1
SYNTHETIC METHODOLOGY DEVELOPMENT TOWARD BUILDING BLOCKS BEARING PENTAFLUOROSULFANYL (SF5) GROUPS AND gem-
DIFLUOROCYCLOPROPYL MOIETIES
By
ZHAOYUN ZHENG
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
2012
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© 2012 Zhaoyun Zheng
3
To my wife, Lijuan Yue, my daughter, Fiona Haoting Zheng, with love
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ACKNOWLEDGMENTS
I would like to thank my supervisor, Dr. William R. Dolbier Jr., for his invaluable
guidance, patience, and generous support through my research career. It has been a
great experience and honor to work with him.
I would also like to thank my committee members, Drs. Ronald K. Castellano,
Sukwon Hong, Brent S. Sumerlin, Benjamin W. Smith and Kenneth Sloan, for their help,
suggestions and support as well. Especially thanks Dr. Castellano and Dr. Hong, who
provided the best synthetic classes I have ever taken.
I am grateful to Dr. Ion Ghiviriga for his help of NMR spectrum.
Many thanks to the former and current members in Dr. Dolbier group. In particular,
I would like to thank Drs. Lianhao Zhang and Henry Martinez, Eric Cornett and Seth
Thomoson, for their unselfish support, helpful discussions and precious contributions to
build such a wonderful research environment.
I deeply appreciate to my parents for their unconditional support and
encouragement.
Finally, I am extremely grateful to my wife, Lijuan Yue, for everything she has done
for me and for our family.
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TABLE OF CONTENTS page
ACKNOWLEDGMENTS .................................................................................................. 4
LIST OF TABLES ............................................................................................................ 7
LIST OF FIGURES .......................................................................................................... 8
LIST OF ABBREVIATIONS ........................................................................................... 12
ABSTRACT ................................................................................................................... 13
CHAPTER
1 AN INTRODUCTION TO THE SYNTHESIS OF PENTAFLUOROSULFANYL(SF5)-CONTAINING AROMATIC COMPOUNDS ...... 15
1.1 Introduction ....................................................................................................... 15 1.2 Applications of Pentafluorosulfanyl Chemistry ................................................. 16
1.2.1 Applications of the SF5 Group in Medicinal Chemistry ............................ 16
1.2.2 Applications of the SF5 Group in Agrochemistry ...................................... 18 1.2.3 Applications of the SF5 group in Functional Materials ............................. 19
1.3 Synthesis of Pentafluorosulfanyl Substituted Aromatic Rings ........................... 20 1.3.1 Synthesis of SF5-Benzene ....................................................................... 20 1.3.2 The Synthesis of SF5-Furan .................................................................... 23
1.3.3 Synthesis of SF5-Naphthalene................................................................. 24 1.3.4 Synthesis of SF5-Pyrazole and –Triazole ................................................ 25
2 THE PREPARATION OF PENTAFLUOROSULFANYL PYRROLE AND THIOPHENE THROUGH 1,3-DIPOLAR CYCLOADDITION ................................... 26
2.1 Initial Investigations of Synthetic Methods toward SF5-bearing Heterocycles ... 26 2.2 Preparation of SF5-pyrrole Carboxylic Acid Esters ............................................ 30
2.2.1 Introduction .............................................................................................. 30
2.2.2 Result and Discussion ............................................................................. 31 2.2.3 Structure Characterization ....................................................................... 34
2.3 Preparation of SF5-pyrrole ................................................................................ 36 2.3.1 Introduction .............................................................................................. 36
2.3.2 Results and Discussion ........................................................................... 37 2.4 Preparation of SF5-Thiophene .......................................................................... 40
2.4.1 Results and Discussion ........................................................................... 40 2.4.2 Structure Characterization ....................................................................... 42
2.5 Conclusion ........................................................................................................ 44
2.6 Experimental Section ........................................................................................ 44
6
3 DIASTEREOSELECTIVE REDUCTION OF gem-DIFLUOROCYCLOPROPENE CATALYZED BY BRӦNSTED ACID ...................................................................... 54
3.1 Introduction ....................................................................................................... 54
3.2 The design of the reaction ................................................................................ 57 3.3 Results .............................................................................................................. 60 3.4 Discussion ........................................................................................................ 64 3.5 Conclusion ........................................................................................................ 66 3.6 Experimental section ......................................................................................... 66
4 FACILE PREPARATION OF SF5-CONTAINING POLYMERS BY RING-OPENING METATHESIS POLYMERIZATION (ROMP) AND PRODUCT CHARACTERIZATION ........................................................................................... 71
4.1 Introduction ....................................................................................................... 71 4.2 Results and Discussion ..................................................................................... 72
4.2.1 Monomer synthesis ................................................................................. 72
4.2.2 Polymer Synthesis and Structure Characterization ................................. 73 4.2.3 Thermal Properties Characterization ....................................................... 76
4.3 Conclusions ...................................................................................................... 78 4.4 Experimental Section ........................................................................................ 78
APPENDIX: NUCLEAR MAGNENETIC RESONANCE (NMR) SPECTRUM ................ 81
LIST OF REFERENCES ............................................................................................... 95
BIOGRAPHICAL SKETCH ............................................................................................ 99
7
LIST OF TABLES
Table page 2-1 Reaction of SF5-alkyne with azomethine ylide .................................................... 31
2-2 Investigation of the reaction of SF5-alkyne with 2-11 .......................................... 38
2-3 One pot preparation of SF5-Pyrrole .................................................................... 39
2-4 The preparation of SF5-thiophene ...................................................................... 41
3-1 Screening the conditions for the reduction of difluorocyclopropenyl ketones ..... 60
3-2 Screening conditions using bulky Brӧnsted acids ............................................... 62
4-1 Preparation and properties of SF5-containing Polymers ..................................... 75
8
LIST OF FIGURES
Figure page 1-1 SF5-substituted analogs of fluoxetine, fenfluramine, and norfenfluramine .......... 16
1-2 SF5- and CF3-substituted analogs of mefloquine ................................................ 17
1-3 Trypanothione reductase inhibitors ..................................................................... 18
1-4 SF5-substituted analogs of triflualin .................................................................... 18
1-5 The various applications of SF5 groups in functional materials ........................... 19
1-6 Early preparation method for SF5-benzene ........................................................ 20
1-7 First practical route to prepare SF5-benzene ...................................................... 21
1-8 Preparation of SF5-benzene from SF5Cl gas ...................................................... 21
1-9 Practical preparation of SF5-benzene developed by Umemoto .......................... 22
1-10 Preparation of SF5-furan through retro-Diels-Alder-reaction ............................... 23
1-11 Preparation of SF5-furan through Diels-Alder- and retro-Diels-Alder-reaction .... 24
1-12 Preparation of SF5-naphthalene ......................................................................... 24
1-13 Preparation of SF5-pyrazole and –triazole by 1,3-dipolar cycloaddition .............. 25
2-1 The first attempt synthetic route for SF5-pyrrole ................................................. 26
2-2 Second synthetic route to SF5-Heterocycles catalyzed by palladium ................. 27
2-3 Proposed mechanism for the synthesis of SF5-heterocycles .............................. 29
2-5 The preparation of SF5-Heterocycles based on cycloaddition chemistry ............ 30
2-6 Preparation CF3-pyrrole from azomethine ylide .................................................. 30
2-7 1,3-Dipolar cycloaddition approach to SF5-heterocycles .................................... 32
2-8 Removal of t-butyl group catalyzed by triflic acid ................................................ 32
2-9 Mechanism for the regioselective cycloaddition chemistry ................................. 33
2-10 Proton NMR of 2-8b ........................................................................................... 34
2-11 Proton NMR of 2-9b ........................................................................................... 34
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2-12 Proton NMR of 2-10 ............................................................................................ 35
2-13 19F-NMR spectrum of compounds 2-10 and 2-9b ............................................... 35
2-14 The high reactivity of azomethine ylide building block 2-11 ................................ 36
2-15 Removal of TIPS group from 2-14f ..................................................................... 39
2-16 Removal of the benzyl group from dihydropyrrole .............................................. 40
2-18 Construction of thiophene through thiocarbonyl ylide ......................................... 41
2-19 1H-NMR of 2-20d ................................................................................................ 42
2-20 1H-NMR of 2-21d ................................................................................................ 43
2-21 19F-NMR of 2-20d and 2-21d .............................................................................. 43
3-1 The reactivity of TFDA and its reaction mechanism ........................................... 54
3-2 Reaction of TFDA with α,β-unsaturated ketones ................................................ 55
3-3 Friedel-Crafts reaction of difluorocyclopropanecarbonyl chloride ....................... 56
3-4 Attempt to prepare substituted difluorocyclopropane ketones ............................ 57
3-5 Preparation of difluorocyclopropenyl ketone and its properties .......................... 57
3-6 Reactivity difluorocyclopropyl ketone with HBr in Ionic Liquid. ........................... 58
3-7 Proposed tautomerization mechanism for β-difluoro enols/enolates .................. 58
3-8 Synthetic approach to substituted difluorocyclopropyl ketones .......................... 59
3-9 Application of HEH as hydride donor .................................................................. 59
3-10 Reactions of difluorocyclopropene with HEH, catalyzed by Brӧnsted acid ......... 63
3-11 Proposed mechanism for the catalytic reduction of difluorocyclopropenyl ketones ............................................................................................................... 64
3-12 Kinetic control reaction ....................................................................................... 65
4-1 Synthetic route toward SF5-polymers ................................................................. 73
4-2 1H-NMR of M1, P1 and P2 .................................................................................. 74
4-3 1H-NMR of M2, P3 and P4 .................................................................................. 75
4-4 The 19F-NMR spectrum of monomers and polymers .......................................... 76
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4-5 Thermogravimetric Analysis for SF5-polymers .................................................... 76
4-6 The Differential Scanning Calorimetry of SF5-polymers ..................................... 77
A-1 1H and 13C NMR assignment of compounds 2a(B) and 3a(A) by Dr Ghiviriga ... 81
A-2 1H NMR spectrum of 3-3a ................................................................................... 82
A-3 1H NMR spectrum of 3-3a (expanded in aromatic region) .................................. 82
A-4 1H NMR spectrum of 3-3a ( expanded in aliphatic region) .................................. 83
A-5 19F NMR spectrum of 3-3a .................................................................................. 83
A-6 gHMQC spectrum of 3-3a ................................................................................... 84
A-7 gHMQC spectrum of 3-3a ( expanded in aromatic region) ................................. 85
A-8 1H NMR spectrum of 3-2a ................................................................................... 85
A-9 1H NMR spectrum of 3-2a ( expanded in aromatic region) ................................. 86
A-10 1H NMR spectrum of 3-2a ( expanded in aliphatic region) .................................. 86
A-11 19F NMR spectrum of 3-2a .................................................................................. 87
A-12 gHMQC spectrum of 3-2a ................................................................................... 87
A-13 1H-NMR spectrum of M1 ..................................................................................... 88
A-14 13C-NMR spectrum of M1 ................................................................................... 88
A-15 19F-NMR spectrum of M1 .................................................................................... 89
A-16 1H-NMR spectrum of M2 ..................................................................................... 90
A-17 13C-NMR spectrum of M2 ................................................................................... 90
A-18 19F-NMR spectrum of M2 .................................................................................... 91
A-19 1H-NMR spectrum of P1 ..................................................................................... 91
A-20 19F-NMR spectrum of P1 .................................................................................... 92
A-21 1H-NMR spectrum of P2 ..................................................................................... 92
A-22 19F-NMR spectrum of P2 .................................................................................... 92
A-23 1H-NMR spectrum of P3 ..................................................................................... 93
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A-24 19F-NMR spectrum of P3 .................................................................................... 93
A-25 1H-NMR spectrum of P4 ..................................................................................... 94
A-26 19F-NMR spectrum of P4 .................................................................................... 94
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LIST OF ABBREVIATIONS
BA Brӧnsted Acid
DCM Dichloromethane
DDQ 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone
DSC Differential Scanning Calorimetry
GPC Gel permeation chromatography HEH Hantzsch Ester
LC Liquid Crystal
NBS N-Bromosuccinimide NMR Nuclear magnetic resonance ROMP Ring opening metathesis polymerization TBAF Tetrabutylammonium Bromide
TFDA Trimethylsilyl 2-(fluorosulfonyl)-2,2-difluoroacetate
TGA Thermogravimetric Analysis
THF Tetrahydrofuran
TIPS Triisopropylsilyl
TLC Thin layer chromatography
TS Transition state
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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
SYNTHETIC METHODOLOGY DEVELOPMENT TOWARD BUILDING BLOCKS
BEARING PENTAFLUOROSULFANYL (SF5) GROUPS AND gem-DIFLUOROCYCLOPROPYL MOIETIES
By
Zhaoyun Zheng
December 2012
Chair: William R. Dolbier, Jr. Major: Chemistry
Pyrrole and thiophene derivatives bearing a pentafluorosulfanyl (SF5) group were
unknown. Utilizing cycloaddition reactions of azomethine ylide with SF5-alkynes, a
series of SF5-pyrrole carboxylic acid esters were prepared in good yield. Further smooth
processes of SF5-alkynes with N-Benzyl-N-(methoxymethyl)-N-(trimethylsilylmethyl)-
amine initiated by triflic acid demonstrated that 1,3-dipolar cycloadditions are a general
approach to construct heterocyclic compounds containing the SF5 group. These
reactions were subsequently extended to prepare SF5-thiophene derivatives.
A novel Brӧnsted acid catalyzed synthetic method for preparation of substituted
gem-difluorocyclopropenyl ketones was designed based on the known tautomerization
mechanism of β-difluoro enols. The reaction, using Hantzsch ester (HEH) as a hydride
transfer reagent, proved to be a general route for preparation of substituted gem-
difluoro-cyclopropyl ketones in high yield. The reaction unexpectedly proceeded to give
largely cis product. Based upon the proposed mechanism, the diastereoselectivity could
be improved by using a more bulky Brӧnsted acid under optimized conditions.
14
A facile method was established for preparing polymers with SF5 group directly
attached to the backbone through ring opening metathesis polymerization (ROMP) of
SF5-substituted cyclooctene followed by hydrogenation. The microstructure of these
novel polymers were well characterized by 1H-NMR, GPC and 19F-NMR. TGA and DSC
experiments showed that the unsaturated polymers and their hydrogenated derivatives
have similar thermal profiles. While P3 and P4 have better thermal stabilities than P1
and P2, the latter pair exhibit higher glass transition temperatures.
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CHAPTER 1 AN INTRODUCTION TO THE SYNTHESIS OF PENTAFLUOROSULFANYL(SF5)-
CONTAINING AROMATIC COMPOUNDS
1.1 Introduction
Because of its small size, high electronegativity and its ability to form hydrogen
bonds, the fluorine atom can dramatically affect the chemical and physical properties of
organic compounds.1 For example: fluorinated macromolecules usually exhibit low
surface energy, low dielectric constants and high chemical stability;2 fluorinated small
bioactive molecules often display amazingly enhanced biophysical activity by a
combination of factors such as increasing metabolic stability and binding affinity, and
altering lipophilicity and acidity.3 Therefore, fluorine chemistry has found wide
applications in the chemical world ranging from materials to medicine. This importance
has significantly accelerated the synthetic methodology development towards selective
and efficient fluorination of organic molecules as well as development of fluorine-
containing building blocks during the last century.
Extensive investigation has been applied toward the incorporation of a single
fluorine atom into organic molecules, with increasing interest shown in the last several
decades for the exploration of synthetic methods of perfluoroalkylation. The goal is to be
able to fine tune the chemical, physical or biological properties of target molecules by
incorporating various numbers of fluorine atoms.4 Among them, the trifluoromethyl (CF3)
group has proved to be a very important substituent as numerous compounds bearing
the trifluoromethyl moiety have become of great interest in the pharmaceutical
community. Thus considerable attention has been devoted to the synthetic development
of trifluoromethylation.5,6 The pentafluorosulfanyl (SF5) group, first introduced into
organic molecules a half-century ago, has been found to be an interesting substituent
16
that mimics the trifluoromethyl group with regard to electronic and steric factors. Hence,
in recent years SF5 chemistry has become one of the fast-growing fields in fluorine
chemistry after a long period of hibernation.
1.2 Applications of Pentafluorosulfanyl Chemistry
The pentafluorosulfanyl group has been regarded as an alternative to the
trifluoromethyl group, with previous investigations revealing that the SF5 group has a
much higher electronegativity than the CF3 moiety (3.65 vs 3.36), and the steric
demand of the SF5 group approaches that of the t-butyl group. Examination of the
stability of the SF5 group to hydrolysis demonstrated that the SF5 group has higher
hydrolysis stability than the CF3 substituent. All these differences indicate that
substitution of the SF5 group for CF3 may have profound effect on bioactivity.7
1.2.1 Applications of the SF5 Group in Medicinal Chemistry
Figure 1-1. SF5-substituted analogs of fluoxetine, fenfluramine, and norfenfluramine
The clinical agents fluoxetine (1-1), fenfluramine (1-2a) and norfenfluramine (1-
2b), which all bear a trifluoromethyl group, were widely used as serotonin (5-
hydroxytryptamine, 5-HT) inhibitors in the 1970s. In order to search analogs with higher
bioactivity and to test the influence of the SF5 group on bioactive molecules, Welch and
coworkers prepared SF5-substituted analogs for 5-HT inhibitors (Figure 1-1) and
evaluated their bioactivity.8 The examination showed that the SF5 substituent could
17
improve these inhibitors’ selectivity toward 5-hydroxytryptamine receptors. Among them,
compound 1-4b could lead to dramatically increased potency against 5-HT2b, 5-HT2c
and 5-HT6 receptors.
Figure 1-2. SF5- and CF3-substituted analogs of mefloquine
Mefloquine (1-5) is a clinically efficient treatment for malaria, which is a global
health problem with millions of casualties per year. However, its undesirable
neuropsychiatric side-effects such as anxiety, depression, seizure, and the emergence
of drug resistance led scientists to look for a better candidate. The Wipf group
synthesized two sets of mefloquine analogs with SF5 or CF3 substituted at the 6- or 7-
position (Figure 1-2), and they evaluated their bioactivities against parasites and
toxicities against mammalian cells.9 The results revealed the SF5 substituted compound
1-6b to have better bioactivity and selectivity than the CF3 substituted substance 1-6a or
mefloquine, while compound 1-7b was almost equivalent to CF3 analog 1-7a and
mefloquine.
18
Figure 1-3. Trypanothione reductase inhibitors
Although numerous SF5-containing analogs of bioactive molecules have been
synthesized, the Diederich group was the first to study the structure-activity relationship
on the molecule’s target level for SF5-bearing derivatives.10 They chose flavoenzyme
trypanothione reductase, which is found in parasites, as a target for the design of SF5-
containing inhibitors. Based on the diphenyl amine core structure, they synthesized
three sets of analogs bearing the SF5 moiety (Figure 1-3). Interestingly, bioactivity tests
showed that all the compounds (1-8b, 9b, 10b) with a SF5 substituent exhibited the low
cytotoxicity as well as good membrane permeability.
1.2.2 Applications of the SF5 Group in Agrochemistry
Figure 1-4. SF5-Substituted analogs of triflualin
Triflualin (1-11a), a widely used herbicide for pre-emergence control of grass, was
one of the annual best sellers in the US. When the Welch group simply modified its
structure by adding a SF5 group, they obtained an amazing result from the herbicidal
activity evaluation.11 In a post-emergence test, 1-11b exhibited almost twice the potency
19
as triflualin while having the same general spectrum of activity. Even more surprisingly,
in pre-emergence screening, 1-11b was approximately 5-fold more potent against
quackgrass and crabgrass. Therefore, 1-11b is a very promising candidate for further
exploration.
1.2.3 Applications of the SF5 group in Functional Materials
Liquid crystals (LC) as display materials have been extensively used in common
electronic devices such as PCs, notebooks, and cell phones. Due to its high polarity and
lipophilicity, the SF5 group was found to significantly improve the properties of LC
materials. When scientists from the Merck corporation prepared various SF5-substituted
LC materials based on the structure of widely-used fluorinated LC molecules (1-12),
they discovered that all these materials had considerably enhanced dielectric anisotropy
and lower birefringence, which are two of the most important parameters for the design
of LC materials.12
Figure 1-5 The various applications of SF5 groups in functional materials
Due to the multiple unique properties of the SF5 group, the Shreeve group found it
to be an excellent motif for the design of energetic materials (1-13). Generally, the SF5-
incorporated compound had high density, good thermal stability and enhanced
detonation performance.13
20
Taking advantage of its high lipophilicity, Gard and researchers from 3M prepared
various SF5-containing surfactants.14 These materials normally exhibited lower surface
tension and better performance than their CF3 analogs (1-14).
1.3 Synthesis of Pentafluorosulfanyl Substituted Aromatic Rings
Fluorinated aromatic compounds are widely used in chemical, pharmaceutical and
agrochemical industries. Thus, there are good reasons to establish practical synthetic
methods to construct SF5-substituted aromatic compounds, which may have great
potential for applications such as those mentioned above. Although the first preparation
of SF5-benzene originated in the 1960s, only in the last decade have several
breakthroughs occurred. In the following sections, a concise introduction of the
synthesis of aromatic rings with an SF5 group directly attached is presented.
1.3.1 Synthesis of SF5-Benzene
Figure 1-6 Early preparation method for SF5-benzene
Because of its significant potential importance, SF5-benzene building blocks
attracted much attention from fluorine chemists working in the field of SF5 chemistry.
Even though Sheppard’s pioneering work on the preparation of SF5-benzene was
reported almost a half-century ago, this molecule remained a challenge to fluorine
scientists for decades because all of the synthetic procedures developed during this
21
period required either harsh reaction conditions or expensive reagents while giving
poor yields (Figure 1-6).15,16,17,18
Figure 1-7 First practical route to prepare SF5-benzene
The first practical and scalable synthetic method was reported by Bowen and
Philip (Figure 1-7).19 Inspired by the previous work, they still used nitro-substituted aryl
disulfides as starting materials (1-16a, b). Diluted F2 gas was creatively employed as a
fluorinating reagent, and the desired product was obtained in reasonable yield at low
temperature. Though the F2 gas was very toxic, corrosive and relatively expensive, this
method was commercialized to facilitate research in other areas during the subsequent
years due to the mild reaction conditions and easy work-up procedure. It is also worth
mentioning that in this article, they investigated the properties of the SF5 group as well.
The investigation revealed that generally the SF5 group could survive in various reaction
conditions such as hydrogenations, coupling reactions, acid-base reactions, and it also
exhibited higher stability than CF3 analogs in a hydrolysis test.
Figure 1-8. Preparation of SF5-benzene from SF5Cl gas
Pentafluorosulfanyl chloride (SF5Cl) gas, one of the few commercially available
SF5 reagents, was used for several decades for construction of SF5-containing building
22
blocks. However, due to its low boiling point (-21oC), normally the reaction required the
use of autoclave and high temperature. In 2002, the Dolbier group discovered that Et3B
was an excellent radical initiator for addition reactions of SF5Cl to alkene and alkyne
substrates.7 This new procedure could be carried out in common glassware at low
temperature with high yield. Based on this creative invention, they designed a novel
route to prepare SF5-benzene.20 Starting from easily available reagent 1,4-
cyclohexadiene, the dichloride substitute intermediate 1-18 was obtained in quantitative
yield through a classical radical process. When this product was submitted to standard
SF5Cl addition conditions initiated by Et3B, followed by simple elimination, the target
molecule was attained with >70% yield over the three steps. Although this method was
quite straight forward, the relatively high price of SF5Cl gas has limited its use.
Figure 1-9. Practical preparation of SF5-benzene developed by Umemoto
A major milestone for preparation of SF5-aromatics was established by Umemoto
and his coworkers (Figure 1-9). In 2012, they reported an innovative construction of the
SF5 group through a novel intermediate bearing the SF4Cl group.21 Starting from
commercially available phenyl disulfide or thiol, the SF4Cl group was assembled by
bubbling chlorine gas into a dry potassium fluoride solution and then stirring overnight at
RT. This intermediate 1-19 was not very stable. Following simple filtration and
evaporation of the solvent, it was further treated with SbF3/SbCl5 in CH2Cl2, and the
desired product 1-20 was obtained via a clean transformation. This procedure, which
has been scaled up by the author’s company, exhibited great substrate scope for
23
preparing SF5-benzene and its derivatives. Since all of the reagents are relatively cheap
and commercially available, and the procedure is readily scaled-up, this invention
should significantly benefit the whole chemical community.
1.3.2 The Synthesis of SF5-Furan
Figure 1-10. Preparation of SF5-furan through retro-Diels-Alder-reaction
With the successful preparation of SF5-benzene from SF5Cl and their continuing
interest in SF5-substituted heterocyclic compounds, the Dolbier group designed a new
route to synthesize SF5-furan based on the process of the retro-Diels-Alder reaction
(Figure 1-10).22 Utilizing the previous Et3B initiated conditions, SF5Cl was smoothly
introduced to the easily prepared starting material 1-21, which is the Diels-Alder adduct
of furan and acrylonitrile. The mixture of two regioisomers 1-22a and 1-22b was treated
with strong base LiOH in DMSO to provide the clean elimination products 1-23a and 1-
23b. At high temperature, they underwent retro-Diels-Alder reaction to give the target
molecule 1-24 with decent yield. Currently, this is the first and only reported preparation
method to construct SF5-furan. However, the utilization of the expensive SF5Cl gas and
the narrow substrate scope limited its wide application.
24
Figure 1-11. Preparation of SF5-furan through Diels-Alder- and retro-Diels-Alder-
reaction
In the same article, they reported an alternative method to prepare SF5-furan in
one pot based on a cascade mechanism (Figure 1-11). Starting material 4-
phenyloxazole is an easily prepared building block for facile construction of furan and its
derivatives. Therefore, they treated SF5-substituted alkyne with oxazole at high
temperature, and after an overnight reaction, the desired product was obtained in high
yield after column purification. The reaction was believed to proceed through a Diels-
Alder mechanism with the generation of an unstable adduct 1-25, which underwent a
Diels-Alder reaction to result in the target molecule. This method has relatively broader
substrate scope as SF5-substituted alkynes can be prepared from terminal alkynes
through addition-elimination steps.
1.3.3 Synthesis of SF5-Naphthalene
Figure 1-12. Preparation of SF5-naphthalene
25
With the achievement of SF5-furan through Diels-Alder reactions, the Dolbier
group continued to build SF5-naphthalene by such methodology (Figure 1-12).23 Initial
addition of SF5Cl to benzobarralene and subsequent base-catalyzed elimination of HCl
led to the key intermediate 1-29 in high yield. The ethylene bridge of 1-29 was smoothly
eliminated by heating with the commercially available reagent 3,6-bis-(2-pyridyl)-1,2,3,4-
tetrazine (1-30), and the target molecule was obtained in high yield through this
sequence of reactions.
1.3.4 Synthesis of SF5-Pyrazole and –Triazole
Figure 1-13. Preparation of SF5-pyrazole and –triazole by 1,3-dipolar cycloaddition
In 1964, researchers from Dupont reported the first example of construction of
SF5-bearing heterocycles based on 1,3-dipolar cycloaddition (Figure 1-13).17 Simply
adding SF5-acetylene to diazomethane at 0oC, a mixture of regioisomers (1-32a, 1-32b)
with a ratio of 60:40 was readily obtained. In 2007, Shreeve and her coworkers utilized
the same method to prepare SF5-containing energetic materials.13 Starting from bulky
TIPS substituted SF5-acetylene, only one regioisomer (1-33) as product was obtained in
quantitative yield. They also extended this reaction to prepare various SF5-triazoles (1-
34) as high performance materials using ‘click chemistry’.
26
CHAPTER 2 THE PREPARATION OF PENTAFLUOROSULFANYL PYRROLE AND THIOPHENE
THROUGH 1,3-DIPOLAR CYCLOADDITION
2.1 Initial Investigations of Synthetic Methods toward SF5-bearing Heterocycles
Investigations of pentafluorosulfanyl (SF5) chemistry in Dr. Dolbier’s lab were
initiated by Dr. Samia Ait-Mohand in 2002.7 Her great invention provided a practical
method to add SF5Cl to alkene and alkyne substates without utilizing an autoclave
reactor and high temperature. The reactions were usually carried out at low temperature
(-30oC) in ordinary glassware, initiated by catalytic amount of Et3B (0.1eq.), and
generated the desired products in high yield in a short time (2 hours). Based on this
significant discovery, in subsequent research, Dr. Sergeeva established the earlier-
mentioned approach to SF5-benzene,20 and Dr. Mitani prepared the first furans bearing
an SF5 group through retro-Diels-Alder chemistry.22 With the considerable continued
interest in SF5-containing heterocyclic compounds because of their great potential for
application and commercial value, my challenge was to investigate the preparation
methods for pyrroles and thiophenes bearing an SF5 group, which had never been
made before.
Figure 2-1. The first attempted synthetic route to SF5-pyrrole
With the commercially available SF5Cl gas in hand and inspired by the previous
methods, we designed a short synthetic route for SF5-pyrrole (Figure 2-1). Starting from
the purchased 2,5-dihydropyrrole (2-1a), SF5Cl would be first incorporated into the five-
27
membered ring using the standard Et3B method, followed by elimination of HCl and
oxidation steps, the desired product would be generated using a concise approach.
However, the first step reaction did not occur as we expected. In the beginning we
thought it might be due to the presence of a proton on the dihydropyrrole nitrogen, but
even with the subsequent change of hydrogen to a phenyl group (2-1b) the reaction still
did not occur. Since there have been few reported examples of SF5Cl addition into
internal alkenes compared to reported addition to terminal alkenes, we realized that
steric hindrance could play a key role in this situation, as SF5 group is as bulky as a t-
butyl group.
Figure 2-2. Second synthetic route to SF5-heterocycles catalyzed by palladium
28
After the failure of the first attempt, we considered that SF5Cl might not be a good
starting material for direct construction of heterocycles, due to the narrow substrate
scope of its addition reactions. Compared to SF5Cl gas, SF5-substituted alkynes should
be better building blocks for several reasons. First, numerous chemical transformations
based on alkynes have been established; secondly, the one-step construction of
heterocycles from alkynes catalyzed by transition-metals have been well explored in
recent decades; thirdly, many successful synthetic precedents for preparation of CF3-
heterocycles from CF3-substituted alkynes have been reported, probably correlating
with SF5 chemistry; lastly, SF5-alkynes were readily prepared from SF5Cl based on the
previously developed method.
Therefore we designed a second route towards various SF5-containing
heterocyclic compounds based on SF5-alkyne building blocks. Konno and his coworkers
had demonstrated a general method to prepare CF3-containing benzoheterocycles
catalyzed by palladium (Figure 2-2),24,25 and we expected to obtain at least one of the
desired compounds from those diverse transformations. However we did not achieve
any positive results except recycling the starting materials when SF5- alkyne was mixed
with the aromatic iodide (2-3a, b, c). From the proposed mechanism, we rationalized
that the problem may be due to steric hindrance, which prevents the addition of the
aromatic palladium intermediate into the alkyne substrate (Figure 2-3).
29
Figure 2-3. Proposed mechanism for the synthesis of SF5-heterocycles
It is worth mentioning that years ago a former postdoc, Ping He in Dr. Dolbier’s
group, had attempted to utilize a van Leusen approach to prepare SF5-pyrroles.26 The
reaction of TosMIC with SF5-substituted α,β-unsaturated ester (2-4) led only to a
fluorine-free product, presumably pyrrole 2-6, formed by preferential elimination of SF5○-
rather than loss of Tos○- , which is the usual final, pyrrole-forming step of a van Leusen
synthesis.
Figure 2-4. Attempt to prepare SF5-heterocycles using a van Leusen approach
30
2.2 Preparation of SF5-pyrrole Carboxylic Acid Esters
2.2.1 Introduction
Figure 2-5. The preparation of SF5-heterocycles based on cycloaddition chemistry
After all attempts mentioned above to generate the desired SF5-heterocyclic
compounds failed, we carefully examine the possible reasons via a literature review.
When carefully analyzing the previous cases for preparing SF5-aromatic compounds,
we rationalized that concerted cycloaddition chemistry could be one possible method as
furan, pyrazole and triazole had all been generated by cycloaddition reactions starting
from SF5-alkynes (Figure 2-5).22,13
Figure 2-6. Preparation CF3-pyrrole from azomethine ylide
The 1,3-dipolar cycloaddition of azomethine ylide, generated from thermal opening
of 2-7, to alkynes or alkenes has been demonstrated to be a general approach to
construct pyrrolines or pyrrolidines, respectively. La Porta and co-workers successfully
implemented this method to prepare trifluoromethyl pyrroles starting from cycloaddition
31
of CF3-alkyne with azomethine ylide and following with DDQ oxidation.27 Therefore, we
expected this to be a feasible way to our desired product.
2.2.2 Result and Discussion
Table 2-1. Reaction of SF5-alkyne with azomethine ylide
2-7(equiv) 5h 20h 40%
1 -- 32% 37%
3 40% 100% --
When the readily prepared aziridine 2-7 was heated with equimolar amount of
SF5-alkyne 2-2b in xylene, to our delight, a clean chemical transformation occurred as
shown by 19F-NMR, even though in 20h it only gave moderate conversion and
prolonging of the reaction time did not help. By increasing the amount of 2-2b to 3
equiv, the reaction rate was dramatically accelerated and full conversion could be
achieved overnight (Table 2-1). The isolated yield of 2-8b was 60% and its structure
was fully characterized. Smooth DDQ (2equiv) oxidation provided the target molecule 2-
9b in quantitative yield.
32
Figure 2-7. 1,3-Dipolar cycloaddition approach to SF5-heterocycles
To explore the reaction’s limitations, more substrates were prepared and
submitted to the reaction. In order to simplify the procedure, the crude pyrroline
intermediate was treated with DDQ directly after removing the solvent without isolation.
Generally the one pot reaction showed good substrate scope with moderate to good
yields (Figure 2-7).
Figure 2-8. Removal of t-butyl group catalyzed by triflic acid
To demonstrate the full scope of this method, the removal of t-butyl group was
accomplished by utilizing the reported method. While heating 2-9b in CH2Cl2 with a
catalytic amount triflic acid for 2h, the unprotected pyrrole 2-10 was obtained in an
unoptimized yield of 72% (Figure 2-8).
33
Figure 2-9. Mechanism for the regioselective cycloaddition chemistry
Notably, the present procedure gave exclusively one regioisomer based on SF5-
alkyne compared to the regioisomeric mixture (~75:25) obtained from CF3-alkyne.27 The
mechanistic analysis clearly explained the regioselective chemistry (Figure 2-9). As for
the CF3 substrate, the reaction was dominated by the electronic effect while the steric
effect led to the minor product, as the strain was greatly released between ester group
and CF3 part. When it came to the SF5 substrate, the electronic and steric effects both
preferred the same regioselectivity. This result also agreed well with the structural
properties of CF3 and SF5 groups as both are strong electron-withdrawing groups but
have considerably different size.
34
2.2.3 Structure Characterization
Figure 2-10. Proton NMR of 2-8b
Figure 2-11. Proton NMR of 2-9b
35
Figure 2-12. Proton NMR of 2-10
Figure 2-13. 19F-NMR spectrum of compounds 2-10 and 2-9b
In Figure 2-10, the appearance of the aromatic proton signals (7.23, 7.34 ppm),
the sharp t-butyl (0.98 ppm) and methyl peak (3.72 ppm) clearly indicate the formation
of a dihydropyrrole ring by the cycloaddition reaction. After oxidation with DDQ, the
signal of CH2 (3.92, 4.10 ppm) and CH (4.49 ppm) groups in compound 2-8b
disappeared, and a new peak in the aromatic region emerged by integration, which
proved the success of aromatization. In Figure 2-12, the characteristic t-butyl signal
36
(1.68 ppm) of compound 2-9b completely disappeared and a new broad singlet peak at
9.34 ppm appeared when 2-9b was treated with catalytic triflic acid, which confirmed the
removal of the protecting group.
19F-NMR is also a powerful tool to monitor the reaction with the advantage of little
interference from solvents and other substrates when compared to proton NMR. The
SF5 group gives 19F-NMR signals with the characteristic AB4 system. Therefore, the
doublet peaks around 74.30 ppm in 2-9b that moved to 73.56 ppm in 2-10 clearly
demonstrate the cleavage of the N-C bond (Figure 2-13).
2.3 Preparation of SF5-pyrrole
2.3.1 Introduction
Based on the above successful preparation of SF5-pyrrole carboxylic acid ester
where SF5-alkynes acted as dipolarophiles, we wondered if the cycloaddition reaction
could be a good general approach to SF5-pyrrole. If so, a wide variety of SF5-pyrrole
structures could be built for potential medicinal applications. Therefore, another
azomethine ylide building block 2-11 was selected to examine this hypothesis.
Figure 2-14. The high reactivity of azomethine ylide building block 2-11
N-Benzyl-N-(methoxymethyl)-N-(trimethylsilylmethyl)amine 2-11 was first
recognized as an azomethine ylide synthon by Hosomi and coworkers in 1984,28 and
later on its properties and reactivity were fully investigated by Padwa etc.29 All studies
demonstrated that this compound had unique advantages over others: First, 2-11 is
37
readily prepared and is already commercially available; secondly, the reaction condition
is adjustable as it could be initiated by either catalytic amount of H+ or an F- source; and
thirdly, it has been widely used to build bioactive molecules or natural products because
of its extensive substrate scope; 30,31 last but not the least, it has excellent reactivity as
even under mild condition the dearomization occurred when it interacted with
dinitrobenzene (Figure 2-14).32 Hence, there are good reasons to believe that 2-11
could also react with SF5-alkynes.
2.3.2 Results and Discussion
The initial investigation followed the reported conditions of using an equal amount
of cesium fluoride and 2-11 with acetonitrile as solvent at RT, however, no desired
product was detected by 19F-NMR. The attempt to increase the temperature or switch to
lithium fluoride did not lead to the target either. When 1.0M TBAF solution was
employed, instead of recovering SF5-alkyne, all of the substrate decomposed for
unknown reasons.
Gratefully after switching to an acid catalyzed system, 65% conversion was
obtained with 0.2 eq trifluoroacetic acid applied in CH2Cl2 at RT. As shown in Table 2-2
full conversion was readily achieved by increasing the amount of 2-11 to 4 eq.
Additional optimization reactions demonstrated that only 2.5 eq of azomethine ylide was
required under reflux conditions, with isolated yield as high as 96%.
More SF5-alkynes were prepared according with previous methods in order to test
the reaction scope. In practice the intermediate dihydropyrroles were not separated but
were converted, in situ, to the respective pyrroles directly by treatment with DDQ.
Generally the reaction provided good to excellent yields with wide substrate scope
38
(Table 2-3). Even for the considerably bulky TIPS-substituted SF5-alkyne, it still gave
78% yield.
Table 2-2. Investigation of the reaction of SF5-alkyne with 2-11
entry 2-11(eq) Catalyst Solvent T(°C) Conversion(%)
1 2 CsF CH3CN rt NR
2 2 CsF CH3CN reflux NR
3 2 LiF CH3CN rt NR
4 2 LiF CH3CN reflux NR
5 2 TBAF THF rt --a
6 2 TFA CH2Cl2 rt 65
7 4 TFA CH2Cl2 rt 100
8 2.5 TFA CH2Cl2 reflux 100b
a the starting material decomposed b isolated yield was 96%
Usually the silyl group could be easily removed by a fluoride source. Therefore,
pyrrole 2-2f was treated with TBAF and refluxed overnight (Figure 2-15). A clean
conversion was shown by 19F-NMR, and 95% yield was obtained for the isolated
desilylated product.
39
Table 2-3. One pot preparation of SF5-Pyrrole
entry substrate Yield(%)
1
96
2
79
3
80
4
88
5 78
Figure 2-15. Removal of TIPS group from 2-14f
Lastly, it was desirable to demonstrate the ability to remove the protective benzyl
group from the pyrrole products. However, catalytic hydrogenolysis of the N-
benzylpyrroles using either Pd/C or Pd(OH)2/C catalyst proved unsuccessful. Instead it
was found to be necessary to carry out the debenzylation at the dihydropyrrole stage by
a method developed by Olofson and Senet to dealkylate tertiary amines using the
reagent α-chloroethyl chloroformate (Figure 2-16).33 Debenzylated dihydropyrrole could
then be aromatized in the usual manner by treatment with DDQ to form pyrrole 2-17.
40
Figure 2-16. Removal of the benzyl group from dihydropyrrole
2.4 Preparation of SF5-Thiophene
2.4.1 Results and Discussion
With the successful preparation of SF5-pyrrole derivatives and demonstrating that
cycloadditions are a good general approach to prepare SF5-heterocycles we wanted to
extend this method to synthesize SF5-thiophene, which might also have great potential
for application, since thiophene and its analogs have been extensively used in materials
science.
Figure 2-17. Construction of thiophene from thiazole building block
Inspired by the previous example of preparing SF5-furan from oxazole building
blocks, we tried to apply the same strategy to prepare SF5-thiophene, since it only
requires one step to achieve the target molecule compared to a possible1,3-dipolar
cycloaddition approach. Therefore, we prepared compound 2-18, which was first found
by Ye and his coworkers34 to undergo Diels-Alder reaction to build thiophene structures
(Figure 2-17). However when the SF5-alkyne was mixed with thiazole, no desired
product was found and all the starting materials decomposed, mainly due to the
41
required extremely high reaction temperature. The attempt to lower the temperature did
not provide any positive results.
Figure 2-18. Construction of thiophene through thiocarbonyl ylide
With the failure of the initial trial, we returned to 1,3-dipolar addition reactions and
searched the synthetic pathways of thiophene utilizing thiocarbonyl ylide. We found
compound 2-19, first invented by Sakurai,35 was an excellent ylide precursor (Figure 2-
18) with generally wide substrate scope and mild reaction conditions.36
Table 2-4. The preparation of SF5-thiophene
R Step 1 Step 2
71% 83%
67% 71%
67% 74%
When mixing the readily prepared 2-19 with SF5-alkyne and initiating with cesium
fluoride in acetonitrile at RT, to our delight, the reaction proceeded smoothly to give
moderate conversion. After optimizing the conditions, we found TBAF/THF was a better
activating system. However, the next oxidation step proved to be considerably
42
challenging. Various oxidants were screened for the reaction such as DDQ, CuBr2,
NBS, etc., and finally SO2Cl2 was found effective for the oxidizing the aromatic
substituted substrates while aliphatic substrates still remained a challenge.
Nonetheless, many aromatic substituted SF5-alkynes could proceed in this pathway and
thus provided the desired product with good yields over two steps.
2.4.2 Structure Characterization
Figure 2-19. 1H-NMR of 2-20d
43
Figure 2-20. 1H-NMR of 2-21d
Figure 2-21. 19F-NMR of 2-20d and 2-21d
44
In Figure 2-19, the appearance of characteristic peaks for the p-toluene group
(2.33ppm for CH3 and 7.04, 7.15ppm for the AB system) and two sets of CH2 signals
(3.97, 4.30ppm) unambiguously confirmed the ring formation. Interestingly, one of the
CH2 groups gave a singlet peak, while the other was a triplet with a coupling constant of
4.6Hz, which might be attributed to coupling with the SF5 group. In Figure 2-20 the
disappearance of the signal for the two CH2 groups accompanied by the appearance of
two new peaks in the aromatic region proved the achievement of oxidation by SO2Cl2.
The 19F-NMR spectrum was also used to characterize the product. The SF5 group of
compound 2-20d gives the doublet peak at 66.8ppm with a coupling constant 149Hz.
After oxidation, the peak moved to 72.3Hz, and the coupling constant increased to
152Hz (Figure 2-21).
2.5 Conclusion
Pyrrole and thiophene derivatives bearing a pentafluorosulfanyl (SF5) group were
previously unknown. Utilizing the cycloaddition reaction of azomethine ylides with SF5-
alkynes, a series of SF5-pyrrole carboxylic acid esters were prepared in good yield.
Further the smooth reaction of SF5-alkyne with N-benzyl-N-(methoxymethyl)-N-
(trimethylsilylmethyl)amine initiated by triflic acid demonstrated that 1,3-dipolar
cycloadditions are a good general approach to construct heterocyclic compounds
containing the SF5 group. This chemistry was successfully extended to prepare SF5-
thiophene derivatives.
2.6 Experimental Section
All reagents and solvents were purchased from commercial sources and used
without further purification unless otherwise specified. Thin layer chromatography (TLC)
45
was performed on SiO2-60 F254 aluminum plates with visualization by UV light or
staining. Flash column chromatography was performed using Purasil SiO2-60,230−400
mesh from Whatman. Melting points were uncorrected. 1H, 19F and 13C NMR were
recorded in CDCl3 at 300 MHz, 282MHz and 75MHz respectively. ESI-TOF- and DART-
TOF-MS spectrum were recorded on an Agilent 6210 TOF spectrometer. CI-MS
spectrum were recorded on a Thermo Trace GC DSQ (single quadrupole)
spectrometer. Elemental analyses were performed on a Carlo Erba-1106 instrument.
SF5Cl gas was obtained from Airproducts. Compound 2-7, 2-19 was prepared
according to the reported method.27,36
Typical synthetic procedure for 2-2:
Into a round-bottom flask equipped with a dry ice reflux condenser were added at -
40 0C, 20 mL of anhydrous hexane, alkyne (3-4 mmol) and SF5Cl (1.2 equiv). The
solution was stirred at this temperature for 10min, and then Et3B (0.1 equiv., 1 M in
hexane) was added slowly using a syringe. The solution was stirred for 1 h at -30 0C,
and then warmed to RT. The mixture was hydrolyzed with aqueous NaHCO3 and the
organic phase was dried with MgSO4. The solvent was removed and the residue was
treated with LiOH (5 equiv) in DMSO at RT for 2 h, then the mixture was poured into ice
water and neutralized with 2 M HCl, extracted with ether twice and the ether phase was
dried with MgSO4, finally purified by column.
2-2b: (43%). 1H NMR(CDCl3), 2.55-2.62 (m, 2H), 2.85-2.90 (t, J=10 Hz, 2H), 7.18-
7.33 (m, 5H); 13CNMR, δ20.41, 33.52, 127.03, 128.50, 128.81, 139.20; 19F NMR, δ77.37
(p, J = 158 Hz, 1F), 82.60 (d, J = 160 Hz, 4F).
46
2-2d: (45%). 1H NMR(CDCl3), 2.40 (s, 3H), 7.20-7.22 (d, J = 7.8 Hz, 2H), 7.44-
7.47 (d, J = 7.8 Hz, 2H); 13C NMR, δ21.86, 129.70, 132.72, 142.12; 19F NMR, δ77.26 (p,
J = 162 Hz, 1F), 88.05 (d, J = 177 Hz, 4F).
2-2e: (60%). 1H NMR(CDCl3), δ7.18-7.20 (dd, J = 1.2, 3.6 Hz, 1H), 7.32-7.34 (dd,
J = 3.0, 2.1 Hz, 1H), 7.73-7.34 (m, 1H); 13C NMR, δ126.7, 129.8 (m), 134.0 (m)； 19F
NMR , δ83.6 (m, 4F), 76.9 (m, 1F).
Typical synthetic procedure for 4a-d.
A mixture of 2-7 (2.05 mmol, 3 eq), 2-2 (0.68 mmol, 1 eq) and 2.5 mL xylene was
heated at about 135 oC for 24 h (monitor by 19F-NMR), when the reaction was over,
purified 2-8 directly by flash column to remove the solvent and excess 2-7. Then 5 mL
CCl4 and 310 mg DDQ were added to the 2-8 at RT. The mixture was stirred for 3 h
(TLC), the solvent was distilled and the residue was submitted to column
chromatography. 2-9 was obtained as white solid.
2-9a: mp 108-1100C. 1H NMR(CDCl3), δ1.66 (s, 9H), 3.34 (s, 3H), 7.18-7.31 (m,
6H); 13C NMR, δ30.71, 52.00, 59.83, 121.67 (m), 122.70 (m), 126.93 (m), 127.39,
127.44, 130.12, 134.27, 135.20 (m), 163.93; 19F NMR, δ87.35 (p, J = 153Hz, 1H), 75.40
(d, J = 153 Hz, 4H). HRMS, calcd.for C16H18F5NO2S, 383.0978; found, 383.0973.
2-9b: mp 115-1170C. 1HNMR(CDCl3), δ1.67 (s, 9H), 2.77-2.83 (dd, J = 6.6 & 4.5
Hz, 2H), 2.96-3.02 (dd, J = 6.6 & 4.5 Hz, 2H), 3.91 (s, 3H), 7.21-7.34 (m, 6H); 13C NMR,
δ28.83, 30.78, 37.86, 52.18, 59.97, 121.38 (m), 123.06 (m), 126.15, 127.10 (m), 128.51,
47
128.61, 134.96 (m), 142.24, 163.59; 19F NMR, δ88.65 (p, J = 150 Hz, 1H), 74.30 (d, J =
150Hz, 4F). HRMS, calcd.for C18H22F5NO2S, 411.1291; found, 411.1277.
2-9c: mp 41-440C. 1H NMR(CDCl3), δ0.88- 0.93 (t, J = 14.4 Hz, 3H), 1.13-1.50
(m, 4H), 1.64 (s, 9H), 2.63-2.69 (t, J = 15.9 Hz, 2H), 3.86 (s, 3H), 7.26 (s, 1H); 13C NMR,
δ13.97, 23.31, 25.94, 30.75, 33.77, 52.06, 59.71, 121.07 (m), 122.67 (m), 128.12 (m),
134.86 (m), 163.70; 19F NMR , δ88.75 (p, J = 155 Hz, 1H), 74.25 (d, J = 155 Hz, 4F).
HRMS, calcd.for C14H22F5NO2S, 363.1291; found, 363.1316.
2-9d: mp 114-1160C. 1H NMR(CDCl3), δ1.68 (s, 9H), 2.36 (s, 3H), 3.41 (s, 3H),
7.12 (s, 4H), 7.33 (s, 1H); 13C NMR, δ21.42, 30.71, 52.05, 59.72, 121.52 (m), 122.72
(m), 126.76 (m), 128.15, 129.95, 131.11, 135.29 (m), 136.99,164.08; 19F NMR , δ87.63
(p, J = 152 Hz, 1H), 75.44 (d, J = 152 Hz, 4H). HRMS, calcd.for C17H20F5NO2S,
397.1135; found, 397.1120.
Two drops of CF3SO3H was added to a flask equipped with 80 mg 2-9b and 2mL
DCM at RT. The reaction mixture was then stirred for about 2 h (TLC), purify by column
directly to give 2-10 as white solid in a yield of 78%. mp 165-1670C. 1HNMR(CDCl3),
δ2.78-2.84 (dd, J = 8.1 & 4.2 Hz, 2H), 3.16-322 (dd, J = 8.1 & 4.2 Hz, 2H), 3.92 (s, 3H),
7.191-7.34 (m, 6H), 9.34 (s, 1H); 13C NMR, δ28.38, 37.49, 52.12, 118.81 (m), 122.02
(m), 126.19, 128.00 (m), 128.58, 128.61, 138.50 (m), 142.07, 161.26; 19F NMR , δ88.87
(p, J = 148 Hz, 1F), 73.56 (d, J = 148 Hz, 4F). HRMS, calcd.for C14H14F5NO2S,
355.0665; found, 355.0648.
48
General procedure for preparation of pyrroles 4a-f.
Trifluoroacetic acid solution (0.9 mL, 0.2 equiv, 1 M in CH2Cl2) was slowly added
to a mixture of 2-2 (4.27 mmol, 1 equiv) and N-Benzyl-N-(methoxymethyl)-N-
(trimethylsilylmethyl)- amine (2-11, 10 mmol, 2.5 equiv) in 10 mL CH2Cl2. After addition,
the reaction mixture was refluxed for 24 h, then cooled with an ice-water bath. DDQ (4.7
mmol, 1.1 equiv) was carefully added to the light-yellow solution. The mixture was
stirred for another 2 h, the dark-red mixture was diluted with 10 mL CH2Cl2 and poured
into saturated NaHCO3 solution(20 mL). The organic phase was separated the solvent
was evaporated. The residue was submitted to column chromatography. The product
was obtained as white solid or colorless liquid.
The intermediate 2-13 was separated and characterized by NMR analysis prior to
its oxidative conversion to pyrrole 2-14e.
2-13: 1H NMR(CDCl3), δ3.79 (s, 2H), 3.84-3,87 (m, 2H), 4.00-4.03 (t, J = 4.2 Hz,
2H), 7.13-7.14 (d, J = 4.8Hz, 1H), 7.26-7.36 (m, 7H); 13C NMR, δ60.1, 61.8 (m), 64.8,
125.5 (m), 125.7, 127.6 (m), 127.7, 128.8, 128.9, 132.5, 137.0 (m), 138.1, 144.4(m)；
19F NMR , δ83.9 (p, J = 164 Hz, 1F), 66.4(d, J = 166 Hz, 4F).
2-14a:(80%). 1H NMR(CDCl3), δ5.05 (s, 2H), 6.56 (s, 1H), 7.19 (s, 1H), 7.26-7.28
(d, J = 7.5 Hz, 2H), 7.37-7.44 (m, 8H); 13C NMR, δ54.3, 120.3, 121.8, 122.9, 127.3,
127.8, 127.9, 128.7, 129.3, 130.1, 134.9, 135.9；19F NMR , δ88.6 (p, J = 169 Hz, 1F),
76.2 (d, J = 163 Hz, 4F). HRMS:calcd for C17H14F5NS, 359.0767; found, 359.0786.
49
Anal. Calcd for C17H14F5NS: C, 56.82; H, 3.93; N, 3.90. Found: C, 56.47; H, 3.82; N,
4.01.
2-14b:(79%). 1H NMR(CDCl3), δ2.93 (m, 4H), 4.95 (s, 2H), 6.33 (s, 1H), 7.06-7.07
(d, J = 2.4 Hz, 1H), 7.13-7.16 (m, 2H), 7.22-7.25 (m, 3H), 7.30-7.37 (m, 2H), 7.38-7.44
(m, 3H); 13C NMR, δ28.6, 36.8, 54.1, 118.9 (m), 120.7 (m), 121.6 (m), 126.2, 127.6,
128.50, 128.6, 128.7, 129.2, 136.4, 142.0；19F NMR , δ89.6 (p, J = 164 Hz, 1F), 74.6(d,
J = 161Hz, 4F). HRMS:calcd for C17H18F5NS, 387.1080; found, 388.1153(M+H). Anal.
Calcd for C17H18F5NS: C, 58.90; H, 4.68; N, 3.62. Found: C, 58.74; H, 4.29; N, 3.78.
2-14d: (88%). 1H NMR(CDCl3), δ2.43 (s, 3H), 5.05 (s, 2H), 6.54 (s, 1H), 7.18-7.23
(m, 3H), 7.25-7.28 (m, 2H), 7.32-7.35 (m, 2H), 7.40-7.45 (m, 3H); 13C NMR, δ21.4, 54.2,
120.1, 121.6, 122.8, 127.8, 128.6, 129.2, 129.9, 131.9, 135.9, 136.9； 19F NMR , δ88.6
(p, J = 160Hz, 1F), 76.1 (d, J = 150 Hz, 4F). HRMS:calcd for C18H16F5NS, 373.0923;
found, 373.0921. Anal. Calcd for C18H16F5NS: C, 57.90; H, 4.32; N, 3.75. Found: C,
57.65; H, 4.35; N, 3.80.
2-14e: (96%) mp 69-71oC. 1H NMR(CDCl3), δ5.00 (s, 2H), 6.57 (s, 1H), 7.13-7.15
(m, 2H), 7.19-7.23 (m, 3H), 7.25-7.28 (m, 1H), 7.35-7.42 (m, 3H); 13C NMR, δ54.3,
117.5 (m), 120.3 (m), 122.1 (m), 123.1, 124.6, 127.9, 128.7, 129.30, 129.5 (m), 134.3,
135.9；19F NMR , δ88.4 (p, J = 168 Hz, 1F), 75.7 (d, J = 163 Hz, 4F). HRMS:calcd for
C15H12F5NS2, 365.0331; found, 365.0319. Anal. Calcd for C15H12F5NS2: C, 49.31; H,
3.31; N, 3.76. Found: C, 49.58; H, 3.25; N, 3.76.
2-14f: (78%) mp 37-39oC. 1H NMR(CDCl3), δ1.07-1.09 (d, J = 7.2 Hz, 18H), 1.31-
1.41 (m, 3H), 5.05 (s, 2H), 6.67 (s, 1H), 7.08-7.11 (m, 2H), 7.18-7.19 (m, 1H), 7.31-7.39
(m, 3H); 13C NMR, δ12.6, 19.3, 53.8, 110.9 (m), 123.6 (m), 127.2, 128.4, 129.2, 129.4,
50
136.5, 142.5 (m)；19F NMR , δ89.4 (p, J = 164 Hz, 1F), 72.6 (d, J = 156 Hz, 4F).
HRMS:calcd for C20H30F5NSSi, 439.1788; found, 440.1859(M+H). Anal. Calcd for
C20H30F5NSSi: C, 54.64; H, 6.88; N, 3.19. Found: C, 54.67; H, 6.62; N, 3.19.
1-benzyl-3-pentafluorosulfanyl-pyrrole(2-15): TBAF (0.9 mL, 1 M in THF) was
added to a round flask containing 2-14f (200 mg, 0.455 mmol) and 3 ml THF, then it
was heated to reflux overnight. The mixture was poured into water (5 mL), extracted
with CH2Cl2 (5mL x 3), the solvent was removed and the residue was submitted to
column. 0.12 g product was obtained as colorless oil. (95%). 1HNMR(CDCl3), δ5.04 (s,
2H), 6.43-6.45 (m, 1H), 6.60 (s, 1H), 7.05 (s, 1H), 7.15-7.18 (m, 2H), 7.32-7.42 (m, 3H);
13C NMR, δ54.2, 107.3 (m), 120.1 (m), 120.4, 127.6, 128.6, 129.2, 136.2；19F NMR ,
δ87.6 (p, J = 162 Hz, 1F), 70.8 (d, J = 163 Hz, 4F). HRMS:calcd for C11H10F5NS,
283.0454; found, 283.0458. Anal. Calcd for C11H10F5NS: C, 46.64; H, 3.56; N, 4.94.
Found: C, 46.82; H, 3.55; N, 5.15.
1-hydro-3-pentafluorosulfanyl-4-(3-thienyl)-2,5-dihydro-pyrrole(2-16): 1-
Chloroethyl chloroformate (156 mg, 1.1 mmol) was added to a solution of 3a (200 mg,
0.55mmol) and triethylamine (55 mg, 0.55 mmol) in 2 mL CH2Cl2 at 0°C with stirring.
51
Tthe mixture was concentrated after 30 min, and dissolved in methanol (2 mL), then
stirred overnight. The solvent was removed and the residue was submitted to column. A
colorless oil (102mg) was obtained. (68%). 1H NMR(CDCl3), δ2.17 (s, 2H), 4.06 (m, 2H),
4.19-4.21 (t, J = 7.2 Hz, 2H), 7.10-7.11 (d, J= 4.8 Hz, 1H), 7.26-7.29 (m, 1H), 7.33-7.34
(m, 1H); 13C NMR, δ56. 9 (m), 59.8, 125.2 (m), 125.7, 127.5, 132.2, 139.1 (m), 47.1 (m)
；19F NMR , δ84.2 (p, J = 162 Hz, 1F), 67.4 (d, J = 164 Hz, 4F).
1-hydro-3-pentafluorosulfanyl-4-(3-thienyl)-pyrrole(2-17): DDQ (125 mg, 0.66
mmol) was added to a solution of 5 in CH2Cl2 at 0 oC with stirring. After standing for 2
hs, the mixture was submitted to column directly. A colorless oil (95 mg) was obtained.
(95%). 1H NMR(CDCl3), δ6.67 (s, 1H), 7.12-7.14 (d, J = 5.1 Hz, 1H), 7.21-7.22 (m, 2H),
7.26-7.29 (m, 1H), 8.43 (s, 1H); 13C NMR, δ117.4 (m), 119.4 (m), 123.2, 124.7, 129.6,
134.1, 136.6 (m)；19F NMR , δ87.9 (p, J = 167 Hz, 1F), 75.5 (d, J = 163 Hz, 4F).
HRMS:calcd for C8H6F5NS2, 274.9862; found, 274.9864. Anal. Calcd for C8H6F5NS2: C,
34.91; H, 2.20; N, 5.09. Found: C, 35.29; H, 2.25; N, 4.75.
General synthetic procedure for SF5-thiphene
TBAF (1.0 M in THF, 1.3-5 equiv) was added to a mixture of chloromethyl
trimethylsilylmethylsulfide (1.3-5 equiv) and SF5-alkynes (1 equiv) in THF at RT. After
stirring for several hours (monitored by 19F-NMR), the reaction was quenched with water
and submitted to column to give 2-20 as a white solid.
52
A solution of 2-20 in DCM was cooled to -30 0C. Sulfury chloride ( 2 equiv) was
added slowly over 10 min. After stirring the mixture for another 30 min, the reaction was
quenched with water and the organic phase was dried by Na2SO4. The solvent was
Evaporated and the residue was purified by column to give 2-21 as white solid or
colorless oil.
3-pentafluorosulfanyl-4-p-tolyl-dihydrothiophene(2-20d): 1H NMR(CDCl3),
δ2.36 (s, 3H), 3.99 (s, 2H), 4.31-4.34 (t, J = 5.1 Hz, 2H), 7.06-7.08 (d, J =8.1 Hz, 2H),
7.17-7.19 (d, J = 7.8 Hz, 2H); 13C NMR, δ21.43, 39.68, 44.09, 126.86, 129.12, 132.40,
138.34, 145.50, 148.34 (m)； 19F NMR , δ83.12 (p, J = 153 Hz, 1F), 67.05 (d, J = 163
Hz, 4F).
3-pentafluorosulfanyl-4-phenyl-dihydrothiophene(2-20a): 1H NMR(CDCl3),
δ3.99-4.04 (m, 2H), 4.33-4.39 (t, J = 4.8 Hz, 2H), 7.17-7.20 (m, 2H), 7.35-7.38 (m, 3H);
13C NMR, δ39.74, 44.10, 127.00, 128.36, 135.51, 145.32, 148.62 (m)；19F NMR ,
δ83.00 (p, J = 152 Hz, 1F), 66.11 (d, J = 163 Hz, 4F).
3-pentafluorosulfanyl-4-(3’-thienyl)-dihydrothiophene(2-20e): 1H NMR(CDCl3),
δ3.96-4.01 (m, 2H), 4.26-4.29 (t, J = 4.8 Hz, 2H), 6.96-6.98 (d, J = 5.1 Hz, 1H), 7.19-
7.20 (d, J = 1.8 Hz, 1H), 7.28-7.31 (dd, J = 5.1 Hz, 1H); 13C NMR, δ39.54, 43.23,
123.82, 125.94, 127.12, 134.22, 140.91，148.72 (m)； 19F NMR , δ82.97 (p, J = 161
Hz, 1F), 66.11 (d, J = 164 Hz, 4F).
3-pentafluorosulfanyl-4-p-tolyl-thiophene(2-21d): mp 73-75oC. 1H NMR
(CDCl3), δ2.40 (s, 3H), 7.07 (m, 1H), 7.19 (s, , 4H), 7.87-7.88 (d, J = 3.9 Hz, 1H); 13C
NMR, δ21.43, 124.93, 127.90, 128.50, 129.64, 133.09, 137.85, 139.77, 150.65 (m) ; 19F
NMR , δ84.27 (p, J = 167 Hz, 1F), 72.55 (d, J = 162 Hz, 4F). HRMS:calcd for
53
C11H9F5S2, 300.0066; found, 300.0060. Anal. Calcd for C11H9F5S2: C, 43.99; H, 3.02.
Found: C, 43.91; H, 3.06.
3-pentafluorosulfanyl-4-phenyl-thiophene(2-21a): 1H NMR(CDCl3), δ7.10-7.12
(m, 1H), 7.31-7.34 (m, 2H), 7.38-7.40 (m, 3H), 7.89-7.90 (d, J = 3.9 Hz, 1H); 13C NMR,
δ125.02, 127.80, 128.10, 129.81, 136.07, 139.80, 150.65 (m)；19F NMR , δ84.11 (p, J =
161 Hz, 1F), 72.08 (d, J = 162 Hz, 4F). HRMS:calcd for C10H7F5S2, 285.9909; found,
285.9929. Anal. Calcd for C10H7F5S2: C, 41.95; H, 2.46. Found: C, 42.28; H, 2.49.
3-pentafluorosulfanyl-4-(3’-thienyl)-thiophene(2-21e): 1H NMR(CDCl3), δ7.07-
7.08 (d, J = 4.8 Hz, 1H), 7.12-7.14 (m, 1H), 7.23-7.24 (dd, J = 1.2, 2.1 Hz, 1H), 7.28-
7.31 (dd, J = 3, 1.8 Hz, 1H), 7.85-7.87 (d, J = 3.9Hz, 1H); 13C NMR, δ124.7, 125.3,
128.3, 129.3, 134.6, 135.3, 150.3； 19F NMR , δ84.0 (m, 1F), 72.1 (d, J = 162 Hz, 4F).
HRMS:calcd for C8H5F5S3, 291.9474; found, 291.9504. Anal. Calcd for C8H5F5S3.
54
CHAPTER 3 DIASTEREOSELECTIVE REDUCTION OF GEM-DIFLUOROCYCLOPROPENE
CATALYZED BY BRӦNSTED ACID
3.1 Introduction
Bioactive molecules bearing fluorine atoms can greatly enhance properties
compared to the non-fluorinated compounds. This leads to the widespread use of
fluorochemistry in pharmaceutical, agrochemical and fine chemical communities.37,38,39
Highly strained gem-difluorocyclopropanes, unique members of the fluorine chemistry
family, have attracted a great deal of interest in recent years.40 With the development of
numerous difluorocarbene reagents,41 the [2+1] addition reaction has proved to be a
straightforward method to construct difluorocyclopropane rings. Among those reagents,
TFDA (trimethylsilyl 2-(fluorosulfonyl)-2,2-difluoroacetate), which readily reacts with
electron deficient substrates, is distinct (Figure 3-1).
Figure 3-1. The reactivity of TFDA and its reaction mechanism
Before the invention of the TFDA reagent, there were only a few difluorocarbene
reagents that were capable of reacting with moderately electron deficient alkenes, and
all of them suffered a range of limitations which reduced their application scope.41a For
example, the most famous, Seyferth’s phenyl(trifluoromethyl) mercury (PhHgCF3) is
55
seldom used nowadays due to its high toxicity and tedious preparation procedure. The
cheapest commercially available reagent, sodium chlorodifluoroacetate (ClCF2COONa),
which requires over 180oC to decompose to difluorocarbene species and must be used
in large excess (more than 10 equiv), does not make the reaction affordable for many
situations. The serious drawbacks of gaseous reagent hexafluoropropylene oxide
(HFPO), generally used in an autoclave with high temperature and pressure, also
tremendously diminish its synthetic potential.
In 2000, Dr.Tian and his coworkers in the Dolbier group designed the novel
difluorocarbene reagent TFDA based on the chain mechanism shown in Figure 3-1.41a
With a catalytic amount of sodium fluoride (0.1eq), TFDA was slowly added to the
substrate under nitrogen at 110oC, generally full conversion was achieved in 2 hours
with high isolated yield. Therefore, TFDA has several significant advantages over other
reagents. First, TFDA is a very efficient reagent, with usually at most 2 equiv being
required for a satisfactory yield; secondly, the reaction is performed in common
glassware under relatively mild conditions; thirdly, the catalytic amount of NaF makes
the reaction almost homogeneous, which helps it to reach full conversion in a short
time; last but not least, it works with a broad range of substrates including many
unreactive electron deficient alkenes.
Figure 3-2. Reaction of TFDA with α,β-unsaturated ketones
56
Although TFDA is a highly efficient reagent, its reaction with α,β-unsaturated
ketones only provided moderate yields,42 probably due to the competing polymerization
of the substrates, which not only affects the scale-up of this reaction, but also
challenges its repeatability. In order to solve this problem, Cornett and his coworkers
attempted to utilize the Friedel-Crafts reaction, based on the readily prepared building
block difluorocyclopropanecarbonyl chloride. To their surprise, the reaction led to a
mixture with an unexpected ring-opening product (Figure 3-3).43 The ratio of the two
products depended on the reactivity of the arenes.
Figure 3-3. Friedel-Crafts reaction of difluorocyclopropanecarbonyl chloride
Nonetheless, the unsubstituted difluorocyclopropane ketone could be approached
either from the addition of TFDA to simple α,β-unsaturated ketones or from Friedel-
Crafts reactions. But as to the substituted difluorocyclopropane ketone, the case still
remains a challenge because the substituted α,β-unsaturated ketones did not react with
TFDA at all. 44 An alternative approach was used by the Chen group. In order to avoid
the electron deficient substrate issue, the ketone group was protected prior to being
treated with TFDA. However, in the acetal hydrolysis step, the product was dominated
by formation of an unexpected monofluoro substituted furan in the case of electron rich
substrates (Figure 3-4).44
57
Figure 3-4. Attempt to prepare of substituted difluorocyclopropane ketones
3.2 The design of the reaction
Although the direct reaction of substituted α,β-unsaturated ketones with TFDA
does not occur, when TFDA underwent reaction with substituted propynones, the
reaction yielded the cyclopropenyl ketones with high yield under mild conditions.45
Figure 3-5. Preparation of difluorocyclopropenyl ketone and its properties
The chemical properties of cyclopropenyl ketones as determined by Chen’s group
indicated that they were not stable and they tended to be attacked by nucleophiles in
neutral or basic environment with generation of an enolate ion. During the process of
tautomerization from enolate to ketone, one HF molecule was eliminated, leading to
another monofluoro substituted cycloprepenyl ketone intermediate. This intermediate
was even less stable and ending up losing a fluorine ion to form a ring-opened product
(Figure 3-5).46 On the contrary, a ring-opened product was obtained without loss of
58
fluorine during the reaction of difluorocyclopropanyl ketones with strong acid HBr in an
ionic liquid (Figure 3-6).42 The mechanism was proposed to be SN2-like in character.
With the activation of ketone by protonation, the CH2 group in the cyclopropane ring
was attacked by bromide. This led to an enol intermediate which, interestingly,
tautomerized to ketone with the two fluorine atoms remaining intact.
Figure 3-6. Reactivity of difluorocyclopropyl ketone with HBr in Ionic Liquid.
Based on the above two very different results, one can conclude that with fluorine
atoms standing at β-position of an enolate during the process of its tautomerization to
ketone in basic environment, probably one HF molecule will be displaced, while under
acidic conditions, the fluorine atoms will remain intact (Figure 3-7).
Figure 3-7. Proposed tautomerization mechanism for β-difluoro enols/enolates
If this hypothesis is true, we could propose the following routes to solve the
preparing problem of substituted difluorocyclopropyl ketone. Starting from readily
available precusor, the difluorocyclopropenyl ketones, the carbonyl group is first
activated by a Brӧnsted acid, subsequent conjugated addition by a hydride donor leads
59
to an enol form, which tautomerize to ketone under acidic conditions with the fluorine
atoms remaining intact (Figure 3-8).
Figure 3-8. Synthetic approach to substituted difluorocyclopropyl ketones
Therefore, the next issue to be concerned about is the choice of the correct
hydride donor. Obviously, hydrogen and metal hydride do not fit for this system as they
either open the ring or reduce the ketone group. After examining the literature, it was
found that Hantzsch ester (HEH) might be a possible candidate for the reaction. Not
only because of its facile preparation,47 but also because it has been widely used as a
hydride transfer reagent, usually catalyzed by Brӧnsted acids under mild conditions
(Figure 3-9).48
Figure 3-9. Application of HEH as hydride donor
60
3.3 Results
Table 3-1. Screening the conditions for the reduction of difluorocyclopropenyl ketones
Entry Catalyst Amount solvent Conversion(%)a, b, c cis:transc
1 BA-1a 10% CH3CN 60 67:33
2 BA-1b 10% CH3CN 45 61:39
3 BA-1c 10% CH3CN 54 56:44
4 BA-1d 10% CH3CN 50 62:38
5 BA-1d 10% THF 100 --d
6 BA-1d 10% Toluene 54 73:27
7 BA-1d 10% MTBE 30 74:26
8 BA-1d 10% DCM 90 73:27
9e BA-1d 10% DCM 35 73:27
10 BA-1d 2% DCM 65 73:27
a) RT, 20 h; b) 2 equiv HEH; c) characterized by 19F-NMR; d) no desired products found; e) 0 oC, 20 h.
The Hantzsch ester and gem-difluorocyclopropene were prepared according to the
literature methods.45,47 To initiate reduction, p-toluenesulfonic acid was chosen as the
catalyst with 10% loading. In fact, the reaction provided 60% conversion when simply
mixing the substrate with 2 equiv HEH in CH3CN at RT overnight (Table 2-3, entry 1),
61
TLC showed the consumption of the HEH. Except for the remaining starting material
and the products, no other detectable impurity peaks appeared in the 19F-NMR
spectrum. Interestingly the cis isomer, which is believed to be thermodynamically less
stable than the trans isomer, dominated the products with a cis/trans ratio of 67:33.
More common Brӧnsted acids were tested and they all favored the cis product and gave
similar conversion and selectivity. Using the catalyst pivalic acid (BA-1d), the solvent
effects were evaluated. Ether solvent THF did not lead to the desired product (entry 5),
while more non-polar solvents slowed down the reaction but facilitated better selectivity.
Dichloromethane provided the best combination of conversion and selectivity (entry 8).
Since the conversion is sensitive to the solvents, the selectivity may be related to the
temperature. However, it was found that the lower temperature (0 oC) did not enhance
any selectivity based on the condition of entry 8. It is noteworthy that the reaction was
very sensitive to the acidic environment. Even with using 2% of the catalyst, a good
conversion was achieved (entry 10).
62
Table 3-2. Screening conditions using bulky Brӧnsted acids
Entry Catalyst Amount solvent Conversion(%) cis:trans
1 BA-1e 10% DCM 78 80:20
2 BA-1f 10% DCM 64 79:21
3 BA-1g 10% DCM 72 78:22
4 BA-1h 10% DCM 71 59:41
5 BA-1i 10% DCM 64 74:26
6 BA-1e 10% ClCH2CH2Cl 71 76:24
7 BA-1e 10% toluene 48 85:15
8 BA-1e 10% MTBE 23 82:18
With the hope of increasing the selectivity, more bulky benzoic acids were tested.
As shown in Table 3-4, catalysts BA-1e, f and g gave similar selectivities with a
cis/trans ratio around 80/20, which is better than the result for catalyst BA-1d. Although
catalyst BA-1h looks very bulky, the two isopropyl groups at the ortho position may not
play any role in the reaction (entry 4). As the reaction was very sensitive to the acid,
even the bulky phenol BA-1i could catalyze the reaction and gave similar results.
Further solvent optimization based on use of catalyst BA-1e, which overall gave
relatively better conversion, showed that toluene is the best solvent with the highest
cis/trans ratio of 85/15 with an acceptable conversion (entry 7). The non-polar solvent
63
methyl t-butyl ether also gave high selectivity but the conversion was not practical (entry
8).
Figure 3-10. Reactions of difluorocyclopropene with HEH, catalyzed by Brӧnsted acid
To explore the limitations of this reaction, more substrates were prepared and
tested (Figure 3-10). Due to the relatively slow reaction rate, 20% catalyst was applied,
resulting in over 97% conversion in 4 days. The reaction had very broad substrate
scope, including both electron-deficient and electron-rich substrates giving almost
quantitative NMR yields when the cis/trans isomer mixture was the product. It is
noteworthy that most of the cis/trans isomers could be separated easily by column
chromatography, with the less polar trans isomer eluting first. Therefore, the yields
64
reported here are mainly for the isolated major, cis isomers. While 2a was obtained with
high diastereoselectivity and excellent yield, a better result was expected with more
sterically demanding substrates. However, to our surprise, when more substituents
were attached to the phenyl ring, the selectivity was slightly decreased (2b, 2c, 2d, 2e)
except for 2f, which had almost the same selectivity as 2a. Not surprisingly, an electron-
withdrawing group could accelerate the reaction and led to a lower selectivity (2g).
Although 2h gave relatively low selectivity, this compound cannot be prepared by other
methods. Also, the steric hindrance effect on the other phenyl ring was tested, but there
was no effect on the selectivity.
3.4 Discussion
Figure 3-11. Proposed mechanism for the catalytic reduction of difluorocyclopropenyl ketones
65
The proposed mechanism for the catalytic cycle is shown in Figure 3-11. The
ketone is first activated by Brӧnsted acid, followed by attack by HEH, with the ketone
functional group being transformed to its enol form. This enol form, which can eliminate
an HF molecule under basic condition, tautomerizes back to ketone under acidic
conditions, leaving the ring intact. During the tautomerization process, the Brӧnsted acid
can approach the enol from either the top face or the bottom face. However, due to the
steric interaction between substituents and the catalyst, the acid prefers attack on the
top face, which resulted in the cis product being favored. A control reaction was
conducted whereby a pure cis product was treated under the standard reaction
conditions. No trans isomer was detected by 19F-NMR, showing that the reaction is
kinetically controlled.
Figure 3-12. Kinetic control reaction
Based on this mechanism in Figure 3-11, it is reasonable that when more bulky
benzoic acids were used, a stronger steric interaction would occur between substituents
and the catalyst, resulting in better selectivity. Indeed the selectivity was observed to be
enhanced from 73/27 to 80/20 with the use of pivalic acid (BA-1d) and 3,5-di-t-butyl-
benzoic acid (BA-1e), respectively. Interestingly, catalysts BA-1e, f and g gave almost
the same high selectivity, while the apparently more bulky 2,4,6-triisopropy benzoic
(BA-1h) dramatically decreased the selectivity, indicating that the substituent at the
ortho position of benzoic acids do not have much influence on the transition state.
66
However, the less bulky ortho substituted phenol catalyst (BA-1i) gave much better
results that from BA-1h, probably due to the reduced size of the hydroxyl group
compared with carboxyl moiety, shortening the distance between phenyl ring and the
enol structure, leading to a more compact TS, where a substituent at the ortho position
of the catalyst might play a more important role regarding selectivity.
3.5 Conclusion
A novel synthetic method for preparing substituted gem-difluocyclopropyl ketone in
a reaction catalyzed by Brӧnsted acid was designed based on the rationalized
tautomerization mechanism of β-difluoro enolate. The reaction, using HEH as a hydride
transfer reagent, proved to be a general route to prepare substituted gem-
difluorocyclopropyl ketones in high yield. Moreover, the reaction was dominated by
formation of the cis product. Based on the proposed mechanism, the
diastereoselectivity was improved by using more bulky Brӧnsted acids under optimized
conditions. Further exploration of enantioselective preparation of gem-
difluorocyclopropyl ketones based on this research is ongoing in this lab and will be
reported in due course.
3.6 Experimental section
NMR spectrum were obtained in CDCl3 using TMS and CFCl3 as the internal
standards for 1H and 13C NMR and 19F NMR respectively; substituted propynones49 and
TFDA50 were prepared according to the previous literature, and all other chemicals were
purchased from Aldrich, Alfa, or Fisher without further purification.
Procedure for preparation of gem-difluorocyclopropenyl ketones: A mixture of
substituted propynone (3.55 mmol), NaF (10%mol), Diglyme (2 ml) was heated to 120oC
under the flow of N2. TFDA was then added dropwise (about 40 min), with stirring at this
67
temperature for 1 h, the solution was cooled and submitted to column for purification
directly with hexane/dichloromethane.
1b: (87%). 1H NMR: 2.46 (s, 3 H), 7.37 (d, J = 6.0 Hz, 2 H), 7.59 (m, 2 H), 7.69 (m,
1 H), 7.92 (d, J = 6.0 Hz, 2 H), 8.16 (m, 2 H). 19FNMR: δ -104.3 (s, 2F).
1c: (89%). 1H NMR: 2.46 (s, 3 H), 7.43 (m, 2 H), 7.60 (m, 2 H), 7.70 (m, 1 H), 7.84
(m, 2 H), 8.16 (m, 2 H). 19F NMR:δ -104.3 (s, 2F).
1d: (91%). 1H NMR: 2.41 (s, 6 H), 7.25 (s, 1H), 7.65 (m, 5 H), 8.16 (m, 2 H). 19F
NMR: δ -104.4 (s, 2F).
1e: (88%). 1H NMR: 1.39 (s, 18 H), 7.59 (m, 2H), 7.70 (m, 2 H), 7.88 (m, 2 H), 8.17
(m, 2 H). 19FNMR: δ -104.1 (s, 2F).
1f : (86%). 1H NMR: 1.37 (s, 9 H), 7.59 (m, 4H), 7.69 (m, 1 H), 7.96 (m, 2 H), 8.16
(m, 2 H). 19F NMR: δ -104.3 (s, 2F).
1g: (85%). 1H NMR: 7.60 (m, 2 H), 7.72 (m, 3H), 7.89 (m, 2 H), 8.14 (m, 2 H). 19F
NMR: δ -104.1 (s, 2F).
1h: (75%). 1H NMR: 2.59 (s, 1 H), 7.56 (m, 3H), 7.86 (m, 2 H). 19F NMR:δ -107.7
(s, 2F).
1i: (90%). 1H NMR: 1.38 (s, 9 H), 7.60 (m, 5H), 8.02 (m, 2 H), 7.96 (m, 2 H), 8.12
(m, 2 H). 19F NMR: δ -104.2 (s, 2F).
1j: (55%). 1H NMR: 0.91 (t, J = 9.0 Hz, 3 H), 1.38 (m, 4H), 1.77 (m, 2H), 2.74 (m,
2H), 7.55 (t, J = 9.0 Hz, 2 H), 7.67 (m, 1 H), 8.04 (m, 2 H). 19F NMR: δ -102.2 (s, 2F).
Procedure for Reduction of gem-Difluorocyclopropenyl Ketone with HEH: Brӧnsted
acid (20% mol) was added to a mixture of gem-difluorocyclopropenyl ketone (100 mg),
HEH ( 2 equiv), toluene (1mL) in round bottom flask at RT, the solution was stirred until
68
the ketone was consumed (monitored by TLC or 19F NMR), then the mixture was
purified by column chromatography.
2a: (79%). 1H NMR: 3.47 (td, J = 11.3 and 2.8 Hz, 1 H), 3.69 (td, J = 12.4 and 1.8
Hz, 1 H), 7.29 (s, 5 H), 7.42 - 7.53 (m, 2 H), 7.54 - 7.71 (m, 1 H), 7.89 - 8.05 (m, 2 H).
13C NMR: δ 33.19 (dd, J = 8.2 and 3.0 Hz) , 34.59 (dd, J = 9.0 and 3.0 Hz), 113.04 (dd,
J = 284.2 and 6.0 Hz), 127.9, 128.3, 128.6, 128.9, 129.8, 133.7, 138.0, 190.3. 19F
NMR: δ -115.7 (dt, J = 155 and 14 Hz, 1F), -147.4 (d, J = 155 Hz, 1F). HRMS: calcd for
C16H12F2O[M+Na]+, 281.0748; found, 281.0759.
3a: 1H NMR: 3.62-3.69 (m, 1 H), 3.83-3.91 (m, 1 H), 7.34 (m, 5 H), 7.54 (m, 2 H),
7.65 (m, 1 H), 8.05 (m, 2H). 13C NMR: δ 32.7 (m), 36.9 (m), 111.9 (m), 128.1, 128.5,
128.7, 128.9, 129.1, 132.1, 134.1, 137.2, 190.4. 19F NMR: δ -132.55 (m). HRMS: calcd
for C16H12F2O[M+Na]+, 281.0748; found, 281.0755.
2b: (72%). 1H NMR: 2.27 (s, 3 H), 3.42 (m, 1 H), 3.64 (m, 1H), 7.14 (dd, J = 18.0
and 9.0 Hz, 4H), 7.44 (m, 2 H), 7.55 (m, 1 H), 7.89 (m, 2 H). 13C NMR: δ 21.43, 33.22
(dd, J = 8.2 and 3.0 Hz) , 34.52 (dd, J = 9.7 and 2.3 Hz), 113.12 (dd, J =284.2 and 6.0
Hz), 126.5, 128.3, 128.9, 129.3, 129.6, 133.6, 137.7, 138.1, 190.4. 19F NMR: δ -115.6
(dt, J = 155 and 14 Hz, 1F), -147.4 (d, J = 156 Hz, 1F). HRMS: calcd for
C17H14F2O[M+Na]+, 295.0905; found, 295.0913.
2c: (70%). 1H NMR: 2.30 (s, 3 H), 3.42 (t, J = 15.0 Hz, 1 H), 3.66 (t, J = 12.0 Hz,
1H), 7.08 (m, 4H), 7.47 (t, J = 6.0 Hz, 2 H), 7.58 (m, 1 H), 7.92 (m, 2 H). 13C NMR: δ
21.63, 33.21(dd, J = 8.2 and 3.7 Hz) , 34.57 (dd, J = 9.0 and 2.3 Hz), 113.10 (dd, J =
285.0 and 6.0 Hz), 126.8, 128.3, 128.4, 128.8, 128.9, 129.6, 130.5, 133.6, 138.2, 190.4.
19F NMR: δ -115.7 (dt, J = 155 and 11 Hz, 1F), -147.4 (d, J = 155 Hz, 1F). HRMS: calcd
69
for C17H14F2O[M+Na]+, 295.0905; found, 295.0918. Anal. Calcd for C17H14F2O: C, 74.99;
H, 5.18. Found: C, 74.94; H, 5.57.
2d: (69%). 1H NMR: 2.26 (s, 6 H), 3.40 (t, J = 12.0 Hz, 1 H), 3.65 (t, J = 12.3 Hz,
1H), 6.89(s, 3H), 7.48 (m, 2 H), 7.59 (m, 1 H), 7.95 (d, J = 8.0 Hz, 2 H). 13C NMR: δ
21.51, 33.12 (dd, J = 9.0 and 3.0 Hz) , 34.57 (dd, J = 9.0 and 2.3 Hz), 113.10 (dd, J =
284.3 and 6.0 Hz), 127.5, 128.3, 128.9, 129.4, 129.7, 133.5, 137.9, 138.2, 190.3. 19F
NMR: δ -115.6 (dt, J = 155 and 14 Hz, 1F), -147.4 (d, J = 156 Hz, 1F). HRMS: calcd for
C18H16F2O[M+Na]+, 309.1061; found, 309.1072.
2e: (68%). 1H NMR: 1.20 (s, 18 H), 3.45 (td, J =12.0 and 3.0 Hz, 1 H), 3.65 (td, J =
12.0 and 3.0 Hz, 1 H), 7.01(s, 2H), 7.25(m, 1 H), 7.46 (m, 2 H), 7.57 (m, 1 H), 7.93(m,
2H). 13C NMR: δ 31.5, 32.85 (dd, J = 8.3 and 3.7 Hz) , 34.9, 35.2 (dd, J = 9.7 and 2.3
Hz), 113.10 (dd, J = 284.3 and 6.7 Hz), 121.8, 124.1, 128.4, 128.6, 128.9, 133.6, 138.1,
150.8, 190.4. 19F NMR: δ -115.7 (dt, J =155 and 11 Hz, 1F), -147.9 (d, J = 156Hz, 1F).
HRMS: calcd for C24H28F2O[M+Na]+, 393.2000; found, 393.2009. Anal. Calcd for
C24H28F2O: C, 77.81; H, 7.62. Found: C, 77.51; H, 8.09.
2f: (81%). 1H NMR: 1.26 (s, 9 H), 3.41 (td, J = 12.0 and 3.0 Hz, 1 H), 3.62 (td, J =
12.0 and 3.0 Hz, 1 H), 7.21(dd, J = 8.0 and 9.0 Hz, 4H), 7.44 (m, 2 H), 7.55 (m, 1 H),
7.90 (m, 2H). 13C NMR: δ 31.5, 32.85 (dd, J =8.3 and 3.0 Hz) , 34.5 (dd, J = 9.7 and 2.3
Hz), 34.7, 113.10 (dd, J = 285.0 and 5.3 Hz), 125.5, 126.5, 128.3, 128.9, 129.5, 133.6,
138.2, 150.8, 190.5. 19F NMR:δ -115.8 (dt, J = 155 and 11 Hz, 1F), -147.5 (d, J = 154
Hz, 1F). HRMS: calcd for C20H20F2O[M+Na]+, 337.1374; found, 337.1382.
2g: (75%). 1H NMR: 3.37 (td, J = 12.0 and 3.0 Hz, 1 H), 3.68 (td, J = 15.0 and 3.0
Hz, 1 H), 7.17 (m, 4H), 7.42 (m, 5 H), 7.92 (m, 2H). 13C NMR: δ 33.14 (dd, J = 9 and
70
2.3 Hz) , 33.7 (dd, J = 9.0 and 3.0 Hz), 112.7 (dd, J = 285.0 and 6.0 Hz), 122.2, 128.3,
128.8, 129.0, 131.5, 131.7, 133.9, 137.9, 190.0. 19F NMR:δ -116.1 (dt, J = 155 and 14
Hz, 1F), -147.5 (d, J = 155 Hz, 1F). HRMS: calcd for C16H11BrF2O[M+Na]+, 358.9854;
found, 358.9855. Anal. Calcd for C16H11BrF2O: C, 57.00; H, 3.29. Found: 57.31; H, 3.29.
2h: (61%). 1H NMR: 1.92 (s, 3 H), 2.97 (t, J = 15 Hz, 1 H), 3.33 (td, J = 12 Hz, 1
H), 7.32 (s, 5H). 13C NMR: δ 31.2, 33.8 (dd, J = 9.0 and 3.0 Hz) , 33.08 (dd, J = 10.5
and 1.5 Hz), 112.4 (t, J = 287.3 Hz), 128.3, 128.9, 129.6, 129.8, 199.3. 19F NMR: δ -
116.6 (d, J = 160 Hz, 1F), -144.9 (d, J = 164 Hz, 1F). HRMS: calcd for
C11H10F2O[M+Na]+, 219.0592; found, 219.0599. Anal. Calcd for C11H10F2O: C, 67.34; H,
5.14. Found: C, 67.06; H, 5.46.
2i: (80%). 1H NMR: 1.35 (s, 9 H), 3.44 (t, J = 12 Hz, 1 H), 3.66 (t, J = 15 Hz, 1 H),
7.29 (s, 5 H), 7.50 (d, J = 9 Hz, 2 H), 7.86 (m, J = 9 Hz, 2 H).13C NMR: δ 31.3, 33.09
(dd, J = 8.2 and 3.0 Hz) , 34.429 (dd, J = 9.0 and 2.3 Hz), 35.4, 113.0 (dd, J = 285.7
and 5.2 Hz), 125.9, 127.9, 128.3, 128.5, 129.8, 135.6, 157.5, 189.9. 19FNMR: δ -115.9
(dt, J = 155 and 14 Hz, 1F), -147.4 (d, J = 156 Hz, 1F). HRMS: calcd for
C20H20F2O[M+Na]+, 337.1374; found, 337.1388. Anal. Calcd for C20H20F2O: C, 76.41; H,
6.41. Found: C, 76.17; H, 6.61.
2j (cis/trans mixture): (95%). 1H NMR: 0.89 (m, 6H), 1.26-1.84 (m, 16 H), 2.16 (m,
1H), 2.62 (m, 1H), 3.01 (m, 1H), 3.23 (m, 1H), 7.50 (m, 4H), 7.59 (m, 2H), 7.97 (m, 4H).
19F NMR: δ -115.9 (dt, J = 152 and 14 Hz, 1F), -134.7 (m, 2F), -147.4 (d, J = 152 Hz,
1F).
71
CHAPTER 4 FACILE PREPARATION OF SF5-CONTAINING POLYMERS BY RING-OPENING
METATHESIS POLYMERIZATION (ROMP) AND PRODUCT CHARACTERIZATION
4.1 Introduction
Polymers containing fluorine atom(s) usually exhibit unique properties, such as
excellent thermal and chemical resistance, low dielectric constants, low surface
energies, etc. Hence, fluoropolymers have received considerable attention, from
fundamental research to industrial application.51 While polyethylene with different
fluorine content, poly(vinyl fluoride) (PVF), poly(vinylidene fluoride) (PVDF),
poly(ethylene tetrafluoroethylene) (PETFE), have been well known for their high
performance,52 recent research has also shown that fluoropolymers can be potentially
used in advanced materials area, such as optic material,53 anti-fouling coatings,54 and
supercapacitors.55
The pentafluorosulfanyl (SF5) group, an appealing trifluoromethyl alternative , has
attracted much interest since it is more electronegative, has larger steric size, and has
better chemical stability. Although SF5 chemistry was first studied almost a half-century
ago, this group had not been well explored until several breakthroughs in its synthetic
methodology occurred during last decade. These dramatically facilitated the application
of SF5 chemistry to the organic, pharmaceutical, material, and agrochemical fields. For
example, Et3B was discovered as an excellent radical initiator for the introduction of
commercially available SF5Cl into aliphatic substrates, thereby avoiding need for an
autoclave reactor. The continually active area of synthetic development of SF5-benzene
has allowed it to become an affordable building block for medicinal chemistry.
While small molecules bearing the SF5 group were well developed,
macromolecules modified with the SF5 moiety had potentially interesting properties for
72
the application as lubricants, surface-active reagents, optical materials, and protective
coatings.56 Although numerous SF5-containing monomers were prepared, the synthesis
of polymers with the SF5 group directly attached to the polymer main chain still remains
a challenge. This may be explained in several ways: First, only a few SF5-based
reagents, such as SF5Cl or SF5-benzene, are commercially available; secondly, few
synthetic methods were available for the incorporation of the SF5 moiety into the
monomer; thirdly, the steric and electronic properties of the SF5 substituent dramatically
affects the polymerization process. For example, Ameduri et al reported that SF5-
substituted ethylene would not undergo radical initiated homopolymerization. Even in
the case of terpolymerization with vinyldenefluoride (VDF) and hexafluoropropene, the
polymers contained only a low percentage of the SF5 units (<1%) or had very low
macromolecular weight (Mn = 600).57
Hence, we thought it would be valuable to prepare the polymer with an SF5 group
directly attached to the backbone, to further study its structure property relationships.
Inspired by the well-established Ring Opening Metathesis Polymerization (ROMP)
method,58,59 which is a powerful tool to prepare functionized polyethylene, we designed
SF5-substituted cyclooctene monomers for polymerizations initiated by ruthenium-based
catalyst and subsequent hydrogenation (Figure 4-1).
4.2 Results and Discussion
4.2.1 Monomer synthesis
Based on the Et3B-initiation methodology, SF5Cl was readily added to 1,5-
cyclooctadiene with high yield at low temperature after two hours. A satisfactory purity
of M1 was obtained by vacuum distillation followed by flash column chromatography.
Neither method alone provided clean spectrum. The byproduct could derive from the
73
reaction of the second double bond with excess SF5Cl gas, or a possible intramolecular
cyclization reaction. The clean elimination step was achieved by using the LiOH/DMSO
method to give a colorless oil M2 at RT while another efficient elimination system for
SF5-chemistry, CH3ONa/CH3OH, did not work at all for this reaction.
4.2.2 Polymer Synthesis and Structure Characterization
The first attempt to prepare P1 failed with a substrate/solvent ratio of 1 g/10 mL.
We then realized that the amount of solvent and temperature were crucial for this
reaction, as was also demonstrated by Hillymer et al.58 By utilizing the minimum amount
of CH2Cl2, just enough to dissolve the catalyst, light yellow rubber-like P1 was attained
in high yield. The 1H NMR spectrum (Figure 4-2) clearly indicated that the
polymerization occurred, since the two proton peaks (5.9 and 5.6 ppm) on unsaturated
carbon converged to a single peak (5.4 ppm), accompanied by the peaks for two
hydrogens (5.2 and 4.3 ppm) on the substituted carbons moving upfield (4.6 and 3.8
ppm). Initially hydrogenation of P1 with p-toluenesulfonhydrazide/tributylamine in xylene
did not lead to the desired product.58 Instead all the starting materials decomposed.
Figure 4-1. Synthetic route toward SF5-polymers
74
Luckily, without using tributylamine, the same conditions gave clean conversion after
refluxing for two hours. The olefin proton peak (5.4 ppm) noticeably disappeared in the
P2 NMR spectrum. M2 was also polymerized under identical conditions. Figure 4-3
unambiguously shows the movement of olefin peaks from 6.5 and 5.6 ppm to 6.3 and
5.4 ppm after reaction. The subsequent disappearance of the 5.4 ppm peak in the P4
spectrum indicated its successful hydrogenation.
Figure 4-2. 1H-NMR of M1, P1 and P2
75
Figure 4-3. 1H-NMR of M2, P3 and P4
The molecular weights and polydispersity index (PDI) of all products except P3,
which was not very soluble in any known solvents, were further characterized by gel
permeation chromatography (GPC). The results were consistent with the well-
established ROMP reaction products (Table 4-1). Although the molecular weight of P1
dropped down after hydrogenation to P2, Coughlin et al proposed that this may be due
to an increase in the degrees of freedom after reduction of the double bonds, possibly
leading to a more compact conformation with diminished hydrodynamic radius.59
Table 4-1. Preparation and properties of SF5-containing Polymers
entry polymer Yield (%) Mn (kg/mol) PDI Td (oC) Tg (oC)
1 P1 86 73.9 1.57 201 26
2 P2 88 72.5 1.7 197 15
3 P3 90 --- --- 294 -13
4 P4 81 44.2 1.98 280 -13
76
Figure 4-4. The 19F-NMR spectrum of monomers and polymers
Fluorine NMR was also used to monitor the reactions. Since four fluorine atoms
are equatorial, and one axial, 19F-NMR spectrum of all SF5-containing compounds in
Figure 4-4 showed characteristic doublet, around 54-58 ppm and pentet, with fine
structure at 85-87 ppm (AB4 system). The expanded area of the spectrum
demonstrates the clean and clear transformation of each step.
4.2.3 Thermal Properties Characterization
Figure 4-5. Thermogravimetric Analysis for SF5-polymers
Thermogravimetric Analysis (TGA) showed the unsaturated and hydrogenated
polymers to have similar thermal behavior such as close Td’s (temperature at 10%
weight loss), with two-stage decomposition. All the polymers lost around 50% weight at
the first stage which is close to the wt% composition of the SF5 group. Interestingly, The
Td’s of P3 and P4 are about 90 oC higher than those of P1 and P2, indicating that the
77
presence of chlorine atoms decreases the thermal stability, probably due to the
elimination of HCl at high temperature.
Figure 4-6. The Differential Scanning Calorimetry of SF5-polymers
Differential Scanning Calorimetry (DSC) was also used to characterize the thermal
profile of the polymers. A Tm was not observed due to the lack of regularity in the
microstructure (mainly because of head-tail, head-head, tail-tail mixture). Though P3
and P4 have higher Td’s than P1 and P2, Table 4-1 shows that the latter pair has higher
glass transition temperatures (Tg), indicating that the presence of double bonds has
more impact on Tg than the chlorine atoms. With the introduction of more double bonds,
the flexibility of the polymer backbone was highly limited compared to C-C single bond
rotation, leading to a decrease in free volume and higher Tg. This effect can also
explain the higher Tg of P1 compared to P2.59
78
4.3 Conclusions
We have successfully established a facile method to prepare two polymers with
SF5 group directly attached to the backbone using ring opening metathesis
polymerization of SF5-substituted cyclooctenes followed by hydrogenation. The
microstructures of these novel polymers were characterized by 1H-NMR, GPC and 19F-
NMR. TGA and DSC experiments showed the unsaturated polymers and their
hydrogenated derivatives have similar thermal profiles. Polymers P3 and P4 without
chlorine substituent have better thermal stabilities than P1 and P2 with chlorine, while
the latter pair exhibit higher glass transition temperatures.
4.4 Experimental Section
Gel permeation chromatography (GPC) measurements for the polymers were
performed in tetrahydrofuran (THF) at a flow rate of 1.0 mL/min using Waters
Associates GPCV2000 liquid chromatography system with an internal differential
refractive index detector (DRI). Molecular weights were calibrated using polystyrene
standards. Thermogravimetric analyses (TGA) were carried on a Perkin-Elmer 7 series
thermal analysis system with a heating rate of 10oC per min, sweeping temperatures
ranging from 25 to 700oC under inert atmosphere. Differential scanning calorimetry
(DSC) measurements were performed on a DSC-Q1000 V9.6 Build 290 with a heating
rate of 10oC per min from 25 to 250oC.
Preparation of M1. Into a three-neck round bottom flask equipped with a dry ice
reflux condenser were added at -40 0C, 50 mL of anhydrous hexane , 5 g 1,5-cycloocta-
diene and 11.5 g SF5Cl (1.2 equiv). The solution was stirred at this temperature for 10
min, and 5 mL Et3B (0.1 equiv., 1 M in hexane) was added slowly using a syringe. The
solution was stirred for 1 h at -30 0C, and then warmed to rt. The mixture was
79
hydrolyzed with aqueous NaHCO3 and the organic phase was separated and dried with
MgSO4. After evaporated the solvent, the crude product was first purified by vacuum
distillation and then submitted to column chromatography with hexane as eluent. (78%).
1H NMR(CDCl3), δ1.86-2.28 (m, 5H), 2.38 (m, 1H), 2.54-2.78 (m, 2H), 4.29 (m,
1H), 5.1 (m, 1H), 5.57-5.67 (m, 1H), 5.83-5.92 (m, 1H); 13C NMR, δ21.65, 22.85, 29.27,
36.69, 60.95, 89.23, 128.39, 132.03；19F NMR, δ85.81 (p, J = 138 Hz, 1F), 54.41 (d, J
= 141 Hz, 4F). HRMS: calcd for C8H12ClF5S, 270.0268; found, 270.0267.
Preparation of M2. Into a round bottom flask, 1.62 g LiOH.5H2O was slowly
added to a DMSO (21 mL) solution of 2.1 g M1 at RT. The mixture was stirred for 2 h
and then poured into ice-water mixture, following by extraction with ether and washed
with brine. The organic phase was separated and the solvent was evaporated. The
crude product was purified by column. (96%). 1H NMR (CDCl3), δ2.46 (m, 6H), 2.88 (m,
2H), 5.59 (m, 2H), 6.51 (m, 1H); 13C NMR, δ26.21, 27.69, 27.95, 28.89, 128.27, 128.61,
134.34, 157.07；19F NMR, δ87.53 (p, J = 147 Hz, 1F), 56.88 (d, J = 147 Hz, 4F).
HRMS: calcd for C8H11F5S, 234.0502; found, 234.0490.
General procedure for polymerization. Under nitrogen atmosphere, a highly
concentrated CH2Cl2 solution containing Grubbs’ catalyst ([M]/[C] = 500) was added to a
sealed tube filled with monomer via syringe. The mixture was stirred at 40 oC overnight.
Then the oil bath was removed, 1 mL vinyl ether and 5 ml chloroform was added to
solidified solution, after stirring for 2 h, the orange solution was poured into 200 ml
methanol and white solid was precipitated. The product was collected and dried
overnight by vacuum.
80
P1: (89%). 1H NMR (CDCl3), δ1.73-1.84 (bm, 3H), 2.21-2.34 (bm, 5H), 3.90 (b,
1H), 4.57 (bm, 1H), 5.46 (bs, 2H)；19F NMR, δ85.55 (p, J = 147 Hz, 1F), 58.03 (d, J =
144 Hz, 4F).
P3: (85%). 1H NMR (CDCl3), δ1.58 (bs, 3H), 2.17 (bs, 5H), 2.46 (bs, 2H), 5.44 (bs,
2H), 6.26 (bm, 1H)；19F NMR, δ87.05 (p, J = 152 Hz, 1F), 57.91 (d, J = 147 Hz, 4F).
General procedure for hydrogenation. The 0.25 g P1 was added to a flask filled
with 8 mL o-xylene, the flask was heated to 80 oC to dissolve the solid and then cooled
to RT. p-Toluenesulfonhydrazide (0.4 g) was added in one potion and the solution was
refluxed for 2 h, then the reaction mixture was poured to separation funnel and washed
with water twice. The organic phase was slowly added with stirring to methanol. The
polymer precipitated as light orange solid, which was filtered and dried over vacuum.
P2: (83%). 1H NMR (CDCl3), δ 1.38-1.80 (bm, 10H), 2.27 (bm, 2H), 3.90 (bs, 1H),
4.58 (bm, 1H)；19F NMR, δ 85.73 (p, J = 141 Hz, 1F), 57.57 (d, J = 144 Hz, 4F).
P4: (80%). 1H NMR (CDCl3), δ 1.34-1.48 (bm, 8H), 2.13 (bs, 2H), 2.41 (bs, 2H),
6.25 (bs, 1H)；19F NMR, δ 87.63 (p, J = 147Hz, 1F), 58.07 (d, J = 147 Hz, 4F).
81
APPENDIX NUCLEAR MAGNENETIC RESONANCE (NMR) SPECTRUM
Figure A-1. 1H and 13C NMR assignment of compounds 2a(B) and 3a(A) by Dr. Ghiviriga
82
Figure A-2. 1H NMR spectrum of 3-3a
Figure A-3. 1H NMR spectrum of 3-3a (expanded in aromatic region)
83
Figure A-4. 1H NMR spectrum of 3-3a ( expanded in aliphatic region)
Figure A-5. 19F NMR spectrum of 3-3a
84
Figure A-6. gHMQC spectrum of 3-3a
85
Figure A-7. gHMQC spectrum of 3-3a ( expanded in aromatic region)
Figure A-8. 1H NMR spectrum of 3-2a
86
Figure A-9. 1H NMR spectrum of 3-2a ( expanded in aromatic region)
Figure A-10. 1H NMR spectrum of 3-2a ( expanded in aliphatic region)
87
Figure A-11. 19F NMR spectrum of 3-2a
Figure A-12. gHMQC spectrum of 3-2a
88
zzy-H-70-H
6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5
Chemical Shift (ppm)
7.692.231.961.00
Figure A-13. 1H-NMR spectrum of M1
zzy-H-23-C
136 128 120 112 104 96 88 80 72 64 56 48 40 32 24
Chemical Shift (ppm)
Figure A-14. 13C-NMR spectrum of M1
89
zzy-H-23-F
85 80 75 70 65 60 55 50
Chemical Shift (ppm)
Figure A-15. 19F-NMR spectrum of M1
zzy-H-34-H
7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5
Chemical Shift (ppm)
6.152.151.961.00
90
Figure A-16. 1H-NMR spectrum of M2
zzy-H-34-C
168 160 152 144 136 128 120 112 104 96 88 80 72 64 56 48 40 32 24 16
Chemical Shift (ppm)
Figure A-17. 13C-NMR spectrum of M2
zzy-H-34-F
90 85 80 75 70 65 60 55 50
Chemical Shift (ppm)
91
Figure A-18. 19F-NMR spectrum of M2
zzy-H-63-or-28-H
6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5
Chemical Shift (ppm)
3.055.061.111.042.00
Figure A-19. 1H-NMR spectrum of P1
zzy-H-28-F
88 86 84 82 80 78 76 74 72 70 68 66 64 62 60 58 56 54
Chemical Shift (ppm)
92
Figure A-20. 19F-NMR spectrum of P1
zzy-H-67-H
6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0
Chemical Shift (ppm)
10.261.561.021.00
Figure A-21. 1H-NMR spectrum of P2
zzy-H-67-F
90 88 86 84 82 80 78 76 74 72 70 68 66 64 62 60 58 56 54
Chemical Shift (ppm)
Figure A-22. 19F-NMR spectrum of P2
93
zzy-H-65-H
6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0
Chemical Shift (ppm)
2.255.321.971.871.00
Figure A-23. 1H-NMR spectrum of P3
zzy-H-65-F
90 85 80 75 70 65 60 55 50
Chemical Shift (ppm)
Figure A-24. 19F-NMR spectrum of P3
94
zzy-H-70-H
6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5
Chemical Shift (ppm)
7.692.231.961.00
Figure A-25. 1H-NMR spectrum of P4
zzy-H-vinylSF5-Hydro-F
90 88 86 84 82 80 78 76 74 72 70 68 66 64 62 60 58 56
Chemical Shift (ppm)
Figure A-26. 19F-NMR spectrum of P4
95
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BIOGRAPHICAL SKETCH
Zhaoyun Zheng was brought up in Nanjing, People’s Republic of China. He
received his B.S. degree from Nanjing Normal University in 2003 and his M.S. degree
from Nankai University in 2006. After that he worked for a pharmaceutical company in
Tianjin as a synthetic research scientist. In July 2008, he came to University of Florida
and worked in the group of Dr. William R. Dolbier, Jr. as a research scholar. In spring
2010 he enrolled in the PhD program of the Department of Chemistry, University of
Florida, under Dr. Dolbier’s supervision. In the fall of 2012, he received his Ph.D. from
the University of Florida.
Zhaoyun and his wife, Lijuan Yue, have one lovely daughter, Fiona Haoting
Zheng.
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