
123.9, 129.4, 131.8, 132.7.
19
F NMR (CDCl
3
): δ –81.6 (s, 3F), -122.3 (dd, J =
276.8 Hz, 7.5 Hz, 1F), -129.7 (dd, J = 276.8 Hz, 15.7 Hz, 1F). MS (EI, m/z): 305
(M
+
), 184, 76.
4-Methyl-α-(pentafluoroethyl)-benzenemethanol (6c): pale yellow oil.
1
H
NMR (CDCl
3
): δ 3.38 (s, 3H), 2.52 (br, 1H), 5.07 (dd,
3
J
H, F
= 16.9 Hz,
3
J
H, F
=
7.5 Hz, 1H), 7.23 (d, J = 8.1 Hz, 2H), 7.35 (d, J = 8.1 Hz, 2H).
13
C NMR
(CDCl
3
): δ 21.1; 71.8 (dd, J = 28.3 Hz, 22.2 Hz), 113.0 (tq, J = 258.1 Hz, 35.7
Hz), 118.9 (qt, J = 286.0 Hz, 35.7 Hz), 127.7, 129.3, 130.9, 139.7.
19
F NMR
(CDCl
3
): δ –81.8 (s, 3F), -122.5 (dd, J = 275.2 Hz, 7.5 Hz, 1F), -130.0 (dd, J =
275.2 Hz, 16.9 Hz, 1F).

162
4,4,5,5,5-Pentafluoro-1-phenyl-1-penten-3-ol (6d): pale yellow oil.
1
H NMR
(CDCl3): δ 2.65 (br, 1H), 4.75 (dt,
3
J
H, F
= 15.0 Hz,
3
J
H, F
,
3
J
H, H
= 7.6 Hz, 1H),
6.25 (dd,
3
J
H, H
= 15.9 Hz,
3
J
H, H
= 7.6 Hz, 1H), 6.85 (d, J = 15.9 Hz, 1H),
7.33~7.47 (m, 5H).
13
C NMR (CDCl
3
): δ 71.1 (dd, J = 26.8 Hz, 23.8 Hz), 113.2
(tq, J = 257.1 Hz, 35.3 Hz), 119.0 (qt, J = 286.0 Hz, 35.3 Hz), 120.2, 126.9,
128.7, 128.8, 135.3, 136.7.
19
F NMR (CDCl
3
): δ –81.8 (s, 3F), -124.2 (dd, J =
274.9 Hz, 7.6 Hz, 1F), -129.1 (dd, J= 274.9 Hz, 15.0 Hz, 1F).
α-(Pentafluoroethyl)-benzenepropanol (6e):
19
F NMR (CDCl
3
): δ –81.9 (s,
3F), -124.5 (dd, J = 276.6 Hz, 7.6 Hz, 1F), -130.6 (dd, J = 276.6 Hz, 15.7 Hz),
1F).
4,4’-Dichloro- α-(pentafluoroethyl)-benzhydrol (6f): white solid.
1
H NMR
(CDCl
3
): δ 4.57 (br, 1H), 7.31 (d, J = 8.5 Hz, 4H), 7.48 (d, J = 8.5 Hz, 4H).
13
C
NMR (CDCl
3
): δ 78.4 (t, J = 26.8 Hz), 115.3 (tq, J = 257.1 Hz, 35.3 Hz), 119.1
(qt, J = 286.0 Hz, 35.3 Hz), 128.71, 128.74, 135.0, 138.2.
19
F NMR (CDCl
3
): δ
–77.5 (s, 3F), -116.9 (s, 2F). MS (EI, m/z): 371 (M
+
), 250, 151, 139, 111.
4-Methoxy- α-(4-methoxyphenyl)- α-(pentafluoroethyl)-benzenemethanol (6g):
pale yellow solid.
1
H NMR (CDCl
3
): δ 3.76 (s, 6H), 4.17 (br, 1H), 6.83 (d, J = 8.9
Hz, 4H), 7.45 (d, J = 8.9 Hz, 4H).
13
C NMR (CDCl
3
): δ 55.0, 78.2 (t, J = 23.0
Hz), 113.3, 115.5 (tq, J = 265.4 Hz, 35.0 Hz), 119.2(qt, J = 289.6 Hz, 35.0 Hz),
128.5, 132.5, 159.2.
19
F NMR (CDCl
3
): δ –77.5 (s, 3F), -116.7 (s, 2F). MS (EI,
m/z): 362 (M
+
), 242, 135.

163
3-Nitro- α-phenyl- α-(pentafluoroethyl)-benzenemethanol (6h): white solid.
1
H
NMR (CDCl
3
): δ 3.37 (s, 1H), 7.32~7.44 (m, 3H), 7.50~7.61 (m, 3H), 7.88 (d, J
= 8.0 Hz, 1H), 8.18 (d, J = 8.0 Hz, 1H), 8.50 (s, 1H).
13
C NMR (CDCl
3
): δ 78.4 (t,
J = 24.0 Hz), 115.0 (tq, J = 266.8 Hz, 35.2 Hz), 118.9(qt, J = 289.6 Hz, 35.2 Hz),
122.2, 123.4, 126.7, 128.8, 129.1, 129.2, 133.3, 139.0, 141.5, 148.1.
19
F NMR
(CDCl
3
): δ –77.5 (s, 3F), -116.1 (d, J = 279.9 Hz, 1F), -117.9 (d, J = 279.9 Hz,
1F). MS (EI, m/z): 347 (M
+
), 227, 149, 105. HRMS [FAB, (M+1
+
)]: m/z calcd for
C
15
H
11
F
5
NO
3
348.0659, found 348.0661.
2-(Pentafluoroethyl)-tricyclo[3.3.1.13,7]decan-2-ol (6i): white solid.
1
H
NMR (CDCl3): δ 1.59 (s, 1H), 1.62 (s, 1H), 1.72-1.91 (m, 6H), 2.07 (s, 1H),
2.12~2.27 (m, 6H);
13
C NMR (CDCl
3
): δ 26.1, 26.7, 32.8, 33.2 (t, J = 4.2 Hz),
33.4, 38.3, 76.0 (t, J = 21.8 Hz), 116.9 (tq, J = 263.5 Hz, 35.5 Hz), 119.7 (qt, J =
289.5 Hz, 35.5 Hz). .
19
F NMR (CDCl
3
): δ –78.7 (s, 3F), -117.4 (s, 2F).
Typical procedure for nucleophilic pentafluoroethylation of alkyl Iodides
with PhSO
2
CF
2
CF
3
. Under an argon atmosphere, into a 50-mL Schlenk flask
containing (4-iodobutyl)benzene 7a (86 mg, 0.33 mmol) and PhSO
2
CF
2
CF
3
(130mg, 0.5 mmol) in THF 3 mL at -75 °C was added dropwise a THF solution (2
mL) of t-BuOK (168 mg, 1.5 mmol). The reaction mixture was then stirred
vigorously between –75 ~ -70 °C for 2 hrs, followed by quenching with 30 mL
2% HCl aqueous solution at the same temperature. The solution mixture was
extracted with Et
2
O (25 mL x 3), and the combined organic phase was rinsed with

164
saturated NaHCO
3
solution, NaCl solution and water subsequently and then dried
over MgSO
4
. After the removal of volatile solvents under vacuum, the crude
product was further purified by silica gel column chromatography (30: 1 hexane:
ethyl acetate as eluent) to give (6,6,6,5,5-pentafluorohexyl)benzene 8a (20 mg,
57%) as a pale yellow solid and recovered (4-iodobutyl)benzene, 50mg.
1
H NMR
(CDCl
3
): δ 1.60~1.75 (m, 4H), 2.04 (m, 2H), 2.65 (t, J = 7.2 Hz, 2H), 7.16~7.23
(m, 3H), 7.30 (t, J = 7.8 Hz, 2H).
13
C NMR (CDCl
3
): δ 19.9 (t, J = 3.7 Hz), 30.5
(t, J = 22.1 Hz), 30.9, 35.5, 115.7 (tq, J = 251.6 Hz, 38.0 Hz), 119.2 (qt, J =
284.8 Hz, 38.0 Hz), 125.9, 128.3, 128.4, 141.6.
19
F NMR (CDCl
3
): δ –86.0 (s, 3F),
-118.8 (t, J = 18.0 Hz, 2F).
1-Phenoxy-5,5,5,4,4-pentafluoropentane (8b):
19
F NMR (CDCl
3
): δ –85.9 (s,
3F), -118.8 (t, J = 18.6 Hz, 2F).
Typical procedure for nucleophilic trifluoromethylation of imines with
PhSO
2
CF
3
. Under an argon atmosphere, into a 50-mL Schlenk flask containing
N-[(2,4-dichlorophenyl)methylene]-benzenamine 3f (162.5 mg, 0.65 mmol) and
PhSO
2
CF
3
(210mg, 1 mmol) in DMF 5 mL at -70 °C was added dropwise a THF
solution (4 mL) of t-BuOK (336mg, 3 mmol). The reaction mixture was then
stirred vigorously between –70 ~ -60 °C for 1.5 hrs (see Table 1), followed by
quenching with 2% HCl aqueous solution at the same temperature. The solution
mixture was extracted with Et
2
O (25 mL x 3), and the combined organic phase
was rinsed with saturated NaHCO
3
solution, NaCl solution and water

165
subsequently and then dried over MgSO
4
. After the removal of volatile solvents
under vacuum, the crude product was further purified by silica gel column
chromatography (10: 1 hexane: ethyl acetate as eluent) to give
N-(1-(2,4-dichlorophenyl)-2,2,2-trifluoroethyl)aniline 9f (189 mg, 91%) as a pale
yellow oil.
1
H NMR (CDCl
3
): δ 4.47 (d, J = 7.6 Hz, 1H), 5.64 (dq, J = 7.6 Hz, 7.1
Hz, 1H), 6.65 (d, J = 8.0, 2H), 6.85 (t, J = 8.0, 1H), 7.23 (t, J = 8.0, 2H), 7.30 (m,
1H), 7.48~7.56 (m, 2H).
13
C NMR (CDCl
3
): δ 55.8 (q, J = 30.7 Hz), 113.7, 119.6,
124.6 (q, J = 284 Hz), 127.9, 129.4, 129.5, 129.7, 130.6, 135.4, 135.6, 144.6.
19
F
NMR (CDCl
3
): δ –74.5 (d, J =7.1, 3F). MS (EI, m/z): 320 (M
+
), 248, 213, 176.
HRMS (FAB): m/z calcd for C
14
H
11
ClF
3
N (M+1
+
) 320.0221, found 320.0231.
N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)aniline (9a): pale yellow oil.
1
H
NMR (CDCl
3
): δ 4.35 (d, J = 7.1 Hz, 1H), 4.91 (dq, J = 7.1 Hz, 7.6 Hz, 1H), 6.63
(d, J = 8.0 Hz, 2H), 6.82 (t, J = 8.0 Hz, 1H), 7.19 (t, J = 8.0 Hz, 2H), 7.37 (d, J =
8.3 Hz, 2H), 7.55 (d, J = 8.3 Hz, 2H).
13
C NMR (CDCl
3
): δ 60.1 (q, J = 30.2 Hz),
114.0, 119.5, 123.3, 124.7 (q, J = 280 Hz), 129.4, 129.6, 132.1, 133.0, 145.1.
19
F
NMR (CDCl
3
): δ –74.6 (d, J = 7.6 Hz, 3F). MS (EI, m/z): 330 (M
+
), 259, 179, 90.
HRMS (FAB): calcd for C
14
H
12
BrF
3
N (M+1
+
) 330.0105, found 330.0108.
N-(1-(4-fluorophenyl)-2,2,2-trifluoroethyl)aniline (9c): pale yellow oil.
1
H
NMR (CDCl
3
): δ 4.34 (d, J = 6.8 Hz, 1H), 4.93 (dq, J = 6.8 Hz, 7.7 Hz, 1H), 6.64
(d, J = 8.1 Hz, 2H), 6.81 (t, J = 8.1 Hz, 1H), 7.10 (t, J = 8.1 Hz, 2H), 7.19 (m,
2H), 7.47 (m, 2H).
13
C NMR (CDCl
3
): δ 59.9 (q, J = 30.2 Hz), 113.9, 115.9 (d, J

166
= 21.4 Hz), 119.4, 124.8 (q, J = 282 Hz), 129.4, 129.7 (d, J = 8.5 Hz), 129.8,
145.2, 163.1 (d, J = 249 Hz).
19
F NMR (CDCl
3
): δ –74.8 (d, J = 7.7 Hz, 3F),
-112.9 (m, 1F). MS (EI, m/z): 269 (M
+
), 199, 126, 76. HRMS (FAB): m/z calcd
for C
14
H
12
F
4
N (M+1
+
) 270.0906, found 270.0904.
(Rs,S)-(-)-N-(2,3-diphenyl-1-trifluoromethyl-allyl)-2-methylpropane sulfinamide
(9k): white solid. [α]
20
D
-152 (c 1.0, CHCl
3
).
1
H NMR (CDCl
3
): δ 1.15 (s, 9H),
3.79 (d, J = 10.2 Hz, 1H), 5.02 (dq, J = 10.2 Hz, 7.6 Hz, 1H), 6.86 (s, 1H),
7.35~7.50 (m, 10H).
13
C NMR (CDCl
3
): δ 22.2, 56.9, 58.7 (q, J = 31.1 Hz), 124.4
(q, J = 282 Hz), 127.8, 128.0, 128.3, 128.6, 128.8, 130.2, 135.6, 135.7, 136.9,
137.7.
19
F NMR (CDCl
3
): δ –71.6 (d, J= 7.6 Hz, 3F).

167
7.5 Chapter 7 references

1. (a) Organofluorine compounds. Chemistry and Applications, Hiyama, T., Ed.
Springer: New York, 2000. (b) McCarthy, J. R. Utility of Fluorine in
Biologically Active Molecules, ACS Fluorine Division Tutorial, 219
th

National ACS Meeting, San Francisco, March 26, 2000. (c) Banks, R. E.;
Smart, B.E.; Tatlow, J. C. Organofluorine Chemistry: Principles and
Commercial Applications, Plenum Press: New York, 1994.

2. McCarthy, J. R. Fluorine in Drug Design: A Tutorial Review; 17
th
Winter
Fluorine Conference, St. Pete Beach, FL, 2005.

3. (a) Motherwell, W. B.; Storey, L. J. J. Fluorine Chem. 2005, 126, 491. (b)
Prakash, G. K. S.; Mandal, M. J. Fluorine Chem. 2001, 112, 123. (c) Russell,
J.; Roques, N. Tetrahedron, 1998, 54, 13771. (d) Prakash, G. K. S.; Yudin, A.
K. Chem. Rev. 1997, 97, 757. (e) Krishnamurti, R.; Bellew, D. R.; Prakash,
G. K. S. J. Org. Chem. 1991, 56, 984. (f) Prakash, G. K. S.; Krishnamurti, R.;
Olah, G. A. J. Am. Chem. Soc. 1989, 111, 393.
4. (a) Shreeve, J. M.; Yang, J. –J.; Kirchmeier, R. L. U. S. Patent 6215021,
2001. (b) Barhdadi, R.; Troupel, M.; Périchon, J. Chem. Commun. 1998,
1251. (c) Umemoto, T. Chem. Rev. 1996, 96, 1757. (d) Umemoto, T.;
Ishihara, S. J. Am. Chem. Soc. 1993, 115, 2156. (e) Umemoto, T.; Gotoh, Y.
Bull. Chem. Soc. Jpn. 1987, 60, 3307.

5. (a) Dolbier, W. R., Jr. Top. Curr. Chem. 1997, 192, 97. (b) Dolbier, W. R., Jr.
Chem. Rev. 1996, 96, 1557.

6. McClinton, M. A.; McClinton, D. A. Tetrahedron 1992, 48, 6555.

7. (a) Prakash, G. K. S.; Mandal, M.; Olah, G. A. Angew. Chem. Int. Ed. 2001,
40, 589. (b) Prakash, G. K. S.; Mandal, M.; Olah, G. A. Org. Lett. 2001, 3,
2847. (c) Prakash, G. K. S.; Mandal, M.; Olah, G. A. Synlett 2001, 1, 77.

8. Krishnamurti, R.; Bellew, D. R.; Prakash, G. K. S. J. Org. Chem. 1991, 56,
984.

9. Pooput, C.; Dolbier, W. R., Jr.; Médebielle, M. J. Org. Chem. 2006, 71,
3564.

168
10. (a) Gassman, P. G.; O’Reilly, N. J. J. Org. Chem. 1987, 52, 2481. (b)
Gassman, P. G.; O’Reilly, N. J. Tetrahedron Lett. 1985, 26, 5243.

11. (a) Kitazume, T.; Ikeya, T. J. Org. Chem. 1988, 53, 2349. (b) Kitazume, T.;
Ishikawa, N. J. Am. Chem. Soc. 1985, 107, 5186.

12. Prakash, G. K. S.; Hu, J.; Olah, G. A. Org. Lett. 2003, 5, 3253.

13. Roques, N. J. Fluorine. Chem. 2001, 107, 311.

14. Kobayashi, Y.; Yamamoto, K.; Kumadaki, I. Tetrahedron Lett. 1979, 42,
4071

15. Carr, G. E.; Chambers, R. D.; Holmes, T. F. J. Chem. Soc. Perkin Trans. I,
1988, 921.

16. Chen, Q.; Duan, J. Tetrahedron Lett. 1993, 34(26), 4241.

17. (a) Liu, G.; Cogan, D. A.; Ellman, J. A. J. Am. Chem. Soc. 1997, 119, 9913.
(b) Liu, D.; Cogan, D. A.; Owens, T. D.; Tang, T. P.; Ellman, J. A. J. Org.
Chem. 1999, 64, 1278. (c) Davis, F. A.; Zhou, P.; Chen, B. –C. Chem. Soc.
Rev. 1998, 27, 13.

169
Chapter 8
(Trifluoromethyl)trimethylsilane: A New Source of
Singlet Difluorocarbene for the Preparation of
gem-Difluorocyclopropanes

8.1 Introduction
gem-Difluorocyclopropanes have attracted much interest since the substitution
of two fluorine atoms changes the chemical reactivity and biological activity of
these compounds, which is highly useful for the agrochemical and pharmaceutical
applications.
1
Many methods have been developed for the synthesis of
gem-difluorocyclopropanes.
2
The first preparation of gem-difluorocyclopropanes
was reported by Tarrant, Lovelace, and Lilyquist in 1955 by treating
1,3-dibromo-2,2-difluoro-2-methylbutane with zinc in 1-propanol.
3
Since then
singlet difluorocarbene (:CF
2
) addition to an alkene has become the most
important method for the preparation of gem-difluorocyclopropanes. Many
reagents were reported
2
to generate difluorocarbene and react with alkenes very
effectively. However, some of these reagents are toxic, commercially unavailable,
or need high temperature for the addition reaction, which limits their use as a
singlet difluorocarbene source. TMSCF
3
has been known to be the most important
reagent for the nucleophilic trifluoromethylation, which can transfer CF
3
group

170
into various types of substrates, such as aldehydes, ketones, esters, etc.
4
Herein,
we have described the Ruppert-Prakash reagent, (trifluoromethyl)trimethylsilane
(TMSCF
3
), as a new source of singlet difluorocarbene at low temperature (–50 °C)
for the preparation of gem-difluorocyclopropanes (Scheme 8.1) from the
corresponding alkenes.

R
1
R
3
R
2
R
4
+ Me
3
SiCF
3
TBAT (cat.)
THF
°
R
1
R
3
R
2
R
4
F F
-50 C~r.t., 1 hr
213
R
1
, R
2
, R
3
, R
4
= alkyl group, H, etc.

Scheme 8.1 Singlet difluoromethylene insertion to alkenes using TMSCF
3
.

8.2 Results and discussion
The preparation of gem-difluorocyclopropanes from TMSCF
3
was carried out
according to the following protocol. Under an argon atmosphere, TMSCF
3
was
added dropwise to alkenes in THF solution in the presence of
tetrabutylammonium triphenyldifluorosilicate (TBAT) as a catalyst. The reaction
conditions were carefully optimized by using different reaction ratios, reaction
temperatures, solvents and catalysts, and we found that the best product yields can
be obtained with the following reaction conditions: 2 equiv. of alkene, 1 equiv. of

171
TMSCF
3
and 0.15 equiv. TBAT in THF were stirred at –50 °C for 10 min and then
at room temperature for 1 hour. A variety of gem-difluorocyclopropanes were
prepared in moderate to good yields as shown in Table 8.1.
The mechanism of this reaction is proposed in Scheme 8.2. Initially, the
fluorine anion (F
-
) from catalyst TBAT will attack the silicon atom in TMSCF
3
to
form a pentacovalent silicon species 4. Then free trifluoromethyl anion (CF
3
-
)
generated from 4, undergoes fast α-elimination of fluorine anion to generate
relatively stable singlet difluorocarbene (:CF
2
), which will subsequently add to
the alkenes to provide gem-difluorocyclopropanes.

Si CF
3
F
-
Si F
+ CF
3
-
-F
-
:CF
2 +
R
1
R
3
R
2
R
4
R
1
R
2
R
4
F F
R
3
Si
CF
3
F
Singlet
4

Scheme 8.2 Proposed mechanism of difluorocarbene addition of alkene with
TMSCF
3
/TBAT reagents.

172
Table 8.1 Difluorocarbene addition of alkenes using TMSCF
3
/TBAT in THF at
-50 °C ~ RT for 1 hour.

Entry Alkene 2 Product 3 Yield%
a
a
b
c
d
e
f
g
h
i
73
77
56
53
49
48
44 (31
b
)
37
a
Determined by
19
F NMR spectroscopy.
b
Isolated yield
F
F
Me
H
F
F
Me
H
CH
3
H C H
2
C
Me
CH
3
H C H
2
C
Me
F
F
F
F
F
F
F
F
F
F
Me
Me
F
F
35
j
F
F
32
Me
Me
F
F
Me
Me
12
k
Me
Me
Me
H
H
Me
Me
Me
H
H
F
F
l
19
F F

173

To improve the efficiency of difluorocarbene addition reaction, we tried
different reaction ratios and found that the best product yield was obtained when
the ratio of alkene/TMSCF
3
equals 2: 1. Different reaction temperatures were
tested and it showed that higher temperature led to lower yield. At room
temperature no gem-difluorocyclopropane was isolated. This may be due to the
rapid protonation of CF
3
-
to form trifluoromethane (CF
3
H). Besides reaction
ratios and temperature, we also tried different catalysts to optimize the reaction
condition of this difluorocarbene addition. Both TBAT and tetramethylammonium
fluoride were used as catalysts. However, when tetramethylammonium fluoride
was used, gem-difluorocyclopropane formation was not observed. As for the
solvent, both THF and toluene were tried and gave similar yields.
Both electron-rich alkenes and electron-poor alkenes as substrates were tried
for the TMSCF
3
-generate difluorocarbene addition reaction and only the
electron-rich alkenes, such as tetra-, tri-, and 1,1-dialkyl substituted alkenes
worked well with TMSCF
3
to give gem-difluorocyclopropanes with moderate to
good yields. Unreactive alkenes, such as cyclohexene, trans-stilbene, and
norbornylene, did not give any expected products with TMSCF
3
under low
temperatures. This is reasonable since singlet difluorocarbene is stable and less
reactive than other carbenes due to the presence of strong electron-withdrawing
fluorine atoms. Thus, at low temperature, only the alkenes with high reactivity

174
and nucleophilicity react with the difluorocarbene to provide
gem-difluorocyclopropanes.

8.3 Conclusions
The difluorocarbene addition reactions of (trifluoromethyl)trimethylsilane
with alkenes in the presence of catalyst TBAT were achieved successfully. This
reaction takes place under mild conditions and gave moderate to good yields of
gem-difluorocyclopropanes from the electron rich alkenes. Our studies showed
that this methodology works well with tetra-, tri-, and 1,1-dialkyl substituted
alkenes.

8.4 Experimental section
Materials and Instrumentation. Unless otherwise mentioned, all chemicals
were purchased from commercial sources. THF was distilled under nitrogen over
sodium/benzophenone ketyl prior to use. Silica gel column chromatography was
used to isolate the products using 60-200 mesh silica gel (from J. T. Baker).
1
H,
13
C, and
19
F NMR spectra were recorded on Bruker AMX 500 and AM 360 NMR
spectrometers.
1
H NMR chemical shifts were determined relative to the signal of
a residual proton of solvent CDCl
3
δ 7.26.
13
C NMR chemical shifts were
determined relative to the
13
C signal of solvent CDCl
3
δ 77.0.
19
F NMR chemical

175
shifts were determined relative to internal CFCl
3
at δ 0.0. GC-MS data were
recorded on GC-MS spectrometer with a mass selective detector at 70 eV .
Typical Procedure for Difluoromethylene insertion reactions of TMSCF
3

with alkenes. Under an argon atmosphere, tetrabutylammonium
triphenyldifluorosilicate (TBAT) (80mg, 0.15 mmol), 5 mL THF, and
tetramethylethylene (0.23 mL, 1.97 mmol) were added into a dry Schlenk flask
subsequently and cooled to -50 °C. Then, TMSCF
3
(0.146 mL, 0.99 mmol) was
added into it dropwise. The reaction mixture was stirred at -50 °C for 10 min. and
then at room temperature for 1 hour. The completion of the reaction was
monitored by
19
F NMR. (trifluoromethoxy)benzene (160mg, 0.99 mmol) was
added into the resulting solution as the internal standard. Integration of the
product peak and the internal standard peak showed that
1,1-difluoro-2,2,3,3-tetramethylcyclopropane (3a) (97 mg, 73%
19
F NMR yield)
was formed.
19
F NMR (CDCl
3
): δ –148.7 (s, 2F). The data are consistent with the
previous report.
5

1,1-Difluorro-spiro[2,4]heptane (3b): 77%
19
F NMR yield.
19
F NMR
(CDCl
3
): δ-137.6 (t, J = 10.2 Hz)
Mixtures of endo- and exo-2’,2’-difluoro-3’-methyl-spiro[bicycle[2,2,1]hept-
5-ene- 2,1’- cyclopropane, (3c) and (3c’) (1: 2.5): 56%
19
F NMR yield. 3c
19
F
NMR (CDCl
3
): δ -131.4 (dd, J = 151.4 Hz, 12.1 Hz, 1F), -149.6 (d, J = 149.7 Hz,

176
1F). 3c’
19
F NMR (CDCl
3
): -137.2 (dd, J = 152.0 Hz, 14.9 Hz, 1F), -144.0 (d, J =
147.8 Hz, 1F). MS (EI, m/z): 170 (M
+
), 155, 127, 115, 105, 91, 78, 66.
7,7-Difluoro-1-methyl-4-(1-methylethenyl)-bicyclo[4.1.0]heptane (3d): 53%
19
F NMR yield.
19
F NMR (CDCl
3
): δ -136.6 (dd, J = 152.5 Hz, 15.7 Hz, 1F),
-145.3 (d, J = 151.4 Hz, 1F). MS (EI, m/z): 186 (M
+
), 171, 143, 129, 115, 109,
107, 104, 91, 77, 67, 53.
1,1-Difluoro-spiro[2,5]octane (3e): 49%
19
F NMR yield.
19
F NMR (CDCl
3
):
δ -140.7 (t, J = 10.2 Hz). The data are consistent with the previous report.
6

1,1-Difluoro-2,2-dimethyl-3-(4-pentenyl)-cyclopropane (3f): 48%
19
F NMR
yield.
19
F NMR (CDCl
3
): δ -137.9 (dd, J = 151.3 Hz, 14.7 Hz, 1F), -149.9 (d, J =
150.4 Hz, 1F).
1,1-Difluoro-2-methyl-2-heptylcyclopropane (3g): 44%
19
F NMR yield.
Purification of 3g: Into the reaction mixture, excess bromine was added to
convert starting material 2-methyl-1-nonene into 2-bromo-2-methyl-nonane and 1,
2-dibromo-2-methyl-nonane. Subsequently, saturated Na
2
SO
3
solution was added
to destroy the excess bromine. The organic layer was separated and the aqueous
layer was extracted by ether (25 mL × 3). The combined organic solution was
dried over MgSO
4
and the solvent was removed on rotary evaporator. The crude
product was first purified by silica gel column chromatography (hexane: ethyl
acetate = 50: 1) and then by vacuum distillation at 60 °C to give pure 3g (50 mg,
31% yield) as colorless liquid.
1
H NMR (CDCl
3
): δ 0.89 (t, J = 6.4 Hz, 3H), 0.96

177
(m, 2H), 1.16 (s, 3H), 1.21~1.34 (m, 8H), 1.35~1.5 (m, 4H).
13
C NMR (CDCl
3
): δ
14.1, 16.1(d, J = 7.0 Hz), 22.4 (t, J= 10.3 Hz), 22.7, 26.1(t, J = 9.8 Hz), 26.3, 29.2,
29.4, 31.8, 32.7(d, J = 5.4 Hz), 116.9 (t, J = 289.8 Hz).
19
F NMR (CDCl
3
): δ
-138.0 (dd, J = 155.3 Hz, 11.9 Hz, 1F), -139.6 (dd, J = 152.5 Hz, 14.1 Hz, 1F).
MS (EI, m/z): 190 (M
+
), 126, 97, 91, 83, 69, 55.
exo-2’,2’-Difluoro-spiro[bicyclo[2,2,1]hept-5-ene-2,1’-cyclopropane (3h):
37%
19
F NMR yield.
19
F NMR (CDCl
3
): δ -132.8 (dd, J = 152.8 Hz, 11.6 Hz, 1F),
-138.7 (dd, J = 152.5 Hz, 14.7 Hz, 1F).
7,7-Difluoro-1-methyl-bicyclo[4.1.0]heptane (3i): 35%
19
F NMR yield.
19
F
NMR (CDCl
3
): δ -136.1 (dd, J = 152.8 Hz, 15.3 Hz, 1F), -145.5 (d, J = 152.9 Hz,
1F). MS (EI, m/z): 146 (M
+
), 131, 103, 91, 90, 82, 67. The data are consistent with
the previous report.
5

1,1-Difluoro-2-methyl-2-pentylcyclopropane (3j): 32%
19
F NMR yield.
19
F
NMR (CDCl
3
): δ -138.4 (dd, J = 150.9 Hz, 11.8 Hz, 1F), -140.0 (dd, J = 153.1 Hz,
12.2 Hz, 1F). MS (EI, m/z): 162 (M
+
), 127, 106, 100, 98, 91, 70, 69, 56, 55.
7,7-Difluoro-1-isopropyl-bicyclo[4.1.0]heptane (3k): 12%
19
F NMR yield.
19
F NMR (CDCl
3
): δ -139.7 (dd, J = 153.7 Hz, 15.1 Hz, 1F), -142.3 (d, J = 153.7
Hz, 1F).
8,8-Difluoro-3,3,7-trimethyl-tricyclo[5.1.0.01,4]octane (3l): 19%
19
F NMR
yield.
19
F NMR (CDCl
3
): δ -137.5 (dd, J = 147.2 Hz, 14.7 Hz, 1F), -146.4 (d, J =
146.8 Hz, 1F). MS (EI, m/z): 186 (M
+
), 171, 143, 123, 109, 93, 77.

178
8.5 Chapter 8 references

1. (a) Boger, D. L.; Jenkins, T. J. J. Am. Chem. Soc. 1996, 118, 8860. (b) Taguchi,
T.; Kurishita, M.; Shibuya, A.; Aso, K. Tetrahedron, 1997, 53, 9497. (c) Csuk,
R.; Eversmann, L. Tetrahedron, 1998, 54, 6445. (d) Wang, R.; Ksebati, M. B.;
Corbett, T. H.; Kern, E. R.; Drach, J. C.; Zemlicka, J. J. Med. Chem. 2001, 44,
4019.

2. (a) Fedory ński, M. Chem. Rev. 2003, 103, 1099 and the references therein. (b)
Dolbier, W. R. Jr.; Battiste, M. A. Chem. Rev. 2003, 103, 1071 and the
references therein. (c) Brahms, D. L. S.; Dailey, W. P. Chem. Rev. 1996, 96,
1585 and the references therein.

3. Tarrant, P.; Lovelace, A. M.; Lilyquist, M. R. J. Am. Chem. Soc. 1955, 77,
2783.

4. (a) Prakash, G. K. S.; Yudin, A. Chem. Rev. 1997, 757 and the references
therein. (b) Prakash, G. K. S.; Mihirbaran, M. J. Fluorine Chem. 2001, 123.

5. Wheaton, G. A.; Burton, D. J. J. Fluorine Chem. 1977, 9, 25.

6. Greenberg, A.; Y ang, D. J. Org. Chem. 1990, 55, 372.

179
Chapter 9
Difluoromethyl Phenyl Sulfone and
Bromodifluoromethyl Phenyl Sulfone as
Difluorocarbene Reagents and Their Reactions with
Phenols

9.1 Introduction
Incorporation of difluoromethoxy (OCF
2
H) functionality into organic
compounds attracts a lot of interest since the diflouromethoxy-containing
compounds have special properties in biological, medicinal and material
chemistry,
1
among which the aromatic difluoromethoxy compounds (aryl
difluoromethyl ethers) have been widely used as anti-HIV agents,
2
enzyme
inhibitors,
3
antimicrobial agents,
4
fungicides,
5
pesticides,
6
herbicides
7
and
liquid crystals.
8
The most widely used method to synthesize aryl difluoromethyl
ethers is by the addition of the difluorocarbene species (:CF
2
) to phenol
derivatives. The most common difluorocarbene reagents for the preparation of
aryl difluoromethyl ethers are chlorodifluoromethane (CHClF
2
, Freon-22)
9
and
chlorodifluoroacetates (ClCF
2
COONa or ClCF
2
COOMe).
10
Other reported
difluorocarbene reagents for the difluoromethylation of phenols include

180
halodifluoromethane,
11
CF
3
ZnBr,
12
FSO
2
CF
2
COOH
13
and XeF
2
.
14
However,
Freon-22 is an ozone-depleting precursor (ODS) and the other reagents are either
difficult to synthesize or give low product yields. Herein, we wish to report two
new and efficient difluorocarbene precursors: difluoromethyl phenyl sulfone
(PhSO
2
CF
2
H) and bromodifluoromethyl (PhSO
2
CF
2
Br) and their
difluoromethylation reactions with phenols.
The applications of difluoromethyl phenyl sulfone (PhSO
2
CF
2
H) and
bromodifluoromethyl phenyl sulfone (PhSO
2
CF
2
Br) have been described in
previous chapter. PhSO
2
CF
2
H has been developed to be a versatile nucleophile for
the nucleophilic reactions with alkyl halides, carbonyl compounds and imines.
15

PhSO
2
CF
2
Br has been developed for the (dimethylamino)ethylene (TDAE) based
reduction reactions with carbonyl compound and imines.
16
In this chapter, their
new application as difluorocarbene reagents is illustrated. (Scheme 9.1)

OH
+
PhSO
2
CF
2
H(1)
or

PhSO
2
CF
2
Br (2)
KOH
MeCN-H
2
O
OCF
2
H

Scheme 9.1 Reaction of 1 or 2 with phenols

181
9.2 Results and discussion
The difluoromethylation of phenol derivatives using 1 or 2 was carried out
according to the following procedure: difluoromethyl phenyl sulfone (1) or
bromodifluoromethyl phenyl sulfone (2) was added into a mixture of phenol and
aqueous KOH in acetonitrile at -78 ºC in a sealed tube and the reaction solution
was heated to 80 ºC and stirred for 1 to 8 hours.

Table 9.1 Difluoromethylation of phenols 3 with reagent 1 or 2

Phenol 3 Product 4 Reaction time Yield (%)
a
OH
OH
Br
OH
MeO
O OH
N
OH
3 hrs (1)
1 hr (2)
1.5 hrs (1)
1 hr (2)
4 hrs (1)
4 hrs (2)
4 hrs (1)
8 hrs (2)
4 hrs (1)
4 hrs (2)
OCF
2
H
OCF
2
H
Br
OCF
2
H
MeO
O OCF
2
H
N
OCF
2
H
45 (1)
53 (2)
58 (1)
61 (2)
37 (1)
35 (2)
60 (1)
40 (2)
41 (1)
40 (2)
3a
4a
3b
3c
3d
3e
4b
4c
4d
4e
a
isolated yield

182
The reaction conditions were carefully optimized by using different reactant
ratios, bases, solvents and reaction temperatures, and we found the best product
yields were obtained with the following reaction conditions: 4 equiv. of sulfone (1)
or (2), 1 equiv. of phenol (3), and large excess of KOH in acetonitrile-water were
stirred at 70~80 °C for 1~8 hours. A variety of aryl difluoromethyl ethers (4) were
prepared in moderate to good yields as shown in Table 9.1.

PhSO
2
CF
2
H
-
OH
-H
2
O
[PhSO
2
CF
2
-
]
-PhSO
2
-
:CF
2
S
O
O
CF
2
Br
-
OH
S
O
O
-
[CF
2
Br
-
]
-PhSO
3
-
:CF
2
+ Br
-
CF
2
Br
OH
-H
2
O
ArOH
-H
2
O
-
OH
ArO
-
:CF
2
ArOCF
2
-
H
2
O
-OH
-
ArOCF
2
H
3
4
1
5
2
6

Scheme 9.2 Plausible reaction mechanisms of 1 and 2 with phenol

The plausible reaction mechanisms were proposed in Scheme 9.2. In the case
of PhSO
2
CF
2
H, the deprotonation in the basic solution will give
(benzenesulfonyl)difluoromethyl anion species 5, which will further undergo
desulfonylation to provide the singlet difluorocarbene intermediate (:CF
2
). In the
case of PhSO
2
CF
2
Br, the nucleophilic attack by hydroxide on the sulfur center of
2 will release a bromodifluoromethyl anion 6, which upon α-elimination of Br
-
,

183
will provide a signlet difluorocarbene intermediate (:CF
2
) and bromide ion. The
formed difluorocarbene will readily react with phenoxide (ArO
-
) to give
aryloxydifluoromethide, which upon proton capture gives aryl difluoromethyl
ether, 4.

9.3 Conclusions
Novel and efficient difluorocarbene reagents, difluoromethyl phenyl sulfone
and bromodifluoromethyl phenyl sulfone were developed and their applications to
prepare structurally diverse aryl difluoromethyl ethers were carried out in
moderate yields. This method is very useful to introduce difluoromethoxy
(OCF
2
H) building blocks into bioactive organic compounds.

9.4 Experimental section
Materials and instrumentation. Unless otherwise mentioned, all other
chemicals were purchased from commercial sources. Difluoromethyl phenyl
sulfone (1) and bromodifluoromethyl phenyl sulfone (2) were prepared using
known procedures.
1-3,17
Silica gel column chromatography was used to isolate the
products using 60-200 mesh silica gel (from J. T. Baker).
1
H,
13
C and
19
F NMR
spectra were recorded on a 500 MHz NMR.
1
H NMR chemical shifts were
determined relative to the signal of a residual proton of solvent CDCl
3
δ 7.26.
13
C
NMR chemical shifts were determined relative to the
13
C signal of solvent CDCl
3

184
δ 77.0.
19
F NMR chemical shifts were determined relative to internal CFCl
3
at δ
0.0. Mass data were recorded on a GC-MS spectrometer with a mass selective
detector at 70 eV. High-resolution mass data were recorded on a high-resolution
mass spectrometer in the FAB mode.
Typical procedure for the difluoromethylation of phenols using sulfone 1
or 2. 4 equiv. of difluoromethyl phenyl sulfone (1) (384 mg, 2 mmol) or
bromodifluoromethyl phenyl sulfone (2) (542 mg, 2 mmol) was added into a
mixture of 2-naphthol (72 mg, 0.5 mmol), aqueous KOH (30 wt%, 4 mL), and
CH
3
CN (4 mL) at -78 ºC in a sealed tube. The reaction solution was then heated
to 80 ºC and stirred for 3 hours in the case of reagent 1 or 1 hour while using
reagent 2. The reaction mixture was extracted with Et
2
O (25 mL × 3) and the
combined organic phase was dried over MgSO
4
. After removal of volatile
solvents by rotary evaporator, the crude product was further purified by silica gel
column chromatography (9: 1 hexane: ethyl acetate as eluent) to give
2-(difluoromethoxy)-naphthalene 4a (44mg, 45% yield when using 1; 51 mg, 53%
yield when using 2) as colorless liquid.
1
H NMR (CDCl
3
): δ 6.64 (t, J = 74.1 Hz,
1H), 7.29 (dd, J = 8.9 Hz, 2.4 Hz, 1H), 7.46~7.56 (m, 3H), 7.79~7.89 (m, 3H).
13
C NMR (CDCl
3
): δ 115.3, 116.0 (t, J = 260.2 Hz), 119.7, 125.7, 126.9, 127.5,
127.7, 130.0, 131.0, 133.7, 148.9 (t, J = 2.6 Hz).
19
F NMR (CDCl
3
): δ -81.1 (d, J
= 74.1 Hz, 2F).

185
4-Bromo-1-(difluoromethoxy)benzene (4b) as a white solid.
1
H NMR (CDCl
3
):
δ 6.49 (t, J = 74.0 Hz, 1H), 7.02 (d, J = 8.9 Hz, 1H), 7.48 (d, J = 8.9, 2H).
13
C
NMR (CDCl
3
): δ 115.5 (t, J = 261.6 Hz), 118.4, 121.5, 132.7, 150.0 (t, J = 2.5
Hz).
19
F NMR (CDCl
3
): δ -81.7 (d, J = 74.0 Hz, 2F).
1-(difluoromethoxy)-4-methoxy-benzene (4c) as colorless liquid.
1
H NMR
(CDCl
3
): δ 3.80 (s, 3H), 6.42 (t, J = 74.4 Hz, 1H), 6.87 (d, J = 9.0 Hz, 1H), 7.07
(d, J = 9.0, 2H).
13
C NMR (CDCl
3
): δ 55.6, 114.7, 116.2 (t, J = 259.7 Hz), 121.3,
144.5, 157.2.
19
F NMR (CDCl
3
): δ -80.9 (d, J = 74.4 Hz, 2F).
1-(difluoromethoxy)-4-(phenylmethoxy)-benzene (4d) as a white solid.
1
H
NMR (CDCl
3
): δ 5.06 (s, 2H), 6.43 (t, J = 74.4 Hz, 1H), 6.96 (d, J = 9.0 Hz, 1H),
7.08 (d, J = 9.0 Hz, 2H), 7.33~7.47 (m, 5H).
13
C NMR (CDCl
3
): δ 70.5, 115,
116.2 (t, J = 259.6 Hz), 121.3, 127.4, 128.1, 128.6, 136.7, 144.8 (t, J = 2.6 Hz),
156.4.
19
F NMR (CDCl
3
): δ -80.9 (d, J = 74.4 Hz, 2F).
8-(difluoromethoxy)-quinoline (4e) as pale yellow oil.
1
H NMR (CDCl
3
): δ
7.09 (t, J = 75.7 Hz, 1H), 6.46~7.56 (m, 3H), 7.71 (dd, J = 6.6 Hz, 2.8 Hz, 1H),
8.21 (dd, J = 8.2 Hz, 1.5 Hz, 1H), 8.98 (dd, J = 4.1 Hz, 1.5 Hz, 1H).
13
C NMR
(CDCl
3
): δ 116.4 (t, J = 261.7 Hz), 119.8, 121.9, 125.3, 126.4, 129.7, 136.1, 141.0,
147.1, 150.5.
19
F NMR (CDCl
3
): δ -82.1 (d, J = 75.7 Hz, 2F).

186
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Abstract (if available)

Abstract In chapter 1, the history of fluorine chemistry, properties and applications of fluorine-containing compounds, as well as the fluorination reactions are reviewed. Some of the landmark discoveries and accomplishments in the field of fluorine chemistry are mentioned. The important chemical and biological properties of fluorine and fluorinated compounds are described leading to the wide and versatile applications of fluorine compounds in industry. The fluorination reactions, including direct fluorinations and organofluorine building block fluorinations, are introduced. Indeed, fluorine chemistry has played a significant role in many technology fields and its future will remain bright.

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Asset Metadata

Creator Wang, Ying (author)

Core Title Selective fluoroalkylations using sulfur and silicon based reagents

School College of Letters, Arts and Sciences

Degree Doctor of Philosophy

Degree Program Chemistry

Publication Date 10/09/2009

Defense Date 08/29/2007

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

Tag fluoroalkylation,nucleophilic,OAI-PMH Harvest,PhSO₂CF₂Br,PhSO₂CF₂CF₃,PhSO₂CF₂H,PhSO₂CF₃,PhSO₂TMS,TMSCF₃

Language English

Advisor Prakash, G.K. Surya (committee chair), Olah, George A. (committee member), Petruska, John A. (committee member)

Creator Email wang0@usc.edu

Permanent Link (DOI) https://doi.org/10.25549/usctheses-m858

Unique identifier UC1196796

Identifier etd-Wang-20071009 (filename),usctheses-m40 (legacy collection record id),usctheses-c127-581139 (legacy record id),usctheses-m858 (legacy record id)

Legacy Identifier etd-Wang-20071009.pdf

Dmrecord 581139

Document Type Dissertation

Rights Wang, Ying

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

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