syntheses and studies of perfluoroalkyl substituted...

SYNTHESES AND STUDIES OF PERFLUOROALKYL SUBSTITUTED

COMPOUNDS

By

CHAYA POOPUT

A DISSERTATION PRESENTED TO THE GRADUATE SCHOOL OF THE UNIVERSITY OF FLORIDA IN PARTIAL FULFILLMENT

OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY

UNIVERSITY OF FLORIDA

2005

This dissertation is dedicated to my parents, Chatchawan and Payom Pooput.

iii

ACKNOWLEDGMENTS

I express my deep gratitude to my advisor (Dr. William R. Dolbier, Jr.).

Throughout the years I have spent in his laboratory, I was able to acquire invaluable

knowledge to help me achieve my goals. Without his ideas, guidance and support, I

would not have been able to complete my research. I thank Dr. Samia Aït-Mohand for

helping me get started in research in my first year. I thank Dr Dolbier’s group members

for their help. I thank David Duncan for helping me in experiments on TDAE analogue

project. I thank the Chemistry Department of the University of Florida for accepting me

in the graduate program. I thank all my friends, especially Valerie, Igor, Rachel, Rafal,

Janet, Jim, Gary, Rong and Hongfang for their support and friendship. I would like to

thank again Valerie for always being here for me, for cheering me up when I was down

and for sharing with me most of the wonderful moments I have in Gainesville. I also

thank Valerie’s parents (Vale and Iris) for welcoming me in their home in Puerto Rico

and for giving me warmth and love that make me feel like I was a part of their family. I

thank Valerie’s big family in Puerto Rico, Sonia, Mia, Nilda, Nelson and Nydia for their

love. I also thank my aunt Wanee for her support and love when I was in France. I thank

my sister for being who she is and for her love. Finally I am eternally grateful to my

parents. Because of their sacrifices, I was able to achieve this high level of education.

Their constant support and love gave me strength.

iv

TABLE OF CONTENTS page

ACKNOWLEDGMENTS ................................................................................................. iii

LIST OF TABLES........................................................................................................... viii

LIST OF FIGURES .............................................................................................................x

LIST OF SCHEMES........................................................................................................ xiii

ABSTRACT..................................................................................................................... xvi

CHAPTER

1 INTRODUCTION ...................................................................................................1

1.1 General Information.....................................................................................1 1.2 Previous Work .............................................................................................3

1.2.1 Starting Point ...................................................................................3 1.2.2 Preliminary Results in the Group.....................................................4 1.2.3 New and Efficient Method for Synthesis of Trifluoromethyl

Sulfides ............................................................................................5 1.2.4 New and Efficient Method for Synthesis of Trifluoromethyl

Selenides ........................................................................................10

2 SYNTHESIS OF PERFLUOROALKYL THIO AND SELENOETHERS ..........12

2.1 Introduction................................................................................................12 2.2 Synthesis of Pentafluoroethyl Thioethers ..................................................14 2.3 Synthesis of Pentafluoroethyl Selenoethers...............................................16 2.4 Synthesis of Perfluorobutyl Thioethers .....................................................17 2.5 Synthesis of Perfluorobutyl Selenoethers ..................................................19 2.6 Conclusion .................................................................................................19 2.7 Experimental ..............................................................................................20

2.7.1 General Synthesis of Pentafluoroethyl Thio and Selenoethers : Synthesis of Phenyl Pentafluoroethyl Sulfide................................20

2.7.2 General Synthesis of Nonafluorobutyl Thio and Selenoethers : Synthesis of Phenyl Nonafluorobutyl Sulfide................................22

v

3 PERFLUOROALKYLATION OF IMINE TOSYLATES....................................25

3.1 Introduction................................................................................................25 3.2 Synthesis of Tosyl Imines..........................................................................28 3.3 Pentafluoroethylation of Tosyl Imines.......................................................29 3.4 Perfluorobutylation of Tosyl Imines..........................................................31 3.5 Conclusion .................................................................................................33 3.6 Experimental ..............................................................................................33

3.6.1 Syntheses of Tosyl Imines .............................................................33 3.6.2 General Procedure for Pentafluoroethylation of Tosyl Imines :

Synthesis of Methyl-N-(3,3,3,2,2-pentafluoro-1-phenyl-propyl)-benzenesulfonamide (3.1a) ............................................................36

3.6.3 General Procedure for Perfluorobutylation of Tosyl Imines: Synthesis of 4-Methyl-N-[5,5,5,4,4,3,3,2,2-nonafluoro-(4-methyl-phenyl)-propyl]-benzenesulfonamide (3.2b).....................40

4 PERFLUOROAKYLATION OF ALDEHYDES AND KETONES.....................44

4.1 Introduction................................................................................................44 4.2 Pentafluoroethylation of Aldehydes and Ketones......................................45 4.3 Perfluorobutylation of Aldehydes and Ketones.........................................47 4.4 Conclusion .................................................................................................48 4.5 Experimental ..............................................................................................48

4.5.1 General Procedure of Pentafluoroethylation of Aldehydes and Ketones: Synthesis of 1-Phenyl-2,2,3,3,3-pentafluoropropan-1-ol (4.2)............................................................................................48

4.5.2 General Procedure for Perfluorobutylation of Aldehydes and Ketones: Synthesis of 1-Phenyl-2,2,3,3,4,4,5,5,5-nonafluoropentan-1-ol....................................................................50

5 SYNTHESES AND STUDIES OF TETRAKIS(DIMETHYLAMINO)ETHYLENE ANALOGUES.........................52

5.1 Introduction................................................................................................52 5.2 Syntheses of TDAE Analogues .................................................................54

5.2.1 Synthesis of 1,3,1’,3’-Tetraalkyl-2,2’-bis(imidazolidene) ............54 5.2.2 Synthesis of 1,3,1',3'-Tetramethyl-2,2'-bis(benzimidazolylidene).54

5.3 Attempts of Trifluoromethylation using the TDAE Analogues ................56 5.3.1 Attempts of Trifluoromethylation using 1,3,1’,3’-Tetraalkyl-

2,2’-bis(imidazolidene) instead of TDAE......................................56 5.3.2 Nucleophilic Trifluoromethylation of Phenyl disulfide using

1,3,1',3'-Tetramethyl-2,2'-bis(benzimidazolylidene) .....................59 5.4 Conclusion .................................................................................................60 5.5 Experimental ..............................................................................................60

5.5.1 Synthesis of 1,3,1’,3’-Tetraethyl-2,2’-bis(imidazolidene) (5.1) ....60

vi

5.5.4 Synthesis of 1,3,1',3'-Tetramethyl-2,2'-bis(benzimidazolylidene) (5.4)................................................................................................61

6 DIMERIC DERIVATIVES OF OCTAFLUORO[2,2]PARACYCLOPHANE (AF4) : A NEW SOURCE OF PERFLUOROALKYL RADICALS....................63

6.1 Introduction................................................................................................63 6.1.1 General Information.......................................................................63 6.1.2 Synthesis of AF4............................................................................64

6.2 Kinetic Studies of CF3-AF4-dimers...........................................................66 6.2.1 Synthesis of CF3-AF4-dimer..........................................................66 6.2.2 Thermal Decomposition of the CF3-AF4-dimer ...........................68 6.2.3 Kinetic Study of Homolysis of CF3-AF4-Dimers..........................70

6.3 Kinetic Studies of C2F5-AF4-dimers .........................................................74 6.3.1 Synthesis of C2F5-AF4-dimers.......................................................74 6.3.2 Kinetic Studies of the Homolysis of C2F5-AF4-dimers.................76

6.4 Conclusion .................................................................................................80 6.5 Experimental ..............................................................................................80

6.5.1 Synthesis of CF3-AF4-Dimer.........................................................80 6.5.2 Kinetic Studies of CF3-AF4-Dimer ...............................................81

6.5.2.1 General procedure...........................................................81 6.5.2.2 Kinetic data and graphs for CF3-AF4-Dimer

at 140.1 ºC.......................................................................82 6.5.2.3 Kinetic data and graphs for CF3-AF4-Dimer at

151.0 ºC...........................................................................84 6.5.2.4 Kinetic data and graphs for CF3-AF4-Dimer at



179.7 ºC...........................................................................90 6.5.3 Synthesis of C2F5-AF4-Dimer .......................................................92 6.5.4 X-ray Structure of C2F5-AF4-Dimers ............................................93 6.5.5 Kinetic Studies of C2F5-AF4-Dimers.............................................96

6.5.5.1 General procedure...........................................................96 6.5.5.2 Kinetic data and graphs of C2F5-AF4-Dimers at

118.8 ºC...........................................................................97 6.5.5.3 Kinetic data and graphs of C2F5-AF4-Dimers at

125.7 ºC...........................................................................99 6.5.5.4 Kinetic data and graphs of C2F5-AF4-Dimers at

130.5 ºC.........................................................................101 6.5.5.5 Kinetic data and graphs of C2F5-AF4-Dimers at



151.3 ºC.........................................................................107

vii

6.5.5.8 Kinetic data and graphs of C2F5-AF4-Dimers at 156.4 ºC.........................................................................109



GENERAL CONCLUSION ............................................................................................115

LIST OF REFERENCES.................................................................................................116

BIOGRAPHICAL SKETCH ...........................................................................................122

viii

LIST OF TABLES

Table page 1-1 Trifluoromethylation of disulfides .............................................................................7

1-2 Trifluoromethylation of disulfides using a higher amount of CF3I............................8

1-3 Synthesis of trifluoromethyl selenoethers ................................................................11

2-1 Synthesis of pentafluoroethyl thioethers ..................................................................15

2-2 Synthesis of pentafluoroethyl selenoethers ..............................................................16

2-3 Synthesis of perfluorobutyl thioethers .....................................................................17

2-4 Synthesis of perfluorobutyl selenides ......................................................................19

3-1 Synthesis of tosyl imines..........................................................................................28

3-2 Nucleophilic pentafluoroethylation of tosyl imines .................................................30

3-3 Nucleophilic perfluorobutylation of tosyl imines ....................................................32

4-1 Compared yields between pentafluoroethylation and trifluoromethylation of aldehydes and ketones ..............................................................................................46

4-2 Perfluorobutylation of aldehydes and ketones .........................................................47

6-1 Rate constants of the 2 diasteromers of CF3-AF4-dimers........................................71

6-2 Half-life times of the homolysis of CF3-AF4-dimers..............................................72

6-3 Arrhenius plot data ...................................................................................................74

6-4 Activation parameters for CF3-AF4-dimers .............................................................74

6-5 Rate constants of the 2 diasteromers of C2F5-AF4-dimers ......................................77

6-6 Half-life times of the homolysis of C2F5-AF4-dimers .............................................77

6-7 Arrhenius plot data for C2F5-AF4-dimers ................................................................78

ix

6.8 Activation parameters for C2F5-AF4-dimers............................................................78

6-9 Kinetic data of d,l-CF3-AF4-Dimer at 140.1 ºC.......................................................82

6-10 Kinetic data of meso-CF3-AF4-Dimer at 140.1 ºC ..................................................82

6-11 Kinetic data of CF3-AF4-Dimers at 151.0 ºC...........................................................84




6-15 Crystal data and structure refinement.......................................................................95

6-16 Selected bond lengths [Å] and angles [°] .................................................................96

6-17 Kinetic data of C2F5-AF4-Dimers at 118.8 ºC .........................................................97

6-18 Kinetic data of C2F5-AF4-Dimers at 125.7 ºC .........................................................99

6-19 Kinetic graph of C2F5-AF4-Dimers at 130.5 ºC.....................................................101

6-20 Kinetic data of C2F5-AF4-Dimers at 139.6 ºC .......................................................103






x

LIST OF FIGURES

Figure page 1-1 Prozac®......................................................................................................................1

1-2 Celebrex® ..................................................................................................................1

1-3 Fipronil®....................................................................................................................1

2-1 2A28: insecticide .......................................................................................................12

2-2 2B29: insecticide .......................................................................................................12

2-3 2C30: pesticide ..........................................................................................................12

3-1 3A .............................................................................................................................25

3-2 3B .............................................................................................................................25

3-3 3C .............................................................................................................................27

3-4 3D .............................................................................................................................27

3-5 A resonance form of N-(N-methyl-3-indolylmethylene)-p-methylbenzenesulfonamide......................................................................................31

4-1 4A56 : Fungicide .......................................................................................................44

4-2 4B57 : insecticide ......................................................................................................44

5-1. Structure of a chiral TDAE analogue .........................................................................53

5-2 Non chiral TDAE analogue......................................................................................53

5-3 benzimidazole TDAE analogue ...............................................................................54

5-4 Cyclic voltammogram for 1,3,1’,3’-Tetraethyl-2,2’-bis(imidazolidene), C = 3mM in DMF + 0.1 mM Et4NBF4 at 20 °C, scan rate: 0.2V/s.................................59

6-1 [2,2]-paracyclophane................................................................................................64

xi

6-2 AF4...........................................................................................................................64

6-3 Trifluoromethyl-AF4 derivative...............................................................................65

6-4 19F NMR distinction examining the d,l and the meso forms of CF3-AF4-dimers ...67

6-5 Arrhenius plot for the 2 diasteromers of CF3-AF4-dimers ......................................73

6-6 19F NMR distinction examining the d,l and the meso forms of C2F5-AF4-dimers ..75

6-7 Perspective view (ORTEP) of meso-C2F5-AF4-dimer.............................................76

6-8 Arrhenius plot for the 2 diasteromers of C2F5-AF4-dimers .....................................79

6-9 Kinetic Graph of d,l-CF3-AF4-Dimer at 140.1 ºC ...................................................83

6-10 Kinetic Graph of meso-CF3-AF4-Dimer at 140.1 ºC ...............................................83





6-15 Kinetic graph of d,l-CF3-AF4-Dimers at 170.3 ºC...................................................89

6-16 Kinetic graph of meso-CF3-AF4-Dimers at 170.3 ºC ..............................................89

6-17 Kinetic graph of d,l-CF3-AF4-Dimers at 179.7 ºC...................................................91

6-18 Kinetic graph of meso-CF3-AF4-Dimers at 179.7 ºC ..............................................91

6-19 X-ray structure of meso-C2F5-AF4-dimer................................................................94

6-20 Kinetic graph of d,l-C2F5-AF4-Dimers at 118.8 ºC .................................................98

6-21 Kinetic graph of meso-C2F5-AF4-Dimers at 118.8 ºC .............................................98

6-22 Kinetic graph of d,l-C2F5-AF4-Dimers at 125.7 ºC ...............................................100

6-23 Kinetic graph of meso-C2F5-AF4-Dimers at 125.7 ºC ...........................................100




xii



6-29 Kinetic data of meso-C2F5-AF4-Dimers at 145.3 ºC .............................................106

6-30 Kinetic data of d,l-C2F5-AF4-Dimers at 151.3 ºC..................................................108

6-31 Kinetic data of meso-C2F5-AF4-Dimers at 151.3 ºC .............................................108







xiii

LIST OF SCHEMES

Scheme page 1-1 Trifluoromethylation of benzaldehyde using fluoroform...........................................2

1-2 Trifluoromethylation of benzaldehyde using trifluoromethyl zinc iodide .................2

1-3 Examples of trifluoromethylation reactions using Me3SiCF3 ....................................3

1-4 Difluoromethylation reactions of aromatic aldehydes with TDAE ...........................3

1-5 Difluoromethylation reactions of ethyl pyruvates with TDAE..................................4

1-6 Trifluoromethylation reaction of aldehydes and ketones ...........................................4

1-7 Trifluoromethylation reaction of acyl chlorides.........................................................4

1-8 Trifluoromethylation reaction of vicinal diol cyclic sulfate.......................................5

1-9 Synthesis of trifluoromethyl phenyl sulfide via SRN1 type reaction ..........................5

1-10 Synthesis of trifluoromethyl phenyl sulfide using various sources of CF3¯ ..............6

1-11 Synthesis of trifluoromethyl thioethers ......................................................................6

1-12 Efficient synthesis of trifluoromethyl sulfides ...........................................................7

1-13 Mechanism of trifluoromethylation of disulfides.......................................................7

1-14 Another possible mechanism of formation of trifluoromethyl sulfide.....................10

1-15 Synthesis of trifluoromethyl selenoethers ................................................................10

2-1 Different methods for synthesis of perfluoroalkyl sulfides and selenides ...............13

2-2 Synthesis of trifluoromethyl sulfides with CF3I / TDAE methodology...................13

2-3 Tandem CF3I process in the synthesis of trifluoromethyl sulfides ..........................14

2-4 Pentafluoroethylation of disulfides ..........................................................................15

2-5 Pentafluoroethylation of diselenides ........................................................................16

xiv

2-6 Synthesis of perfluorobutyl thioethers .....................................................................17

2-7 Synthesis of perfluorobutyl selenides ......................................................................19

3-1 Trifluoromethylation of imines using Ruppert’s reagent .........................................26

3-2 Trifluoromethylation of imines using CF3I / TDAE ...............................................27

3-1 Synthesis of tosyl imines..........................................................................................28

3-2 Nucleophilic pentafluoroethylation of tosyl imines .................................................29

3-3 Nucleophilic perfluorobutylation of tosyl imines ....................................................31

4-1 Pentafluoroethylation of aldehydes and ketones ......................................................45

4-2 Nucleophilic perfluorobutylation of aldehydes and ketones....................................47

5-1 CF3I / TDAE complex..............................................................................................52

5-2 Synthesis 1,3,1’,3’-tetraalkyl-2,2’-bis(imidazolidene) ............................................54

5-3 Multi-step synthesis of benzimidazol TDAE analogue............................................55

5-4 Nucleophilic trifluoromethylation of benzaldehyde using 1,3,1’,3’-tetraalkyl-2,2’-bis(imidazolidene) ............................................................................................56

5-5 Synthesis of phenyl trifluoromethyl sulfide by using imidazolidene TDAE analogue ...................................................................................................................57

5-6 Possible decomposition pathways for imidazolidene TDAE analogue....................57

5-7 Reactivities of imidazolidene carbene towards benzaldehyde................................58

5-8 Attempt of synthesis of phenyl trifluoromethyl sulfide by using 1,3,1',3'-Tetramethyl-2,2'-bis(benzimidazolylidene) .............................................................59

6-1 Synthesis of AF4 ......................................................................................................64

6-2 Mechanism of formation of AF4..............................................................................65

6-3 Synthesis of CF3-AF4-dimer ....................................................................................66

6-4 Formation of CF3-AF4-dimer...................................................................................66

6-6 Two possible pathways for decomposition of CF3-AF4-dimer ...............................68

6-7 Resulting products from radical trapping in different possible mechanism pathway ....................................................................................................................69

xv

6-8 Kinetic study of homolysis of CF3-AF4-Dimers.....................................................70

6-9 Synthesis of C2F5-AF4-dimers .................................................................................75

xvi

Abstract of Dissertation Presented to the Graduate School of the University of Florida in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy

SYNTHESES AND STUDIES OF PERFLUOROALKYL SUBSTITUTED COMPOUNDS

By

Chaya Pooput

August 2005

Chair: William R. Dolbier, Jr. Major Department: Chemistry

Numerous compounds containing perfluoroalkyl groups are found to be

biologically active and are largely used in pharmaceutical and agrochemical areas.

Although several methods have been developed to incorporate trifluoromethyl group into

molecules, few are for longer perfluoroalkyl chains.

Nucleophilic trifluoromethylation has been largely developed in our laboratory by

using CF3I and Tetrakis(dimethylamino)ethylene (TDAE). This methodology was

extended to longer perfluoroalkyl iodides. Pentafluoroethyl iodide and nonafluorobutyl

iodide were used instead of trifluoromethyl iodide.

Reactions with disulfides and diselenides provided efficiently perfluoroalkyl thio-

and selenoethers, where, in most cases, both halves of the disulfides or diselenides were

converted quantitatively to thio or selenoethers.

Numerous pentafluoroethyl and nonafluorobutyl substituted amines could be

obtained in high yields by extending the methodology with tosyl imines.

xvii

Reactions with aldehydes and ketones provided good yields of pentafluoroethyl

substituted alcohols. But reactions using nonafluorobutyl iodide afforded low yields.

The extension of CF3I / TDAE methodology to longer perfluoroalkyl iodides will

allow us to access to a much larger number of biologically active compounds.

Several TDAE analogues were also synthesized but their reactivity towards CF3I is

completely different from TDAE and couldn’t be used as TDAE substituents.

The syntheses and kinetic studies of perfluoroalkyl substituted AF4 dimers

provided valuable information on the use of these compounds as a stable source of

perfluoroalkyl radicals.

1

CHAPTER 1 INTRODUCTION

1.1 General Information

Pharmaceutical and agrochemical industries have a growing interest in compounds

containing perfluoroalkyl groups. Many new drugs contain trifluoromethyl groups:

examples are shown in Figures 1-1 and 1-2:

O

F3C

NHCH3

NSN CF3O

O

H2N

Figure1-1. Prozac® Figure1-2. Celebrex®

NN

CF3

SNC

ClCl

NH2

O

CF3

Figure1-3. Fipronil®

Among the several methods of incorporating the trifluoromethyl group into a

compound, one of the most useful is to generate in situ the unstable trifluoromethyl anion

to undergo nucleophilic trifluoromethylation on electrophilic substrates.

2

Various methods have been used to generate the trifluoromethyl anion: i) The

groups of Roques1 and Normant2 effectively performed nucleophilic trifluoromethylation

by using fluoroform (CF3H) in the presence of base; and ii) Kitazume3 used

trifluoromethylzinc iodide, prepared from trifluoromethyl iodide and zinc powder with

ultrasonic irradiation, as a trifluoromethylation reagent (Scheme 1-2).

H

O

CF3H +1) DMF, -50 oC

2) tBuOK, 1h3) AcOH, 0 oC - 20 oC

H

OHCF3

Yield = 67%

Scheme 1-1. Trifluoromethylation of benzaldehyde using fluoroform

Curently the most commonly used source of the nucleophilic trifluoromethyl anion

is (trifluoromethyl)trimethylsilane (TMSCF3). In the past few years the groups of Prakash

and Shreeve have developed the method of generating in situ CF3¯ by reaction of

(trifluoromethyl)trimethylsilane (CF3TMS) with TBAF,4 CsF.5 Fuchikami6 reported that

trifluoromethylation reactions of carbonyl compounds can also be catalyzed by Lewis

bases, such as triethylamine, pyridine or triphenyl phosphine.

H

O

ultrasound

H

OHCF3

Yield = 72%

CF3I Zn+ + DMF

Scheme 1-2. Trifluoromethylation of benzaldehyde using trifluoromethyl zinc iodide

Extensive research had been performed on the use of this reagent with different

substrates, such as ketones, esters and disulfides.

3

R1 R2

O

Me3SiCF3 R1 R2

OH

CF3CsF

H3O+

+

R1 OMe

O

Me3SiCF3Bu4N

+ F-

H3O+

+R1 CF3

O

R-S-S-R Me3SiCF3 THF

0 oC+ + R-S-CF3Bu4N

+ F-

Scheme 1-3. Examples of trifluoromethylation reactions using Me3SiCF35, 7, 8

Even though (trifluoromethyl)trimethylsilane is a powerful trifluoromethylation

agent, it is very expensive. Our group wanted to find a less expensive and more direct

way to generate the nucleophilic CF3¯ anion.

1.2 Previous Work

1.2.1 Starting Point

Since 1998, with the collaboration of Dr. Maurice Médebielle, we have

demonstrated that tetrakis(dimethylamino)ethylene (TDAE) can be used as an efficient

reductant to generate nucleophilic difluoromethyl anions from chloro- and

bromodifluoromethyl compounds.9, 10

RCF2X ArCHODMF

OH

Ar

CF2R

H

-20 0 to RT

TDAE

Scheme 1-4. Difluoromethylation reactions of aromatic aldehydes with TDAE

RCF2X CH3COCO2EtDMF

OH

H3C

CF2R

CO2Et

-20 0 to RT

TDAE

4

Scheme 1-5. Difluoromethylation reactions of ethyl pyruvates with TDAE

Pawelke earlier demonstrated that TDAE could be used with trifluoromethyl iodide

to prepare CF3TMS from TMSCl.11 With these results, we decided to use TDAE to

reduce trifluoromethyl iodide into trifluoromethyl anion.

1.2.2 Preliminary Results in the Group

With the aldehydes and ketones, the CF3I / TDAE system provided very good

yields, which were comparable to those obtained in analogous reactions using CF3TMS.12

R1 R2

OCF3I

DMF

OHR1

CF3

R2TDAE-20 0 to RT

hν, 12 hrs

1 eq 2.2 eq 2.2 eq

Scheme 1-6. Trifluoromethylation reaction of aldehydes and ketones

Aryl acyl chlorides also underwent clean recations.13

Cl

O

X

O

OF3C CF3

X X

CF3I / TDAE DME-20O C to RTRT, 2 hrs

Scheme 1-7. Trifluoromethylation reaction of acyl chlorides

Unfortunately the CF3I / TDAE system was not successful in reactions with

epoxides. But in 1988 Gao and Sharpless demonstrated that vicinal diol cyclic sulfates

could be used as epoxide equivalents, with a higher reactivity.14

OS

O

O O

CF3ITHF

CF3HO

IHO

OHF3CTDAE

-20o C to RT

20% H2SO4

55% < 1%

40%

5 hrs

+

1 eq 2.2 eq 2.2 eq

53-95 %

48-98 %

5

Scheme 1-8. Trifluoromethylation reaction of vicinal diol cyclic sulfate

The reaction is highly regioselective because only 1% of the other isomer is

formed. Since the cyclic sulfate is highly reactive, competition between the iodide anion

and the trifluoromethyl anion occurred, which did not happen with other substrates.15

1.2.3 New and Efficient Method for Synthesis of Trifluoromethyl Sulfides

Aryl trifluoromethyl sulfides continue to attract much interest within

pharmaceutical companies, as witnessed by the significant number of process patent

applications recently submitted that are devoted to their preparation17. This interest

derives from the recognized potential of the SCF3 group to have a positive influence on

biological activity.

Diverse methods have been reported for the synthesis of aryl trifluoromethyl

sulfides18, but two seem to emerge as preferred methods.

The first is the SRN1 reaction of aryl thiolates with trifluoromethyl iodide or

bromide. Yagulpolskii was the first to report the reaction in 1977, using trifluoromethyl

iodide and UV irradiation19:

Ph-SH CF3ICH3CN, 0 - 5

oC+ Ph-S-CF3NaOCH3 , UV 89%

Scheme 1-9. Synthesis of trifluoromethyl phenyl sulfide via SRN1 type reaction

Wakselman and Tordeux used trifluoromethyl bromide in high pressure

(2 atm),20, 21 and with other variations,22, 23 this method is generally efficient when using

aryl thiolates but gives a much lower yield when using alkanethiolates.24

The other popular method involves the reaction of trifluoromethyl anion (generated

in situ by various methods) with aryl and alkyl disulfides:

6

PhS-SPh CF3SiMe3THF, 0 oC

+ Ph-S-CF3

32% 8

Ph-S -+Bu4N

+ F-

PhS-SPh CF3CO2K+ Ph-S-CF3sulfolane, ∆

56% 25

84% 26

Ph-S -+

PhS-SPh + Ph-S-CF3

87% 27

Ph-S -+tBuOK

N N

OH

F3C

H

Ph

Scheme 1-10. Synthesis of trifluoromethyl phenyl sulfide using various sources of CF3¯

Although good yields can be obtained, the method suffers from the fact that half of

the disulfide is wasted in the process (formation of thiolates for the other half).

In our investigation16, the CF3I / TDAE system turned out to be a better method for

synthesis of trifluoromethyl sulfides than with Ruppert reagents (Table 1-1). Both aryl

and aliphatic disulfides provided near 100 % yield. The reaction is very fast - only 2

hours of stirring at room temperature was sufficient to give a quantitative yield, as shown

in the entries 4 and 5.

R-S-S-R TDAE CF3I DMF0 oC to RT

R-S-CF3+ +

RT several hr1 eq. 2.2 eq 2.2 eq

Scheme 1-11. Synthesis of trifluoromethyl thioethers

7

Table 1-1. Trifluoromethylation of disulfides

entry R Stirring time at RT (hrs) NMR yield

1 Phenyl 12 80

2 butyl 12 >98

3 ethyl 12 >98

4 butyl 4 >98

5 butyl 2 >98


R-S-CF3+ +


180 - 200%based of equivalentsof disulfides

Scheme 1-12. Efficient synthesis of trifluoromethyl sulfides

It has been demonstrated that the mechanism of the reaction is as shown in the

Scheme 1-13.

TDAE CF3I

CF3R-S-S-R

R-S CF3I

CF3

R-S-CF3

R-S-CF3

I

I

R-S

+ TDAE 2+ +

+ +

+ +

Scheme 1-13. Mechanism of trifluoromethylation of disulfides

It occurred to us that CF3I could also be used as a substrate for reaction, via the

SRN1 mechanism, with the thiolate coproduct; thus, potentially enabling both halves of the

disulfide to be used in a one pot reaction, where CF3I would be used in two different

reactions, both of which lead to the same desired product. First TDAE reduces CF3I to

nucleophilic “CF3¯”, which reacts with the disulfide to form trifluoromethyl sulfide and

8

thiolate. The resulting thiolate reacts with the excess of CF3I, in a SRN1 type mechanism

to create the second molecule of sulfide.

When more than 4.2 equivalents of CF3I are used while the quantity of TDAE stays

at 2.2 equivalents, trifluoromethyl sulfides can be obtained at nearly 200% yield, based

on the number of equivalents of disulfides, as shown in the Table 1-2.

Table 1-2. Trifluoromethylation of disulfides using a higher amount of CF3I

entry R Equiv. of CF3IStirring time at RT

(hrs) NMR yield*

1 Phenyl 5 12 186

2 butyl 5 12 170

3 4-pyridyl 5 12 ≈ 200

4 butyl 5 4 170

5 butyl 4.2 4 175

6 butyl 3.2 4 130

7 butyl 4.2 2 170

8 ethyl 4.2 2 180

9 2-pyridyl 4.2 2 180

10 t-butyl 4.2 12 0

11 2-nitrophenyl 4.2 2 185

12 benzothiazolyl 4.2 2 190

13 4-aminophenyl 4.2 12 20

S

N

benzothiazolyl group

*based of number of equivalents of disulfides

The entries 1 to 3 show that with 5 equivalents of CF3I, yields of nearly 200%

could be obtained whether with aryl disulfide or alkyl disulfide. The following entries are

attempts to optimize the procedure: 3.2 equivalents of CF3I did not seem to be sufficient,

9

since the yield was only 130% (entry 6) whereas more than 4.2 equivalents gave nearly

quantitative yields. Moreover 2 hours of stirring at room temperature was sufficient.

Although with t-butyl disulfide, we were unable to perform the trifluoromethylation

(entry 10), the result is nevertheless interesting because this shows a high influence of the

steric effect for the reaction. Moreover the lack of reactivity of t-butyl disulfide has been

noted previously, when CF3TMS was used as trifluoromethyl anion source.8 The entry 13

revealed another limitation of this methodology: CF3¯ anion being extremely unstable

reacts preferable first towards acidic protons, such as the ones present in the amino group

hence the very low yield for the reaction with 4-aminophenyl disulfide (Table 1-2, entry

13). All the groups containing acidic protons need then to be protected first before

undergoing trifluoromethylation with CF3I / TDAE method. In the case of 4-aminophenyl

disulfide, 4-nitrophenyl disulfide can be used and the nitro group can be reduced later to

obtain the amino group; the amino group can also be protected twice with BOC to avoid

the harsh conditions of reduction of nitro group.

It might be argued that these results could derive from reduction by TDAE of

disulfide to 2 equivalents of thiolate anion. The thiolate could react then with CF3I

proceeding entirely via SRN1 type reaction. If that were the case, the 2.2 equivalents of

CF3I along with 2.2 equivalents of TDAE should have been sufficient to obtain the high

yields observed in the Table 1-2. However, in the case where 2.2 equivalents of CF3I

were used (Table 1-1), yields never exceeded 100%. This probably means that CF3I is

reduced faster than the disulfides.

10

TDAE R-S-S-R

2 R-S 2 CF3I

2 R-S

2 R-S-CF3 2 I

+ TDAE 2+

+ +

Scheme 1-14. Another possible mechanism of formation of trifluoromethyl sulfide

Nevertheless, a control reaction was carried out to provide more definitive evidence

for the proposed dual mechanism synthetic process. CF3I (5 equiv.) and TDAE (2 equiv.)

were added first together at –20°C so that TDAE would be totally oxidized by the

reaction with CF3I. The solution was then allowed to warm to -5°C, at which time, n-

butyl disulfide was introduced. At this point there should be little if any TDAE remaining

to react with the disulfide. Despite this, the observed yield from this reaction was 160%,

which compares well with the 170% obtained when using the normal procedure (Table 1-

2, entry 5). This can be concluded that the reaction likely proceeds via the two-stage

process described earlier. These interesting results mean that the disulfides provide two

molecules of trifluoromethyl sulfides, which was never observed before in the other

methods.

1.2.4 New and Efficient Method for Synthesis of Trifluoromethyl Selenides

Since diselenides have similar reactivities than that of disulfides, reactions of

nucleophilic trifluoromethylation were also performed on diphenyl diselenide16.

R-Se-Se-R TDAE CF3I DMF0 oC to RT

R-Se-CF3

RT overnight1 eq. 2.2 eq

+ +

4.2

~200%based of number of equivalents of diselenides

Scheme 1-15. Synthesis of trifluoromethyl selenoethers

11

Table1-3. Synthesis of trifluoromethyl selenoethers

Entry R NMR Yield (%)*

1 phenyl 198

2 4-Chlorophenyl ≈ 200

3 methyl 180

*based of number of equivalents of diselenides

The methodology is efficient for both aliphatic and aromatic diselenides.

The CF3I / TDAE methodology are very efficient for many electrophilic subtrates,

we are interested now to extend this methodology to longer perfluorinated chains by

using other perfluoroalkyl iodides. We would be able to access to a higher amount

biologically active compounds.

12

CHAPTER 2 SYNTHESIS OF PERFLUOROALKYL THIO AND SELENOETHERS

2.1 Introduction

Parallel to trifluorothioethers, trifluoroselenoethers, longer perfluoroalkyl chains are also

developed to be used as biologically active compounds. Few examples are given below.

Cl CF3

Cl

N

SH3C

SCF2CF3

NH2

HN

Br

Br SCF2CF3O

Figure 2-1. 2A28: insecticide Figure 2-2. 2B29: insecticide

Cl

CF3

Cl

NN

CNSC4F9

NHN

Figure 2-3. 2C30: pesticide

Despite the increasing interest in perfluoroalkyl sulfides, few methods have been

developed to synthesize them. The two main methods consists in first through SRN1

reaction of aryl thiolates with perfloroalkyl iodide31 or bromide.32 The second method

involves perfluoroalkyl anion, generated from thermal decarboxylation of potassium

13

perfluoroalkyl carboxylate,33 with aryl disulfides with the inconvenience of possible

carbanion rearrangement or decomposition and one half of the disulfide is wasted.

Another notable method for synthesis of perfluoroalkyl selenides consists in reaction

between perfluoroalkyl radicals and diselenides.34 So far there is no efficient method for

synthesis of perfluoroalkyl aliphatic sulfides.

PhS-SPh + CF3CF2CO2K∆ PhS-CF2CF3 + PhSK

70 %33

PhSe-SePh + 2 C4F9IHOCH2SO2Na 2 PhSe-C4F9

57%34

PhSH + C4F9I NaH PhS-C4F9

66% 31

PhSK + CF3CF2Br PhS-CF2CF3

33% 32

Scheme 2-1. Different methods for synthesis of perfluoroalkyl sulfides and selenides

Our laboratories have developed a new and efficient method for synthesis of

trifluoromethyl sulfides and selenides, using CF3I / TDAE system.16 This methodology

has now been extended to longer perfluoroalkyl iodides.


R-S-CF3+ +


180 - 200%based of equivalentsof disulfides

Scheme 2-2. Synthesis of trifluoromethyl sulfides with CF3I / TDAE methodology

14

2.2 Synthesis of Pentafluoroethyl Thioethers

The same way that TDAE reduces trifluoromethyl iodide into trifluoromethyl

anion, pentafluoroethyl iodide was also expected to be reduced by TDAE into

pentafluoroethyl anion. The tandem process, involving nucleophilic attack of

trifluoromethyl anion to disulfide followed by SRN1 by the resulting thiolate on the excess

of CF3I (Scheme 2-3), was also expected.

TDAE CF3I

CF3R-S-S-R

R-S CF3I

CF3

R-S-CF3

R-S-CF3

I

I

R-S

+ TDAE 2+ +

+ +

+ +

Scheme 2-3. Tandem CF3I process in the synthesis of trifluoromethyl sulfides16

The first experiment was carried out using 1 equivalent of phenyl disulfide, 4.2

equivalents of C2F5I and 2.2 equivalents of TDAE added at -20 ºC. The color of the

solution turned quickly deep red as TDAE was introduced. This may show the formation

of the complex between TDAE and C2F5I, like in the case between TDAE and CF3I. The

reaction mixture was allowed to warm up slowly. But unlike CF3I where the complex

with TDAE starts decomposing at 0 °C, the complex with C2F5I started decomposing

around -10 ºC, as white salt could be seen forming. Apparently the complex between

C2F5I and TDAE is less stable than that with CF3I. But the fact that TDAE was able to

form a complex with C2F5I was a good sign meaning that the reaction may proceed in the

same way as with CF3I / TDAE. The mixture was stirred overnight. 19F NMR was taken

to calculate the yield. The reaction yielded 198 % based on the number of equivalents of

disulfides (Table 2-1, entry 1).

15

R-S-S-R TDAE CF3CF2I DMF-10 oC to RT

R-S-CF2CF3+ +


Scheme 2-4. Pentafluoroethylation of disulfides

Reactions with different disulfides (aromatic and aliphatic) were then performed.

The results are shown in Table 2-1.

Table 2-1. Synthesis of pentafluoroethyl thioethers

Entry R time at RT (hrs) NMR yield*

1 Phenyl32 12 >198

2 phenyl 2 >198

3 ethyl 2 135

4 ethyl 4 170

5 ethyl 12 175

6 butyl 12 180

7 2-pyridyl35 2 >198

8 4-pyridyl 2 190

*Based on the number of equivalents of disulfides

The entries 2, 7 and 8 proved that, as in the case of CF3I, 2 hours are sufficient to

obtain quantitative yield for aryl disulfides. But in entries 3 to 5, two, even four hours

didn’t seem to be sufficient to obtain good yields in the case of aliphatic disulfides. The

mixture required to stirring overnight to be able to obtain 175 %. Even though, the yields

are very similar to the ones with CF3I, aliphatic disulfides require a much longer time.

This may be explained by the fact that it is more diificult for aliphatic thiolates to

undergo SRN1 reaction. Somehow the presence of TDAE seems to enhance the reactivity

16

of aliphatic thiolates on SRN1 reaction, since we could always obtain good yields from

aliphatic disulfides with CF3I / TDAE system. In the case of C2F5I the complex formed

with TDAE is less stable than with CF3I and this may one of the reasons why the reaction

is slower for aliphatic disulfides. It may also come from the fact that C2F5I is less reactive

as a substrate in the SRN1 process.

In spite of longer reaction time for aliphatic disulfides, the yields obtained are

similar to the ones from CF3I. The two halves of the disulfides are used efficiently to

form two molecules of pentafluorethyl thioethers.

2.3 Synthesis of Pentafluoroethyl Selenoethers

Since diselenides have similar reactivities as disulfides. The reactions of

nucleophilic pentafluoroethylation were also performed on diselenides.

R-Se-Se-R TDAE CF3CF2I DMF-10 oC to RT

R-Se-CF2CF3


+ +

Scheme 2-5. Pentafluoroethylation of diselenides

Table 2-2. Synthesis of pentafluoroethyl selenoethers

Entry R Eq. of C2F5I NMR yield* (%)

1 Phenyl34 2.2 ≈ 100

2 phenyl 4.2 ≈ 200

3 4-chlorophenyl 4.2 ≈ 200

*Based on the number of equivalents of diselenides

As expected, from 1 equivalent of diselenides, 2.2 equivalents of C2F5I gave

quantitatively 1 equivalent of pentafluoroethyl selenides (Table 2-2, entry 1) and 4.2

equivalents provided efficiently 2 equivalents of selenides.

17

2.4 Synthesis of Perfluorobutyl Thioethers

Since the nucleophilic perfluoroalkylation using TDAE was successfully extended

to C2F5I, longer perfluoroalkyl iodides were then considered for experiments, we decided

to performed reactions with nonafluorobutyl iodided

R-S-S-R TDAE C4F9I DMF-20 oC to RT

R-S-C4F9+ +


Scheme 2-6. Synthesis of perfluorobutyl thioethers

The reactions were performed in the same fashion as the usual reactions of

trifluoromethylation of disulfides, with the difference that C4F9I is a liquid instead of a

gas like CF3I or C2F5I, the total reflux condenser was not needed any longer. The

complex C4F9I / TDAE seems to be much less unstable than the ones from CF3I / TDAE,

since the usual TDAE salt was formed just above -20 ºC, very shortly after the addition of

TDAE.

Table 2-3. Synthesis of perfluorobutyl thioethers Entry R Eq. of C4F9I NMR yield* (%)

1 Phenyl36 2.2 70

2 ethyl 2.2 40

3 butyl 2.2 40

4 2-pyridyl37 2.2 ≈100

5 4-pyridyl 2.2 ≈200

6 phenyl 4.4 140

7 butyl 4.4 40

8 2-pyridyl 4.4 195 *Based on the number of equivalents of disulfides

18

Aryl disulfides gave satisfactory to good yields (Table 2-3, entries 1 and 4) when

2.2 equivalents of C4F9I were used. But aliphatic disulfides resulted in only modest

yields, 40%, (Table 2-3, entries 2 and 3). This may be explained by the low stability of

the C4F9I / TDAE complex or the low reactivity of C4F9¯ anion towards aliphatic

disulfides. The case of 4-pyridyl disulfide (Table 2-3, entry 5) proved to be very

interesting. With only 2.2 equivalents of C4F9I, we were able to obtain 2 equivalents of

perfluorobutyl 4-pyridyl sulfide, where usually 4.2 equivalents were needed to obtain the

same results in other cases. This means that the tandem process16 (where the

perfluoroalkyl anion, formed by reduction of perfluoroalkyl iodide by TDAE, attacks

disulfide to form the first thioether and then the resulting thiolate reacts with the excess

of perfluoroalkyl iodide through SRN1 reaction to form the second thioether (Scheme 2-

3)) is not applicable anymore in this case. TDAE didn’t reduce C4F9I into C4F9¯anion but

instead reduced entirely 4-pyridyl disulfide, forming 2 equivalents of thiolate which react

with C4F9I through SRN1 mechanism. It seems that C4F9I is not as reactive towards TDAE

as CF3I or C2F5I and since the disulfide was also present in the reaction mixture when

TDAE was added and aryl disulfides can be easily reduced, TDAE preferably reduced 4-

pyridyl disulfide over C4F9I. This problem was not encountered in the case of CF3I and

C2F5I because their reactivity towards TDAE was high enough that TDAE reduced them

first.

When 4.4 equivalents of C4F9I were used on phenyl or 2-pyridyl disulfide, 140 %

and 195 % of thioethers were obtained respectively (Table 2-3, entries 6 and 8). But 40 %

yield was only obtained for butyl disulfide, the same yield as when 2.2 equivalents of

19

C4F9I were used. It seems that aliphatic thiolates anions couldn’t undergo reaction at all

through an SRN1 reaction with C4F9I.

2.5 Synthesis of Perfluorobutyl Selenoethers

The syntheses of perfluorobutyl selenides were also performed.

R-S-S-R TDAE C4F9I DMF-20 oC to RT

R-S-C4F9+ +


Scheme 2-7. Synthesis of perfluorobutyl selenides

Table 2-4. Synthesis of perfluorobutyl selenides

Entry R Eq. of C4F9I NMR yield* (%)

1 Phenyl34 2.2 ≈ 200

2 methyl 2.2 ≈ 200

*Based on the number of equivalents of diselenides

As with 4-pyridyl disulfide, both aryl and aliphatic diselenides only underwent

through SRN1 process, resulting in nearly 200 % yields when 2.2 equivalents of C4F9I

were used (Table 2-4). Contrary to disulfides, aliphatic deselenides could react

quatitatively with C4F9I via SRN1 process.

2.6 Conclusion

The nucleophilic perfluoroalkylation methodology developed with CF3I / TDAE

system was successfully extended to C2F5I: similar results were obtained and the two

halves of disulfides and deselenides were efficiently used. The methodology seemed to

reach its limits with C4F9I. Whereas some aryl disulfides still gave good yields, aliphatic

disulfides resulted in poor yields. But the most important point is the fact that for some

disulfides and for all the diselenides, TDAE was unable to react with C4F9I and

20

preferably reduced disulfides or diselenides instead, forcing the reactions to undergo

exclusively through SRN1 mechanism of thiolate anion. From a synthetic point of view,

this didn’t present a problem. On the contrary, a smaller amount of TDAE and

perfluorobutyl iodide was used to give 200% yields. But in the mechanistic point of view,

the tandem process, where the perfluoroalkyl iodide switches roles from being a reactant

to being a substrate in one pot reaction, couldn’t be applied anymore and the role of

TDAE was only to reduce the disulfides. Moreover reducing disulfides to form thiolates

seems to be much less convenient than deprotonating a more easily available thiols by a

base, as the usual methods for perfluoralkyl thioether synthesis via SRN1 reactions.

However this C4F9I / TDAE, even when TDAE served only as reductant of

disulfides, still presents an advantage to other methods where the yields were not higher

than 60 %31,34

2.7 Experimental

Nuclear Magnetic Resonance (NMR) spectra were recorded on a Varian Unity plus

300 MHz Spectrometer system. The proton (1H) NMR were recorded at 300 MHz with

external tetramethylsilane (TMS, δ = 0.00 ppm) as a reference. Fluorine (19F) and proton

(1H) NMR were recorded at 300 MHz with external fluorotrichloromethane (CFCl3, δ =

0.00 ppm) as a reference for 19F NMR and TMS (δ = 0.00 ppm) for 1H NMR. Deuterated

chloroform (CDCl3) was used as NMR solvent.

2.7.1 General Synthesis of Pentafluoroethyl Thio and Selenoethers : Synthesis of Phenyl Pentafluoroethyl Sulfide

In 25 mL, 3-neck-round bottom flask, equipped with a dewar type condenser and

N2, diphenyl disulfide (0.8 g, 3.68 mmol) was disolved in 10 mL of anhydrous DMF. The

solution was cooled at -20 ºC. Pentafluoroethyl iodide (3.8 g, 15.45 mmol) was then

21

introduced to the solution. TDAE (2 mL, 8.1 mmol) was added around -15 ºC. The

reaction mixture became quickly dark red. The reaction was allowed to warm up slowly

to room temperature. And as the bath temperature reached -10 ºC white solid was formed.

The reaction mixture was stirred at room temperature for 2 hours (or overnight in the case

of alkyl disulfides). The orange solution was filtered and the solid was washed with

diethyl ether. The orange solution was filtered and the solid was washed with diethyl

ether (20 mL). 20 mL of water was added to the ether solution. The two phases were

separated and the aqueous phase was extracted with 20 mL of ether 2 more times. The

combined ether layers were washed with brine and dried over MgSO4. The solvent was

removed and the crude product was purified by silica gel chromatography (CH2Cl2 /

hexanes = 1:9) to give phenyl pentafluoroethyl sulfide in the yield of 198%

19F NMR(300 MHz, CDCl3) δ -83.00 (t, JFF = 3.1 Hz , 3F, CF3); -92.32 (q, JFF = 3.1

Hz ,2F, CF2) ppm

Ethyl Pentafluoroethyl Sulfide

1H NMR(300 MHz, CDCl3) δ 2.70 (q, J = 7.2 Hz, 2H, CH2); 1.32 (t, J = 7.2 Hz,

3H, CH3)

19F NMR(300 MHz, CDCl3) δ -83.00 (t, JFF = 3.2 Hz ,3F, CF3); -92.32 (q, JFF = 3.2

Hz, 2F, CF2) ppm

Butyl Pentafluoroethyl Sulfide

1H NMR(300 MHz, CDCl3) δ 2.69 (t, J = 7.3 Hz, 2H, CH2); 1.66 (quintet, J = 7.6

Hz, 2H, CH2); 1.42 (sextuplet, J = 7.6 Hz, 2H, CH2); 0.93 (t, J = 7.3 Hz, 3H, CH3)

19F NMR(300 MHz, CDCl3) δ -82.95 (t, JFF = 3.2 Hz ,3F, CF3); -92.55 (q, JFF = 3.2

Hz, 2F, CF2) ppm

22

2-Pyridyl Pentafluoroethyl Sulfide35

1H NMR(300 MHz, CDCl3) δ 8.47 (m, 1H, ArH); 7.62 (m, 2H, ArH); 7.11 (m, 1H,

ArH)

19F NMR(300 MHz, CDCl3) δ -83.17 (t, JFF = 2.01 Hz ,3F, CF3); -91.03 (q, JFF =

2.01 Hz ,2F, CF2) ppm

4-Pyridyl Pentafluoroethyl Sulfide

1H NMR(300 MHz, CDCl3) δ 8.51 (dd, J1 = 4.8 Hz, J2 = 2.0 Hz, 2H, ArH); 7.37

(dd, J1 = 4.7 Hz, J2 = 1.75 Hz, 2H, ArH)

19F NMR(300 MHz, CDCl3) δ -82.95 (t, JFF = 2.14 Hz , 3F, CF3); -90.78 (q, JFF =

2.14 Hz, 2F, CF2) ppm

Phenyl Pentafluoroethyl Selenide34

19F NMR(300 MHz, CDCl3) δ -84.74 (t, JFF = 3.2 Hz, 3F); -92.14 (q, JFF = 3.2 Hz,

2F, CF2) ppm

2.7.2 General Synthesis of Nonafluorobutyl Thio and Selenoethers : Synthesis of Phenyl Nonafluorobutyl Sulfide

In a 25 mL round bottom flask, equipped with a rubber septum and N2, diphenyl

disulfide (0.8 g, 3.68 mmol) was disolved in 10 mL of anhydrous DMF. The solution was

cooled at -30 ºC. Nonafluorobutyl iodide (1.4 mL, 15.45 mmol) was then introduced to

the solution. TDAE (2 mL, 8.1 mmol) was added around -20 ºC. The reaction mixture

became quickly dark red. White solid was formed shortly after the addition of TDAE.

The mixture was allowed to warm up slowly to the room temperature was stirred

overnight. The orange solution was filtered and the solid was washed with diethyl ether

(20 mL). 20 mL of water was added to the ether solution. The two phases were separated

and the aqueous phase was extracted with 20 mL of ether 2 more times. The combined

23

ether layers were washed with brine and dried over MgSO4. The solvent was removed

under vacum and the crude product was purified by silica gel chromatography (CH2Cl2 /

hexanes = 1:9) to give phenyl nonafluorobutyl sulfide in the yield of 140%

19F NMR(300 MHz, CDCl3) δ -81.28 (t, JFF = 10.2 Hz , 3F, CF3); -87.43 (m, 2F,

SCF2); -120.46 (m, 2F, CF2); -125.90 (m, 2F, CF2) ppm

Ethyl Nonafluorobutyl Sulfide

1H NMR(300 MHz, CDCl3) δ 2.70 (q, J = 7.2 Hz, 2H, CH2); 1.32 (t, J = 7.2 Hz,

3H, CH3)


SCF2); -121.05 (m, 2F, CF2); -125.60 (m, 2F, CF2) ppm

Butyl Nonafluorobutyl Sulfide

1H NMR(300 MHz, CDCl3) δ 2.69 (t, J = 7.3 Hz, 2H, CH2); 1.66 (quintet, J = 7.6

Hz, 2H, CH2); 1.42 (sextuplet, J = 7.6 Hz, 2H, CH2); 0.93 (t, J = 7.3 Hz, 3H, CH3)


SCF2); -120.97 (m, 2F, CF2); -125.48 (m, 2F, CF2) ppm

2-Pyridyl Nonafluorobutyl Sulfide37

1H NMR(300 MHz, CDCl3) δ 8.47 (m, 1H, ArH); 7.62 (m, 2H, ArH); 7.11 (m, 1H,

ArH)


SCF2); -120.35 (m, 2F, CF2); -125.70 (m, 2F, CF2) ppm

4-Pyridyl Nonafluorobutyl Sulfide

1H NMR(300 MHz, CDCl3) δ 8.51 (dd, J1 = 4.8 Hz, J2 = 2.0 Hz, 2H, ArH); 7.37

(dd, J1 = 4.7 Hz, J2 = 1.75 Hz, 2H, ArH)

24


SCF2); -120.25 (m, 2F, CF2); -125.60 (m, 2F, CF2) ppm

Phenyl Nonafluorobutyl Selenide34


SCF2); -119.14 (m, 2F, CF2); -126.05 (m, 2F, CF2) ppm

25

CHAPTER 3 PERFLUOROALKYLATION OF IMINE TOSYLATES

3.1 Introduction

Our laboratories have developed methodologies for nucleophilic

trifluoromethylation of numerous substrates, such as aldehydes12, cyclic sulfates15,

benzoyl chlorides13 or disulfides16, using CF3I / TDAE system. Trifluoromethylamines

are very interesting compounds because they can serve as synthetic intermediates to

biologically active molecules, as shown in Figures 3-1 and 3-2, where 3A can be used as

pesticide38 and 3B as pain-reliever39.

NS

S

O OCF3

NNN

NH

F3CNHF3C

Figure 3-1. 3A Figure 3-2. 3B

Previously trifluoromethylamines were only synthesized from precursors (i.e.

ketones) already containing trifluoromethyl group.40-48 Prakash and coworkers have used

Ruppert’s reagent (CF3TMS) with imine derivatives to prepare trifluoromethylamines49

and, in particular, chiral trifluoromethylamines.50,51 Indeed, the use of CF3TMS proved to

be very effective for nucleophilic trifluoromethylation of N-tosyl aldimines and N-(2-

methyl-2- propane-sulfinyl)imines (Scheme 3-1), with the latter reactions exhibiting

excellent diastereoselectivity.

26

Simple alkyl- or aryl-substituted imines are relatively unreactive toward

nucleophilic trifluoromethylation, although Blazejewski and co-workers were able to

obtain modest to good yields for aryl systems by facilitating the reaction of CF3TMS

using TMS-imidazole.52 As Prakash showed, the reactivity of imines toward nucleophilic

trifluoromethylation can be significantly enhanced by using N-tosylimines, with the p-

toluenesulfonyl group being removed from the adduct by its treatment with phenol and

48% HBr to give the respective primary amine products.49

N

Ph

Ts CF3TMS NH

Ts+TBAT

THF, 0 - 5 oC90%

F3C

Ph

N

Ph

S CF3TMS NH

S+TBAT

THF, -55 oC 80%

tBu

O

tBu

OF3C

Ph

d.r > 97%

Scheme 3-1. Trifluoromethylation of imines using Ruppert’s reagent

Using the same CF3I / TDAE methodology than developed for trifluoromethylation

of aldehydes12, similar results53 to Prakash’s methods could be obtained (Scheme 3-2).

Unfortunately, the analogous reactions with imines bearing aliphatic substituents on the

imine carbon did not produce the desired adducts. Such attempts included the N-

tosylimines of acetophenone, p-chloroacetophenone, cyclohexanone, and hexanal. In

contrast, aliphatic aldehydes had been reported to provide adducts using Prakash’s

CF3TMS methodology.49

27

N

Ar

Ts NH

Ts

F3C

ArDMF, -30 - 0 oC

62 - 86%

CF3I / TDAE (2.2 equiv.)

N

Ph

S NH

S

DMF, -30 - 0 oC 66%

Tol

O

Tol

OF3C

Ph

d.r = 87:13

CF3I / TDAE (2.2 equiv.)

Scheme 3-2. Trifluoromethylation of imines using CF3I / TDAE

Parallel to trifluoromethylamines, higher perfluoroalkylamines gather also much

interest from pharmaceutical and agrochemical industries. For example, 3C can be used

as a treatment against osteoporosis54 and 3D as a treatment of Alzheimer’s disease55.

N

HN

NH

OCH3

CF2CF3tBuNC

O

N

OHN O

O NH

O

CF2CF3

Figure 3-3. 3C Figure 3-4. 3D

Since in Chapter 2, we have shown that the CF3I / TDAE methodology could be extend

to longer perfluoroalkyl iodides, such as pentafluoroethyl iodide or nonafluorobutyl

iodide, we decided then to try to synthesize other perfluoroalkyl amines

28

3.2 Synthesis of Tosyl Imines

O

R2

R1

H2N TsBF3.OEt2 or Ts-OH

toluene, refluxN

R2

R1

Ts+

Scheme 3-1. Synthesis of tosyl imines

The imines were easily prepared from aromatic aldehydes and tosyl amine, as shown in

Table 3-1. Unfortunately because of the electron withdrawing character of the tosyl

group, tosyl amine was not reactive towards ketones or alphatic aldehydes (entries 3.14-

3.16)

Table 3-1. Synthesis of tosyl imines entry R1 R2 Yield (%)

3.1

H 80

3.2 Me

H 85

3.3 Cl

H 85

3.4 F

H 88

3.5 F3C

H 80

29

3.6 S

H 30

3.7 O

H 65

3.8 N

CH3

H 95

3.9

CH3 0

3.10

CF3 0

3.11 C7H15 H 0

3.3 Pentafluoroethylation of Tosyl Imines

N

H

Ar

Ts CF3CF2I TDAE DMF

-20 oC to RT

CF2CF3

Ar NH

H

Ts+ +

1 2.2 2.2

Scheme 3-2. Nucleophilic pentafluoroethylation of tosyl imines

30

Table 3-2. Nucleophilic pentafluoroethylation of tosyl imines

Entry Ar Yield (%) Yield with CF3I53 (%)

3.1a

50 86

3.2a Me

70 84

3.3a Cl

70 78

3.4a F

72 81

3.5a F3C

68 -

3.6a S

55 -

3.7a O

60 -

3.8a N

CH3

0 -

31

In general, the reactions provided similar results than with CF3I / TDAE system,

with slightly lower yields. For the case of 1-methylindol-3-imine tosylate (entry 3.10a)

the absence of reactivity may be explained by one of the resonance forms shown in

Figure 3-1: with the carbon being on the position 3, the indole group becomes a good

electron donating group, reducing hugely the electrophilic character of the carbon on the

imine, thus the lack of reactivity towards C2F5¯ nucleophile.

N

N

Ts

N

N

Ts

Figure 3-5. A resonance form of N-(N-methyl-3-indolylmethylene)-p-methylbenzenesulfonamide

3.4 Perfluorobutylation of Tosyl Imines

Since good yields could be obtained with C2F5I, experiments with C4F9I were performed

to extend further the methodology

N

H

Ar

Ts C4F9I TDAE DMF

-20 oC to RT

C4F9

Ar NH

H

Ts+ +

1 2.2 2.2

Scheme 3-3. Nucleophilic perfluorobutylation of tosyl imines

In general the yields are lower than with C2F5I, but when the aryl group contains

electron withdrawing elements, the yields are good and comparable to the ones from

C2F5I (Table 3-3, entries 3.3b - 3.5b). Furyl and thiophenyl tosyl imines are not very

32

reactive but the yields are decent. Like as C2F5I, 1-methyl 3-indolyl tosyl imine is not

reactive at all toward perfluoroalkylation. (Table 3-3, entry 3.8b)

Table 3-3. Nucleophilic perfluorobutylation of tosyl imines

Entry Ar Yield (%)

3.2b Me

50

3.3b Cl

70

3.4b F

70

3.5b F3C

75

3.6b S

45

3.7b O

40

3.8b N

CH3

0

Surprisingly the system C4F9I / TDAE provided rather good yields. Unlike with

disulfides where C4F9I didn’t seem to be reactive enough (Chapter 2), the system C4F9I /

TDAE provided sometimes yields similar to the ones from C2F5I / TDAE.

33

3.5 Conclusion

The nucleophilic trifluoromethylation methodology of tosyl imines using

trifluoromethyl iodide and TDAE could be extended successfully with pentafluoroethyl

iodide and nonafluorobutyl iodide. Different substrates were used and provided fair to

very good yields.

3.6 Experimental

Nuclear Magnetic Resonance (NMR) spectra were recorded on a Varian Unity plus

300 MHz Spectrometer system. The proton (1H) NMR were recorded at 300 MHz with

external tetramethylsilane (TMS, δ = 0.00 ppm) as a reference. Fluorine (19F) and proton

(1H) NMR were recorded at 300 MHz with external fluorotrichloromethane (CFCl3, δ =

0.00 ppm) as a reference for 19F NMR and TMS (δ = 0.00 ppm) for 1H NMR. Deuterated

chloroform (CDCl3) was used as NMR solvent.

3.6.1 Syntheses of Tosyl Imines

Synthesis of N-(benzylidene)-p-methylbenzenesulfonamide (3.1)

In a 100 mL one-neck round bottom flask, 4-toluenesulfonamide (2.57g, 15 mmol)

and benzaldehyde (1.52 mL, 15mmol) was mixed in 40 mL of toluene. BF3·EtO2 (0.15

mL) was added under N2. The flask was equipped with a Dean-Stark apparatus. The

reaction mixture was refluxed for 14 hours, then cooled to room temperature and poured

into 2M NaOH (10mL). The organic phase was washed with brine and water until neutral

pH, dried over anhydrous magnesium sulfate and the solvent was removed by vacuum.

The oily residue was recrystallized from ethyl acetate to give a white solid; yield: 3.11 g

(80 %)

34

1H NMR (CDCl3) δ 9.03 (s, 1H, CH=N-Ts); 7.91 (m, 4H, ArH); 7.62 (m, 1H,

ArH); 7.48 (m, 2H, ArH); 7.34 (m, 2H, ArH); 2.44 (s, 3H, CH3) ppm.

Synthesis of N-(4-methylbenzylidene)-p-methylbenzenesulfonamide (3.2)

The procedure and the workup are the same as the synthesis of N-(benzylidene)-p-

methylbenzenesulfonamide, using 4-methylbenzaldehyde toyield 85 % of white solid

1H NMR (CDCl3) δ 8.99 (s, 1H, CH=N-Ts); 7.88 (d, J = 8.1 Hz, 2H, ArH); 7.82 (d,

J = 8.1 Hz, 2H, ArH); 7.34 (d, J = 8.1 Hz, 2H, ArH); 7.29 (d, J = 8.1 2H, ArH); 2.43 (s,

6H, CH3) ppm.

Synthesis of N-(4-chlorobenzylidene)-p-methylbenzenesulfonamide (3.3)


and 4-chlorobenzaldehyde (2.10g, 15mmol) was mixed in 40 mL of toluene. BF3·EtO2

(0.15 mL) was added under N2. The flask was equipped with a Dean-Stark apparatus. The

reaction mixture was refluxed for 14 hours, and then cooled to room temperature. White

crystals precipitated upon cooling. The solid was filtered, then washed with water and

dried under vacuum. Yield = 2.74 g (85 %)

1H NMR (CDCl3) δ 8.99 (s, 1H); 7.89 (d, J = 6.3 Hz, 2H); 7.86 (d, J = 6.3 Hz, 2H);

7.47 (d, J = 8.4 Hz, 2H); 7.35 (d, J = 8.4 Hz, 2H); 2.44 (s, 3H) ppm.

Synthesis of N-(4-fluorobenzylidene)-p-methylbenzenesulfonamide (3.4)

The procedure and the workup are the same as the synthesis of N-(benzylidene)-p-

methylbenzenesulfonamide, using 4-fluorobenzaldehyde to yield 88% of white solid.

1H NMR (CDCl3) δ 9.00 (s, 1H, CH=N-Ts); 7.96 (m, 2H, ArH); 7.89 (d, J = 8.4

Hz, 2H, ArH); 7.35 (d, J = 8.7 Hz, 2H, ArH); 7.19 (m, 2H, ArH); 2.44 (s, 3H, CH3) ppm.

19F NMR (CDCl3) δ -101.59 (t, J = 8.7 Hz, 1F) ppm.

35

Synthesis of N-(4-trifluoromethylbenzylidene)-p-methylbenzenesulfonamide (3.5)

Following the above procedure for 3.3, by using 4-trifluoromethylbenzaldehyde

(2mL, 15mmol), provided 3.92 g (80% yield) of white solid.


J = 8.4 Hz, 2H, ArH); 7.75 (d, J = 8.1 Hz, 2H, ArH); 7.34 (d, J = 8.4 Hz, 2H, ArH); 2.45

(s, 3H, CH3) ppm.

19F NMR (CDCl3) δ -63.83 (s, 3F, CF3) ppm.

Synthesis of N-(2-thiophenylmethylene)-p-methylbenzenesulfonamide (3.6)


and 2-thiophenecarboxaldehyde (1.4 mL, 15mmol) was mixed in 40 mL of toluene. A

catalytic amount of p-toluenesulfonic acid monohydrate was added. The flask was

equipped with a Dean-Stark apparatus. The reaction mixture was refluxed for 14 hours.

The solution turned quickly dark green and black tar was formed. After 14 hours,

charcoal was added to the hot solution and the mixture was stirred at 100 ºC for 1 hour

and filtered while it was still hot. The solvent was removed under vacuum.

Recrystallization from benzene gave 1.07g (30%) of N-(2-thiophenylmethylene)-p-

methylbenzenesulfonamide as a silvery gray solid


J = 4.2 Hz, 2H, ArH); 7.34 (d, J = 8.7 Hz, 2H, ArH); 7.21 (m, 1H, ArH); 2.44 (s, 3H,

CH3) ppm.

36

Synthesis of N-(2-furanylmethylene)-p-methylbenzenesulfonamide (3.7)

The same procedure and workup as for N-(2-thiophenylmethylene)-p-

methylbenzenesulfonamide, using 2-furfural (1.24mL, 15 mmol), gave 2.43 g (65%) of

light brown solid.

1H NMR (CDCl3) δ 8.81 (s, 1H, CH=N-Ts); 7.87 (d, J = 8.4 Hz, 2H, ArH); 7.74

(m,1H, ArH); 7.34 (m, 3H, ArH); 6.64 (dd, J = 5.1 and 3.3 Hz, 1H, ArH); 2.43 (s, 3H,

CH3) ppm.

Synthesis of N-(N-methyl-3-indolylmethylene)-p-methylbenzenesulfonamide (3.8)


and N-methyl-3-indolcarbaxaldehyde (2.39 g, 15mmol) was mixed in 40 mL of toluene.

A catalytic amount of p-toluenesulfonic acid monohydrate was added. The flask was

equipped with a Dean-Stark apparatus. The reaction mixture was refluxed for 14 hours.

The solution became rapidly deep purple. After reflux, the reaction mixture was cooled to

room temperature and the solvent was removed in vacuo. The crude solid was

recrystallized in benzene to give 4.27 g (95% yield) of N-(N-methyl-3-indolylmethylene)-

p-methylbenzenesulfonamide as a purple solid.


J = 8.1 Hz, 2H, ArH); 7.74 (s, 1H, ArH); 7.33 (3, 5H, ArH); 3.88 (s, 3H, N-CH3); 2.40 (s,

3H, CH3) ppm.

3.6.2 General Procedure for Pentafluoroethylation of Tosyl Imines : Synthesis of Methyl-N-(3,3,3,2,2-pentafluoro-1-phenyl-propyl)-benzenesulfonamide (3.1a)

In 25 mL, 3-neck-round bottom flask, equipped with a total reflux condenser and

N2, N-(benzylidene)-p-methylbenzenesulfonamide (0.259 g, 1 mmol) was disolved in 6

mL of anhydrous DMF. The solution was cooled at -30 ºC. Pentafluoroethyl iodide (0.6

37

g, 2.4 mmol) was then introduced to the solution. TDAE (0.51 mL, 2.2 mmol) was added

around -20 ºC. The reaction mixture became quickly orange red. The reaction was

allowed to warm up slowly to room temperature. And as the bath temperature reached -

10 ºC white solid was formed. The reaction mixture was stirred at room temperature

overnight. About 15 mL of 10% H2SO4 aqueous solution was added slowly to quench the

reaction. As the acid solution was added, the reaction mixture first became clear as the

TDAE salt was dissolved in water. But the mixture became cloudy again as the product

precipitated out. The solution was stirred for a while as more and more product

precipitated. The solid was collected via filtration and dissolved in 30 mL of ether. The

ether solution was washed 3 times with water to eliminate remaining DMF. The ether

phase was dried over anhydrous MgSO4 and the solvent was removed by vacuum. The

pale yellow crude product was recrystallized in toluene to afford 0.189 g of a white solid.

(50%)

1H NMR (CDCl3) δ; 7.52 (d, J = 8.4 Hz, 2H, ArH); 7.24 (m, 3H, ArH); 7.10 (m,

4H, ArH); 5.48 (d, J = 9.9 Hz, 1H, NH); 4.97 (m, 1H, CH-N); 2.33 (s, 3H, CH3) ppm.

19F NMR (CDCl3) δ -81.42 (s, 3F, CF2-CF3); -120.67 (dd, J1 = 291.9 Hz, J2 = 12.9

Hz, 1F, CF-CF3); -122.86 (dd, J1 = 291.6 Hz, J2 = 12.6 Hz, 1F, CF-CF3) ppm.

Anal. Calcd for C16H14F8NO2S: C, 50.670; H, 2.694; N, 3.694. Found: C, 50.390;

H, 3.591; N, 3.590.

38

4-Methyl-N-[3,3,3,2,2-pentafluoro-(4-methyl-phenyl)-propyl]-benzenesulfonamide

(3.2a) White solid (70 % yield)

1H NMR (CDCl3) δ; 7.52 (d, J = 8.1 Hz, 2H, ArH); 7.09 (d, J = 8.1 Hz, 2H, ArH);

7.02 (d, J = 8.4 Hz, 2H, ArH); 6.98 (d, J = 8.7 Hz, 2H, ArH); 5.50 (d, J = 9.9 Hz, 1H,

NH); 4.92 (m, 1H, CH-N); 2.34 (s, 3H, CH3); 2.29 (m, 3H, CH3) ppm.

19F NMR (CDCl3) δ -81.42 (s, 3H, CF2-CF3); -120.72 (dd, J1 = 291.6 Hz, J2 = 12.6



H, 4.015; N, 3.503.

4-Methyl-N-[3,3,3,2,2-pentafluoro-(4-chloro-phenyl)-propyl]-benzenesulfonamide




NH); 4.98 (m, 1H, CH-N); 2.38 (s, 3H, CH3) ppm.



Anal. Calcd for C16H13ClF5NO2S: C, 46.398; H, 3.141; N, 3.383. Found: C, 46.255;

H, 3.122; N, 3.355.

4-Methyl-N-[3,3,3,2,2-pentafluoro-(4-fluoro-phenyl)-propyl]-benzenesulfonamide


1H NMR (CDCl3) δ; 7.52 (d, J = 8.4 Hz, 2H, ArH); 7.12 (m, 4H, ArH); 6.92 (t, J =

8.4 Hz, 2H, ArH); 5.37 (d, J = 9.3 Hz, 1H, NH); 4.98 (m, 1H, CH-N); 2.36 (s, 3H, CH3)

ppm.

39

19F NMR (CDCl3) δ -81.39 (s, 3H, CF2-CF3); -111.84 (m, 1F, ArF) -120.60 (dd, J1

= 291.3 Hz, J2 = 11.1 Hz, 1F, CF-CF3); -123.19 (dd, J1 = 293.7 Hz, J2 = 13.5 Hz, 1F, CF-

CF3) ppm.


H, 3.266; N, 3.333

4-Methyl-N-[3,3,3,2,2-pentafluoro-(4-trifluoromethyl-phenyl)-propyl]-

benzenesulfonamide (3.5a) White solid (68 % yield)

1H NMR (CDCl3) δ 7.47 (d, J = 6.1 Hz, 2H, ArH); 7.45 (d, J = 6.1 Hz, 2H, ArH);


NH); 5.05 (m, 1H, CH-CF2); 2.31 (s, 3H, CH3) ppm.

19F NMR (CDCl3) δ -63.54 (s, 3F, CF3); -81.41 (s, 3H, CF2-CF3); -119.54 (dd, J1 =

292.5 Hz, J2 = 14.4 Hz, 1F, CF-CF3); -123.91 (dd, J1 = 292.5 Hz, J2 = 14.4 Hz, 1F, CF-

CF3) ppm.


H, 2.833; N, 3.011.

4-Methyl-N-[3,3,3,2,2-pentafluoro-(2-thiophenyl)-propyl]-benzenesulfonamide (3.6a)

White solid (55 % yield)

1H NMR (CDCl3) δ 7.58 (d, J = 8.4 Hz, 2H, ArH); 7.25 (m, 1H); 7.17 (d, J = 8.4

Hz, 2H, ArH); 6.88 (m, 2H); 5.34 (m, 1H, CH-N); 5.018 (m, 1H, NH) 2.38 (s, 3H, CH3)

ppm.



40

Anal. Calcd for C14H12F5NO2S2: C, 43.636; H, 3.117; N, 3.636. Found: C, 43.578;

H, 3.099; N, 3.620.

4-Methyl-N-[3,3,3,2,2-pentafluoro-(2-furanyl)-propyl]-benzenesulfonamide (3.7a)

Light brown solid (60 % yield)

1H NMR (CDCl3) δ 7.60 (d, J = 8.4 Hz, 2H, ArH); 7.19 (m, 3H); 6.21 (m, 2H,

ring); 5.33 (d, J = 10.2 Hz, 1H, NH); 5.11 (m, 1H, CH-CF2); 2.38 (s, 3H, CH3) ppm.




H, 3.255; N, 3.747.

3.6.3 General Procedure for Perfluorobutylation of Tosyl Imines: Synthesis of 4-Methyl-N-[5,5,5,4,4,3,3,2,2-nonafluoro-(4-methyl-phenyl)-propyl]-benzenesulfonamide (3.2b)

In a 25 mL round bottom flask, connected with N2, N-(4-methylbenzylidene)-p-

methylbenzenesulfonamide (0.273 g, 1 mmol) was disolved in 6 mL of anhydrous DMF.

The solution was cooled at -30 ºC. Nonafluorobutyl iodide (0.38 mL, 2.2 mmol) was then

introduced to the solution. TDAE (0.51 mL, 2.2 mmol) was added around -20 ºC. The

reaction mixture became quickly orange red and white solid was formed shortly after the

addition of TDAE. The reaction was allowed to warm up slowly to room temperature.

The reaction mixture was stirred at room temperature overnight. About 15 mL of 10%

H2SO4 aqueous solution was added slowly to quench the reaction. As the acid solution

was added, the reaction mixture first became clear as the TDAE salt was dissolved in

water. But the mixture became cloudy again as dark brown oil could be seen forming.

The solution was stirred for several hours as more brown vicous oil was formed. 30 mL

41

of ether were added to dissolve the oil. The two phases were separated and the ether

solution was washed 3 times with water to eliminate remaining DMF. The ether phase

was dried over anhydrous MgSO4 and the solvent was removed by vacuum. The pale

yellow crude product was recrystallized in toluene to afford 0.189 g of a white solid.

(50%)


7.00 (m, 4H, ArH); 5.33 (d, J = 9.9 Hz, 1H, NH); 5.04 (m, 1H, CH-N); 2.34 (s, 3H, CH3);

2.29 (s, 3H, CH3) ppm.

19F NMR (CDCl3) δ -81.43 (t, J = 9.9, 3F, CF2-CF3); -116.98 (dm, J1 = 301.5 Hz, ,

1F, CF-CH); -118.88 (dm, J1 = 301.5 Hz, 1F, CF-CH); -121.47 (m, 2F, CF2); 126.53 (m,

2F, CF2) ppm.


H, 3.185; N, 2.821

4-Methyl-N-[5,5,5,4,4,3,3,2,2-nonafluoro-(4-chloro-phenyl)-propyl]-

benzenesulfonamide (3.3b) White solid (70 % yield)


7.11 (d, J = 7.8 Hz, 2H, ArH); 7.04 (d, J = 8.4 Hz, 2H, ArH) 5.60 (d, J = 9.9 Hz, 1H,

NH); 5.07 (m, 1H, CH-N); 2.37 (s, 3H, CH3) ppm.

19F NMR (CDCl3) δ -81.41 (t, J = 11.1, 3F, CF2-CF3); -116.52 (dm, J1 = 304.8 Hz,

1F, CF-CH); -119.38 (d3, J1 = 304.8 Hz, 1F, CF-CH); -121.37 (m, 2F, CF2); 126.55 (m,

2F, CF2) ppm.

Anal. Calcd for C18H13ClF9NO2S: C, 42.038; H, 2.530; N, 2.724. Found: C, 41.904;

H, 2.457; N, 2.685.

42

4-Methyl-N-[5,5,5,4,4,3,3,2,2-nonafluoro-(4-trifloromethyl-phenyl)-propyl]-



7.22 (d, J = 8.1 Hz, 2H, ArH); 7.04 (d, J = 8.4 Hz, 2H, ArH) 5.99 (d, J = 10.2 Hz, 1H,

NH); 5.16 (m, 1H, CH-N); 2.31 (s, 3H, CH3) ppm.

19F NMR (CDCl3) δ -63.57 (s, 3F, Ar-CF3); -81.41 (t, J = 11.1 Hz, 3F, CF2-CF3); -

115.84 (dm, J = 304.5 Hz, 1F, CF-CH); -119.77 (dm, J = 304.5 Hz, 1F, CF-CH); -121.33

(m, 2F, CF2); 126.52 (m, 2F, CF2) ppm.


H, 2.297; N, 2.553

4-Methyl-N-[5,5,5,4,4,3,3,2,2-nonafluoro-(2-thiophenyl -phenyl)-propyl]-


1H NMR (CDCl3) δ; 7.57 (d, J = 8.1 Hz, 2H, ArH); 7.23 (m, 1H, ring); 7.14 (d, J =

8.1 Hz, 2H, ArH); 6.90 (m, 1H, ring); 6.83 (m, 1H, ring); 5.42 (m, 2H, CH-N and NH);

2.36 (s, 3H, CH3) ppm.

19F NMR (CDCl3) δ -81.39 (t, J = 11.1 Hz, 3F, CF2-CF3); -116.69 (dm, J = 297.9

Hz, 1F, CF-CH); -119.22 (dm, J = 297.9 Hz, 1F, CF-CH); -121.47 (m, 2F, CF2); 126.52

(m, 2F, CF2) ppm.

Anal. Calcd for C16H12F9NO2S2: C, 39.555; H, 2.472; N, 2.884. Found: C, 39.567;

H, 2.421; N, 2.778

43

4-Methyl-N-[5,5,5,4,4,3,3,2,2-nonafluoro-(2-furanyl-phenyl)-propyl]-

benzenesulfonamide (3.7b) Brown solid (40 % yield)

1H NMR (CDCl3) δ; 7

syntheses and studies of perfluoroalkyl substituted...

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