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Synthetic Methodology Development toward Building Blocks Bearing Pentafluorosulfanyl (Sf5) Groups and Gem-Difluorocyclop...

Permanent Link: http://ufdc.ufl.edu/UFE0044932/00001

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Title: Synthetic Methodology Development toward Building Blocks Bearing Pentafluorosulfanyl (Sf5) Groups and Gem-Difluorocyclopropyl Moieties
Physical Description: 1 online resource (99 p.)
Language: english
Creator: Zheng, Zhaoyun
Publisher: University of Florida
Place of Publication: Gainesville, Fla.
Publication Date: 2012

Subjects

Subjects / Keywords: difluorocyclopropane -- heterolycles -- pentafluorosulfonyl
Chemistry -- Dissertations, Academic -- UF
Genre: Chemistry thesis, Ph.D.
bibliography   ( marcgt )
theses   ( marcgt )
government publication (state, provincial, terriorial, dependent)   ( marcgt )
born-digital   ( sobekcm )
Electronic Thesis or Dissertation

Notes

Abstract: 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 Bronsted acid catalyzed synthetic method for preparation of substituted gem-difluorocyclopropenyl ketones was designed based on the known tautomerization mechanism of ß-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 Bronsted acid under optimized conditions. 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.
General Note: In the series University of Florida Digital Collections.
General Note: Includes vita.
Bibliography: Includes bibliographical references.
Source of Description: Description based on online resource; title from PDF title page.
Source of Description: This bibliographic record is available under the Creative Commons CC0 public domain dedication. The University of Florida Libraries, as creator of this bibliographic record, has waived all rights to it worldwide under copyright law, including all related and neighboring rights, to the extent allowed by law.
Statement of Responsibility: by Zhaoyun Zheng.
Thesis: Thesis (Ph.D.)--University of Florida, 2012.
Local: Adviser: Dolbier, William R.

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Source Institution: UFRGP
Rights Management: Applicable rights reserved.
Classification: lcc - LD1780 2012
System ID: UFE0044932:00001

Permanent Link: http://ufdc.ufl.edu/UFE0044932/00001

Material Information

Title: Synthetic Methodology Development toward Building Blocks Bearing Pentafluorosulfanyl (Sf5) Groups and Gem-Difluorocyclopropyl Moieties
Physical Description: 1 online resource (99 p.)
Language: english
Creator: Zheng, Zhaoyun
Publisher: University of Florida
Place of Publication: Gainesville, Fla.
Publication Date: 2012

Subjects

Subjects / Keywords: difluorocyclopropane -- heterolycles -- pentafluorosulfonyl
Chemistry -- Dissertations, Academic -- UF
Genre: Chemistry thesis, Ph.D.
bibliography   ( marcgt )
theses   ( marcgt )
government publication (state, provincial, terriorial, dependent)   ( marcgt )
born-digital   ( sobekcm )
Electronic Thesis or Dissertation

Notes

Abstract: 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 Bronsted acid catalyzed synthetic method for preparation of substituted gem-difluorocyclopropenyl ketones was designed based on the known tautomerization mechanism of ß-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 Bronsted acid under optimized conditions. 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.
General Note: In the series University of Florida Digital Collections.
General Note: Includes vita.
Bibliography: Includes bibliographical references.
Source of Description: Description based on online resource; title from PDF title page.
Source of Description: This bibliographic record is available under the Creative Commons CC0 public domain dedication. The University of Florida Libraries, as creator of this bibliographic record, has waived all rights to it worldwide under copyright law, including all related and neighboring rights, to the extent allowed by law.
Statement of Responsibility: by Zhaoyun Zheng.
Thesis: Thesis (Ph.D.)--University of Florida, 2012.
Local: Adviser: Dolbier, William R.

Record Information

Source Institution: UFRGP
Rights Management: Applicable rights reserved.
Classification: lcc - LD1780 2012
System ID: UFE0044932:00001


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1 SYNTHETIC METHODOLOGY DEVELOPMENT TOWARD BUILDING BLOCKS BEARING PENTAFLUOROSULFANYL (SF 5 ) GROUP S AND gem DIFLUOROCYCLOPROP YL MOIET IES 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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2 20 12 Zhaoyun Zheng

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3 To my wife, Lijuan Yue, my daughter, Fiona Haoting Zheng, with love

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4 ACKNOWLEDGMENTS I would like to thank my supervisor, Dr. William R. Dolbier Jr., for his invaluable guidance, patience, and generous support th r ough 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. Ron ald K. Castellano Sukwon Hong, Brent S. Sumerlin, Benjamin W. Smith and Kenneth Sloan, for their help, suggestion s and support as well. Especially thanks Dr Castellano and Dr. Hong, who provided the best synthetic classes I have ever taken. I am gratefu l to Dr. Ion Ghiviriga for his help of NMR spectr um Many thanks to the former and current members in Dr. Dolbier group. In particular, I would li ke to thank Drs. Lianhao Zhang and Henry Martinez, Eric Cornett and Seth Thomoson, for their unselfish suppor t helpful discussion s and precious contributions to build such a wonderful research environment. I deeply appreciate to my parents for thei r unconditional support and encour a gement Finally, I am extremely grateful to my wife, Lijuan Yue, for everything s he has done for me and for our family.

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5 TABLE OF CONTENTS page ACKNOWLEDGMENTS ................................ ................................ ................................ .. 4 LIST OF TABLES ................................ ................................ ................................ ............ 7 LIST OF FIGURES ................................ ................................ ................................ .......... 8 LIST OF ABBREVIATIONS ................................ ................................ ........................... 12 ABSTRACT ................................ ................................ ................................ ................... 13 CHAPTE R 1 AN INTRODUCTION TO THE SYNTHESIS OF PENTAFLUOROSULFANYL(SF 5 ) CONTAINING AROMATIC COMPOUNDS ...... 15 1.1 Introduction ................................ ................................ ................................ ....... 15 1.2 Applications of Pentafluorosulfanyl Chemistry ................................ ................. 16 1.2.1 Applications of the SF 5 Group in Medicinal Chemistry ............................ 16 1.2.2 Applications of the SF 5 Group in Agrochemistry ................................ ...... 18 1.2.3 Applications of the SF 5 group in Functional Materials ............................. 19 1.3 Synthesis of Pentafluorosulfanyl Substituted Aromatic Rings ........................... 20 1.3.1 Synthesis of SF 5 Benzene ................................ ................................ ....... 20 1.3.2 The Synthesis of SF 5 Furan ................................ ................................ .... 23 1.3.3 Synthesis of SF 5 Naphthalene ................................ ................................ 24 1.3.4 Synthesis of SF 5 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 SF 5 bearing Heterocycles ... 26 2.2 Preparation of SF 5 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 SF 5 pyrrole ................................ ................................ ................ 36 2.3.1 Introduction ................................ ................................ .............................. 36 2.3.2 Results and Discussion ................................ ................................ ........... 37 2.4 Preparation of SF 5 Thiophene ................................ ................................ .......... 40 2.4.1 Results and Discussion ................................ ................................ ........... 40 2.4.2 Structure Characterization ................................ ................................ ....... 42 2.5 Conclusion ................................ ................................ ................................ ........ 44 2.6 Experimental Section ................................ ................................ ........................ 44

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6 3 DIASTEREOSELECTIVE REDUCTION OF gem D IFLUOROCYCLOPROPENE ................................ ................................ ...... 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 SF 5 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 synthesi s ................................ ................................ ................. 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 RESONANC E (NMR) SPECTRUM ................ 81 LIST OF REFERENCES ................................ ................................ ............................... 95 BIOGRAPHICAL SKETCH ................................ ................................ ............................ 99

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7 LIST OF TABLES Table page 2 1 Reaction of SF 5 alkyne with azomethine ylide ................................ .................... 3 1 2 2 Investigation of the reaction of SF 5 alkyne with 2 11 ................................ .......... 38 2 3 One pot preparation of SF 5 Pyrrole ................................ ................................ .... 39 2 4 The preparation of SF 5 thiophene ................................ ................................ ...... 41 3 1 Screening the conditions for the reduction of difluoroc yclopropenyl ketones ..... 60 3 2 ................................ ............... 62 4 1 Preparation and properties of SF 5 containing Po lymers ................................ ..... 75

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8 LIST OF FIGURES Figure page 1 1 SF 5 substituted analogs of fluoxetine, fenfluramine, and norfenfluramine .......... 16 1 2 SF 5 and CF 3 substituted analogs of mefloquine ................................ ................ 17 1 3 Trypanothione reductase inhibitors ................................ ................................ ..... 18 1 4 SF 5 substituted analogs of triflualin ................................ ................................ .... 18 1 5 The various applications of SF 5 groups in functional materials ........................... 19 1 6 Earl y preparation method for SF 5 benzene ................................ ........................ 20 1 7 First practical route to prepare SF 5 benzene ................................ ...................... 21 1 8 Preparation of SF 5 benzene from SF 5 Cl gas ................................ ...................... 21 1 9 Practical preparation of SF 5 benzene developed by Umemoto .......................... 22 1 10 Preparation of SF 5 furan through retro Diels Al der reaction ............................... 23 1 11 Preparation of SF 5 furan through Diels Alder and retro Diels Alder reaction .... 24 1 12 Preparation of SF 5 napht halene ................................ ................................ ......... 24 1 13 Preparation of SF 5 pyrazole and triazole by 1,3 dipolar cycloaddition .............. 25 2 1 The first attempt synthetic route for SF 5 pyrrole ................................ ................. 26 2 2 Second synthetic route to SF 5 Heterocycles catalyzed by palladium ................. 27 2 3 Proposed mechanism for the synthesis of SF 5 heterocycles .............................. 29 2 5 The preparation of SF 5 Heterocycles based on cycloaddition chemistry ............ 30 2 6 Preparation CF 3 pyrrole fro m azomethine ylide ................................ .................. 30 2 7 1,3 Dipolar cycloaddition approach to SF 5 heterocycles ................................ .... 32 2 8 Removal of t butyl group catalyzed by trif lic 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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9 2 12 Proton NMR of 2 10 ................................ ................................ ............................ 35 2 13 19 F NMR spe c trum 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 1 H NMR of 2 20d ................................ ................................ ................................ 42 2 20 1 H NMR of 2 21d ................................ ................................ ................................ 43 2 21 19 F 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 unsaturated ketones ................................ ................ 55 3 3 Friedel Crafts reaction of difluorocyclopropanecarbonyl chloride ....................... 56 3 4 Attempt to prepare substitu ted difluorocyclopropane ketones ............................ 57 3 5 Preparation of difluoro cyclopropenyl ketone and its properties .......................... 57 3 6 Reactivity difluoroc yclopro pyl ketone with HBr in Ionic Liqu id. ........................... 58 3 7 Proposed tautomerization mechanism for difluoro enols/enolates .................. 58 3 8 Synthetic approach to substituted difluorocyclopropyl ketones .......................... 59 3 9 Application of HEH as hydrid e donor ................................ ................................ .. 59 3 10 ......... 63 3 11 Proposed mechanism for the catalyti c reduction of difluorocyclopropenyl ketones ................................ ................................ ................................ ............... 64 3 12 Kinetic control reaction ................................ ................................ ....................... 65 4 1 Synthetic route toward SF 5 polymers ................................ ................................ 73 4 2 1 H NMR of M1 P1 and P2 ................................ ................................ .................. 74 4 3 1 H NMR of M2 P3 and P4 ................................ ................................ .................. 75 4 4 The 19 F NMR spectrum of monomers and polymers ................................ .......... 76

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10 4 5 T hermogravimetric Analysis for SF 5 polymers ................................ .................... 76 4 6 The Differential Scanning Calorim etry of SF 5 polymers ................................ ..... 77 A 1 1 H and 13 C NMR assignment of compounds 2a (B) and 3a (A) by Dr Ghiviriga ... 81 A 2 1 H NMR spectrum of 3 3a ................................ ................................ ................... 82 A 3 1 H NMR spectrum of 3 3a (expanded in aromatic region) ................................ .. 82 A 4 1 H NMR spectrum of 3 3a ( expanded in aliphatic region) ................................ .. 83 A 5 19 F NMR spectrum of 3 3a ................................ ................................ .................. 83 A 6 gHMQC spectrum of 3 3a ................................ ................................ ................... 84 A 7 gHMQ C spectrum of 3 3a ( expanded in aromatic region) ................................ 85 A 8 1 H NMR spectrum of 3 2a ................................ ................................ ................... 85 A 9 1 H NMR spectrum of 3 2a ( expanded in arom atic region) ................................ 86 A 10 1 H NMR spectrum of 3 2a ( expanded in aliphatic region) ................................ .. 86 A 11 19 F NMR spectrum of 3 2a ................................ ................................ .................. 87 A 12 gHMQC spectrum of 3 2a ................................ ................................ ................... 87 A 13 1 H NMR spectrum of M1 ................................ ................................ ..................... 88 A 14 13 C NMR spectrum o f M1 ................................ ................................ ................... 88 A 15 19 F NMR spectrum of M1 ................................ ................................ .................... 89 A 16 1 H NMR spectrum of M2 ................................ ................................ ..................... 90 A 17 13 C NMR spectrum of M2 ................................ ................................ ................... 90 A 18 19 F NMR spectrum of M2 ................................ ................................ .................... 91 A 19 1 H NMR spectrum of P1 ................................ ................................ ..................... 91 A 20 19 F NMR spectrum of P1 ................................ ................................ .................... 92 A 21 1 H NMR spectrum of P2 ................................ ................................ ..................... 92 A 22 19 F NMR spectrum of P2 ................................ ................................ .................... 92 A 23 1 H NMR spectrum of P3 ................................ ................................ ..................... 93

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11 A 24 19 F NMR spectrum of P3 ................................ ................................ .................... 93 A 25 1 H NMR spect rum of P4 ................................ ................................ ..................... 94 A 26 19 F NMR spectrum of P4 ................................ ................................ .................... 94

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12 LIST OF ABBREVIATION S BA 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 R in g opening metathesis polymerization TBAF Tetrabutylammonium Bromide TFDA T rimethylsilyl 2 (fluorosulfonyl) 2,2 difluoroacetate TGA Thermogravimetric Analysis THF Tetrahydrofuran TIPS T riisopropylsilyl TLC Thin layer chromatography TS Transition state

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13 Ab stract 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 PENTAFL UOROSULFANYL (SF 5 ) GROUPS AND gem DIFLUOROCYCLOPROPYL MOIETIES By Zhaoyun Zheng December 2012 Chair: William R. Dolbier Jr. Major: Chemistry Pyrrole and thiophene derivatives bearing a pentafluorosulfanyl (SF 5 ) group were unknown. Utilizing cycloadd ition reaction s of azomethine ylide with SF 5 alkyne s a series of SF 5 pyrrole carboxylic acid ester s were prepared in good yield. Further smooth process es of SF 5 alkyne s with N Benzyl N (methoxymethyl) N (trimethylsilylmethyl) amine initiated by triflic a cid demonstrated that 1 ,3 dipolar cycloaddition s are a general approach to construct heterocyclic compounds containing the SF 5 group. These reaction s were subsequently extended to prepare SF 5 thiophene derivatives. A novel acid catalyzed synthetic method for preparation of substituted gem difluo ro cyclopropen yl ketone s was designed based on the known tautomerization mechanism of difluoro enol s The reaction, using Hantzsch ester ( HEH ) as a hydride transfer reagent, proved to be a general route for preparation of substituted gem difluoro cycloprop yl ketone s in high yield. T he reaction unexpectedly proceeded to give largely cis product. Based up on the proposed mechanism, the diastereoselectivity could be improved by using a more bulky a cid u nder optimized conditions.

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14 A facile method was established for prepar ing polymers with SF 5 group directly attached to the backbone through ring opening metathesis polymerization (ROMP) of SF 5 substituted cyclooctene follow ed by hydrogenation. The microstr ucture of these novel polymers w ere well characterized by 1 H NMR, GPC and 19 F NMR. TGA and DSC experiments show ed that the unsaturated polymers and their hydrogenated derivatives have similar thermal profiles. W hile P3 and P4 have better thermal stabilitie s than P1 and P2 the latter pair exhibit higher glass transition temperatures.

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15 CHAPTER 1 AN INTRODUCTION TO T HE SYNTHESIS OF PENT AFLUOROSULFANYL(SF 5 ) CONTAINING AROMATIC COMPOUNDS 1.1 Introduction Because of its small size, high electronegativity and its ability to form hydrogen bond s the fluori ne atom can dramatically affect the chemical and physical properties of organic compounds. 1 For example: fluorinated macromolecules usually exhibit low surface energy, low dielectr ic constants and high chemical stability ; 2 fluorinated small bioactive molecules often display amazing ly enhanced biophysical activity by a combination of factors such as increasing metabolic stability and binding affinity, and altering lipophilicity and acidity. 3 Theref ore, fluorine c hemistry has found wide application s in the chemical world ranging from materials to medicine This importance has significantly accelerate d the synthetic methodology development toward s selective and efficient fluorinati o n of organic molecule s as well as development of fluor ine containing building blocks during the last century. E xtensive investigation has been appli ed toward the incorporation of a single fluorine atom in to organic molecule s 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 molecule s by incorporating various number s of fluorine atoms. 4 Among them, the trifluoromethyl (CF 3 ) 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 trifluo romethylation. 5 6 The pentafluorosulfanyl (SF 5 ) group, first introduced in to organic molecule s a half century ago, has been found to be an interesting substituent

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16 that mimic s the trifluoromethyl group with regard to electronic and steric fac tors. Hence, in recent years SF 5 chemistry has b ecome one of the fast growing fields in fluorine chemistry after a long period of hibernation. 1.2 Application s of Pentafluorosulfanyl Chemistry The pentafluorosulfanyl group has been regarded as an alternative to the trif luoromethyl group, with previous investigation s reveal ing that the SF 5 group has a much higher electronegativity than the CF 3 moiety (3.65 vs 3.36), and the steric demand of the SF 5 group approaches that of the t butyl group Examination of the stability of the SF 5 group to hydrolysis demonstrated that the SF 5 group has higher hydrolysis stability than the CF 3 substituent. All these differences indicate that substitution of the SF 5 group for CF 3 m ay have profound effect on bioactiv ity 7 1.2.1 Application s of the SF 5 G roup in Medicinal Chemistry Figure 1 1. SF 5 substituted analogs of fluoxetine, fenfluramine, and norfenfluramine The c linical agent s fluoxetine ( 1 1 ), fenfluramine ( 1 2 a ) 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 bioactiv ity and to test the influence of the SF 5 group on bio active molecules, Welch and coworkers prep ared SF 5 substituted analogs for 5 HT inhibitors ( Figure 1 1 ) and evaluated their bioactivity. 8 The examination showed that the SF 5 substituent could

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17 improve the se hydroxytryptamine receptor s Among them, compound 1 4b coul d lead to dramatically increased potency against 5 HT 2b 5 HT 2c and 5 HT 6 receptors. Figure 1 2. SF 5 and CF 3 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 effect s such as anxiety, depression, seizure, and the emergence of drug resistance led scientists to look for a better candidate. The Wipf group syn thesized two sets of mefloquine analogs with SF 5 or CF 3 substituted at the 6 or 7 position (Figure 1 2), and they evaluated their bioactivities against parasites and toxicities against mammalian cell s 9 The results revealed the SF 5 substituted compound 1 6b to have better bioactivity and selectivity than the CF 3 substituted substance 1 6a or mefloquine, while compound 1 7b was almost equivalent to CF 3 analog 1 7a and mefloquine.

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18 Figure 1 3 T rypanothione reductase inhib itors Although numerous SF 5 containing analogs of bioactive molecule s ha ve been synthesized, the Diederich group was the first to study the structure activity relationship on the target level for SF 5 bearing derivatives. 10 They chose flavoenzyme trypanothione reductase, which is found in parasite s as a target for the design of SF 5 contai ni ng in hibitors. Based on the diphenyl amine core structure, they synthesized three sets of analogs bearing the SF 5 moiety (Figure 1 3). Interestingly, bioactivit y test s showed that all the compounds ( 1 8b 9b 10b ) with a SF 5 substituent exhibited the low cytotoxicity as well as good membrane permeability. 1.2.2 Application s of the SF 5 G roup in Agrochemistry Figure 1 4 SF 5 S ubst ituted 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 SF 5 group, they obtained an amazing re sult from the herbicidal activity evaluation. 11 In a post emergence test, 1 11b exhibited almost twice the potency

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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. T herefore, 1 11b is a very promising candidate for further exploration. 1.2.3 Application s of the SF 5 group in Functional Materials Liquid crystals (LC) as display materials have been extensively used in common electronic devices such as PC s notebook s, and cell phone s Due to its high polarity and lipophilicity, the SF 5 group was found to significantly improve the properties of LC materials. When scientists from the Mer c k corporation prepared various SF 5 substituted LC materials based on the structure of widely used fluorinated LC molecule s ( 1 12 ) they discovered that all th ese materials ha d considerably enhanced dielectric anisotropy and lower birefringence, which are two of the most important parameter s for the design of LC materials. 12 Figure 1 5 The various applications of SF 5 groups in functional materials Due to the multiple unique properties of the SF 5 group, the Shreeve group found it to be an excellent motif for the design of energetic materials ( 1 13 ) Generally the SF 5 incorporated compound had high density, good thermal stability and enhanced detonation performance. 13

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20 Taking advantage of its high lipophilicity, Gard and researchers from 3M prepared various SF 5 containing surfactants. 14 These materials normally exhibite d low er surface tension and better performance than their CF 3 analogs ( 1 14 ) 1.3 Synthesis of Pentafluorosulfanyl Substituted Aromatic Ring s Fluorinated aromatic compounds are widely used in chemi cal, pharmaceutical and agrochemical industr ies T hus there are good reason s to establish practical synthetic methods to construct SF 5 substituted aromatic compounds, which m ay ha ve great potential for application s such as those mentioned above. Although the first preparation of SF 5 benzene originated in the 1960s, only in the last decade have several breakthroughs occurred. In the following sections, a concise introduction of the synthesi s of aromatic rings with an SF 5 group directly attached is presented 1.3.1 Synthesis of SF 5 Benzene Figure 1 6 E arly preparation method for SF 5 benzene Because of its significant potential importance, SF 5 benzene building blocks attracted much attention from fluorine chemist s working in the field of SF 5 chemistry. ing work on the preparation of SF 5 benzene was reported almost a half century ago, this molecule remained a challenge to fluorine scientist s for decades because all of the synthetic procedure s de veloped during this

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21 period required either harsh reaction conditions or expensive reagents while giving poor yields (Figure 1 6) 15 16 17 18 Figure 1 7 F irst practical route to prepare SF 5 benzene The first practical and sc alable synthetic method was reported by Bowen and Phil i p (Figure 1 7) 19 Inspired by the previous work, they still used nitro substituted aryl disulfide s as starting materials ( 1 16a, b ) D iluted F 2 gas was creatively employed as a fluorinating reagent, and the desired product was obtained in reasonable yield at low temperature. T hough the F 2 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 mention ing that in this article, they investigated the properties of the S F 5 group as well The investigation revealed that generally the SF 5 group could survive in various reaction conditi ons such as hydrogenation s coupling reaction s acid base reaction s and it also exhibited higher stability than CF 3 analog s in a hydroly sis test. Figure 1 8. P reparation of SF 5 benzene from SF 5 Cl gas Pentafluorosulfanyl chloride (SF 5 Cl) gas, one of the few commercial ly available SF 5 reagents, was used for several decades for construct ion of SF 5 contain in g building

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22 blocks. However, due to its low boiling point ( 21 o C), normally the reaction required the use of autoclave a nd high temperature. In 2002, the Dolbier group discovered that Et 3 B was an excellent radical initiator for addition reactions of SF 5 Cl 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 SF 5 benzene. 20 Start ing from easily available reagent 1,4 cyclohexadiene, the dichloride substitute intermediate 1 18 was obtain ed in quantitative yield th r ough a classic al radical process When this product w as submitted to standard SF 5 Cl addition condition s initiated by Et 3 B, follow ed by simple elimination, the target molecule was attaine d with >70% yield over the three steps. Al though this method was quite straight forward, the relatively high price of SF 5 Cl gas has limited its use Figure 1 9. P ractical preparation of SF 5 benzene developed by Umemoto A major milestone for preparation of SF 5 ar omatics was established by Umemoto and his coworkers (Figure 1 9) In 2012, they reported an innovative construction of the SF 5 group through a novel intermediate bearing the SF 4 Cl group. 21 Starting from commercially available phenyl disulfide or thiol, the SF 4 Cl 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 simpl e filtration and evaporat ion of the solvent, it was further treated wit h SbF 3 /SbCl 5 in CH 2 Cl 2 and the desired product 1 20 was obtained via a clean transformation. This procedure, which has been scaled up by the exhibited great substrate scope for

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23 preparing SF 5 benzene and its derivatives. Since all of the reagents are relatively cheap and commercially available and the procedure is readily scale d up this invention should significantly benefit the whole chemical community 1.3.2 The Synthesis of SF 5 Furan Figure 1 10. P re paration of SF 5 furan through retro D iels A lder reaction With the success ful preparation of SF 5 benzene from SF 5 Cl and their continuing interest in SF 5 substituted heterocycl ic compound s the Dolbier group designed a new route to synthes ize SF 5 furan based on the process of the retro Diels Alder reaction (Figure 1 10) 22 Utilizing the previous Et 3 B initiated condition s SF 5 Cl was smoothly introduced to the easily prepared starting material 1 21 which is the Diels Alder adduct of furan and acrylonitrile. Th e mixture of two regioisomers 1 22a and 1 22b was treated with strong base LiOH in DMSO to provide the clean elimination product s 1 23a and 1 23b At high temperature, they under went retro Diels Alder reaction to give the target molecule 1 24 with decent y ield. Currently, t his is the first and only reported preparation method to construct SF 5 furan However, the utilization of the expensive SF 5 Cl gas and the narrow substrate scope limited its wide application.

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24 Figure 1 11 P reparation of SF 5 furan through Diels A lder and retro D iels A lder reaction In the same article, they reported an alternative method to prepare SF 5 furan in one pot based on a cascade mechanism (Figure 1 11) Starting material 4 p henyloxazole is an eas ily prepared building block for facile construction of furan and its derivatives. Therefore, they treated SF 5 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 t o proceed t hrough 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 SF 5 substituted alkyne s can be prepared from termina l alkynes through addition elimination steps. 1.3.3 Synthesis of SF 5 Naphthalene Figure 1 12. P reparation of SF 5 naphthalene

PAGE 25

25 With the achievement of SF 5 furan throug h D iels A lder reactions, t he Dolbier group continued to build SF 5 naphthalene by such methodology (Figure 1 12) 23 Initial addition of SF 5 Cl to benzobarralene and subsequent base catalyzed elimination of HCl led to the key intermediate 1 2 9 in high yield. T he ethylene bridge of 1 29 was smoothly eliminated by heating with the commercial ly available reagent 3,6 bis (2 pyridyl) 1,2,3,4 tetrazine ( 1 30 ) and the target molecule was obtained i n high yield through this sequence of reactions. 1.3.4 Synthesis of S F 5 Pyrazole and Triazole Figure 1 13. P reparation of SF 5 pyrazole and triazole by 1,3 dipolar cycloaddition In 1964, researchers from Dupont reported the first example of construction of SF 5 bearing heterocycles based o n 1,3 dipolar cycloaddition (Figure 1 13) 17 Simply adding SF 5 acetylene to diazomethane at 0 o C, a mixture of regioisomers ( 1 32a, 1 32b ) with a ratio of 60:40 was readily obtained. In 2007, Shreeve and her coworke rs utilized the same method to prepare SF 5 containing energetic materials. 13 Starting from bulky T IPS substituted SF 5 acetylene, only one regioi s omer ( 1 33 ) as product was obtained in quantitative yield. They also extended this reaction to prepare various SF 5 triazole s ( 1 34 )

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26 CHAPTER 2 THE PREPARATION OF P ENTAFLUOROSULFANYL P YRROLE AND THIOPHENE THROUGH 1,3 DIPOLAR CYCLOADDITIO N 2.1 Initial Investigation s of S ynthetic Method s toward SF 5 bearing Heterocycles Investigations of penta fluoro sulfanyl (SF 5 ) chemistry in Dr. Dolbier lab w ere initiated by Dr. S a mia Ait Mohand in 2002 7 Her great invention provided a practical method to add SF 5 Cl to alkene and alkyne substates without utilizing an autoclave reactor and high temperature. The reactions were usually carried out at low temperature ( 30 o C) in ordinary glassware initiated by catalytic amount of Et 3 B (0.1eq.), and ge nerat ed the desired products in high yield in a short time (2 hours). Based on this significant disco very, in subsequent research, Dr. Sergeeva established the earlier mentioned approach to SF 5 benzene, 20 and Dr. M itani prepared the first furan s bearing an SF 5 group through retro Diels Alder chemistry 22 With the considerable continued interest in SF 5 containing heterocyclic compounds because of their great potential for app lication and commercial value, my challenge was to investigate the preparation methods for pyrrole s and thiophene s bearing an SF 5 group which ha d never been made before Figure 2 1. The first attempt ed synthetic route to SF 5 pyrrole With the commercial ly available SF 5 Cl gas in hand and inspired by the previous methods, we designed a short synthetic route for SF 5 pyrrole (Figure 2 1) Starting from the purchased 2,5 dihydropyrrole ( 2 1a ) SF 5 Cl wo u ld be first in corporated in to the five

PAGE 27

27 membered ring using the standard Et 3 B method follow ed 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 expect ed In the beginning we thought it might be due to the presence of a proton on the dihydropyrrole nitrogen b ut 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 SF 5 Cl addition in to internal alkene s compared to reported addition to terminal alkene s, we realized that s teric hindrance could play a key role in this situation as SF 5 group is as bulky as a t butyl group. Figure 2 2. S econd synthet ic route to SF 5 h eterocycles catalyzed by palladium

PAGE 28

28 After the failure of the first attempt we considered that SF 5 Cl might not be a good starting material for direct construct ion of heterocycles due to the narrow substrate scope of its addition reaction s. Compared to SF 5 Cl gas, SF 5 substituted alkyne s should be better building block s for several reasons. First, numerous chemical transformations based on alkyne s have been established; s econdly, the one step construction of heterocycles from alkyne s cataly zed by transition metals have been well explored in recent decades; t hirdly, many successful synthetic precedents for preparation of CF 3 heterocycles from CF 3 substituted alkyne s ha ve been reported probably correlat ing with SF 5 chemistry ; l astly, SF 5 alky ne s w ere readily prepared from SF 5 Cl based on the previous ly developed method. Therefore we designed a second route toward s various SF 5 containing heterocyclic compounds based on SF 5 alkyne building block s Konno and his coworkers had demonstrated a gener al method to prepare CF 3 containing benzoheterocycles catalyzed by palladium (Figure 2 2) 24 25 and we expect ed to obtain at least one of the desired compound s from those diverse transformations. However we did no t achieve any positive result s except recycli ng the starting materials when SF 5 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 in t o the alkyne substrate (Figure 2 3)

PAGE 29

29 Figure 2 3. Proposed mechanism for the synthesis of SF 5 h eterocycles It is worth mentioning that years ago a former postdoc Ping He in Dr. Dolbier group had attempted to utilize a van L eusen approach to prepare SF 5 pyrroles 26 T he reaction of TosMIC with SF 5 substituted unsaturated ester ( 2 4 ) led only to a fluorine free product, presumably pyrrole 2 6 formed by preferential elimination of SF 5 rather than loss of Tos which is the usual final, pyrrole forming step of a van L eusen synt hesis. Figure 2 4. Attempt to prepare SF 5 h eterocycles using a van L eusen approach

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30 2.2 Preparation of SF 5 pyrrole Carboxylic Acid Esters 2.2.1 Introduction Figure 2 5. The preparation of SF 5 h eterocycles based on cycloaddition chemistry After all attempts mentioned above to generate the desired SF 5 heterocyclic compounds failed, we carefully examine the possible reasons via a literature review When carefully analyzing the previous case s for preparing SF 5 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 SF 5 alkyne s (Figure 2 5) 22 13 Figure 2 6. P reparation CF 3 p yrrole from azomethine ylide The 1,3 dipolar cycloaddition of azomethine ylide, generated from thermal opening of 2 7 to alkyne s or alkene s has been demonstrated to be a general approach to construct pyrroline s or pyrrolidine s respectively. La Porta and co workers successfully implemented this method to prepare trifluoromethyl pyrroles starting from cycloadditio n

PAGE 31

31 of CF 3 alkyne with azomet h ine ylide and following with DDQ oxidation. 27 Therefore, we expect ed this to be a feasible way to our desired product. 2.2.2 Result and Discussion Table 2 1. Reaction of SF 5 alkyne with azomethine ylide --When the readily prepared aziridine 2 7 was heated with equimolar amount of SF 5 alkyne 2 2b in xylene, to our delight, a clea n chemical transformation occurred as shown by 19 F NMR even though in 20h it only gave moderate conversion and prolong ing o f the reaction time did not help. By increasing the amount of 2 2 b to 3 equiv, the reaction rate was dramatically accelerated and full conversion could be achieved overnight (Table 2 1) The isolate d yield of 2 8 b was 60% and its structure was fully characterized. S mooth DDQ (2equiv) oxidation provided the target molecule 2 9b in quantitative yield.

PAGE 32

32 Figure 2 7. 1,3 D ipolar cycloaddition approach to SF 5 h eterocycle s To explore the reaction limitation s 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 R emoval of t butyl group catalyzed by triflic acid To demonstrate the full scope of this method, the removal of t b utyl group was accomplished by utilizing the reported method. While heating 2 9 b in CH 2 Cl 2 with a catalytic amount triflic acid for 2h, the unprotected pyrrole 2 10 was obtained in a n un optimized yield of 72% (Figure 2 8)

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33 Figure 2 9 Mechanism for the regioselective cycloaddition chemistry Notably, the present procedure gave exclusively one regioisomer based on SF 5 alkyne compared to the regioisomer ic mixture (~75:25) obtained from CF 3 alkyne. 27 The mechanis tic analysis clearly explained the regioselective chemistry (Figure 2 9) As for the CF 3 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 CF 3 part. When it came to the SF 5 substrate, the electronic and steric effects both preferred the same regioselectivity. This result als o agreed well with the structural properties of CF 3 and SF 5 groups as both are strong e lectron withdrawing group s but have considerabl y differen t size.

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34 2.2.3 Structure Characterization Figure 2 10. Proton NMR of 2 8b Figure 2 11 Proton NMR of 2 9b

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35 Figure 2 12 Proton NMR of 2 10 Figure 2 13 19 F NMR spectrum of compounds 2 10 and 2 9b In Figure 2 10, the appearance of the aromatic proton signal s ( 7.23, 7.34 ppm), the sharp t butyl (0.98 ppm) and met hyl peak (3.72 ppm) clearly indicate the formation of a dihydropyrrole ring by the cycloaddition reaction. After oxidation with DDQ, the signal of CH 2 (3.92, 4.10 ppm) and CH (4.49 ppm) groups in compound 2 8b disappeared, and a new peak in the aromatic re gion emerged by integration, which proved the success of aromatization. In Figure 2 12, the characteristic t butyl signal

PAGE 36

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 cataly tic triflic acid, which confi rmed the removal of the protecting group. 19 F NMR is also a powerful tool to monitor the reaction with the advantage of little interference from solvents and other substrates whe n compared to proton NMR. The SF 5 group gives 19 F NMR signa ls with the characteristic AB 4 system. Therefore, the double t peak s around 74.30 ppm in 2 9b that moved to 73.56 ppm in 2 10 clearly demonstrat e the cleavage of the N C bond (Figure 2 13). 2.3 Preparation of SF 5 pyrrole 2.3.1 Introduction Base d on the above successful preparation of SF 5 p yrrole carboxylic acid ester where SF 5 alkyne s acted as dipolar o philes, we wonder ed if the cycloaddition reaction could be a good general approach to SF 5 pyrrole. If so, a wide variety of SF 5 pyrrole structures could be built for potential medicinal application s Therefore, another azomethine ylide building block 2 11 was selected to examine this hypothesis Figure 2 1 4 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 w ere fully investigated by Padwa etc. 29 All studies demo nstrate d that this compound had unique advantages over others: First, 2 11 is

PAGE 37

37 readily prepared and i s already commercial ly available; s econdly, t he reaction condition is adjustable as it could be initiated by either catalytic amount of H + or a n F source; and thi rdly, i t has been widely used to build bioactive molecules or natural products because of its extensive substrate scope; 30 31 l ast but not the least, it has excellent reactivity as even under mild condition the dearomization occurred when it interacted with di nitrobenzene (Figure 2 1 4 ) 32 Hence, there are good reason s to believe that 2 11 could also react with SF 5 alkyne s 2.3.2 Results and Discussion The initial investigation follow ed the reported condition s of using an equal amount of cesium fluoride and 2 11 with acetonitrile as solvent at RT h owever no desired product was detected by 19 F 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 recoverin g SF 5 alkyne, all of the substrate decomposed for unknown reason s Gratefully after switching to an acid catalyzed system, 65% conversion was obtained with 0.2 eq trifluoroacetic acid applied in CH 2 Cl 2 at RT. As shown in Table 2 2 full conversion was re adily 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 SF 5 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 excel lent yields with wide substrate scope

PAGE 38

38 (Table 2 3). Even for the considerably bulky TIPS substituted SF 5 alkyne, it still gave 78% yield. Table 2 2. Investigation of the reaction of SF 5 alkyne with 2 11 entry 2 11 (eq) C atal yst S olvent T( C) C onversion(%) 1 2 CsF CH 3 CN rt NR 2 2 CsF CH 3 CN reflux NR 3 2 LiF CH 3 CN rt NR 4 2 LiF CH 3 CN reflux NR 5 2 TBAF THF rt -a 6 2 TFA CH 2 Cl 2 rt 65 7 4 TFA CH 2 Cl 2 rt 100 8 2.5 TFA CH 2 Cl 2 reflux 100 b 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 19 F NMR, and 95% yield was obtained for th e isolated desilylated product.

PAGE 39

39 Table 2 3. One pot preparation of SF 5 Pyrrole entry substrate Y ield(%) 1 96 2 79 3 80 4 88 5 78 Figure 2 1 5 R emoval of T IPS 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 catalys t proved unsuccessful. Instead it was found to be necessary to carry out the debenzylation at t he dihydropyrrole stage by a method developed by Olofson and Senet to dealkylate tertiary amines using the reagent chloroethyl chloroformate (Figure 2 1 6 ) 33 Debenzylated dihydropyrrole could then be aromatized in the usual manner by treatment with DDQ to form pyrrole 2 17

PAGE 40

40 Figure 2 1 6 R emoval of the benzyl group from dihydropyrrol e 2.4 Preparation of SF 5 Thiophene 2.4.1 Results and Discussion With the succe ssful preparation of SF 5 pyrrole derivatives and demonstrating that cycloaddition s are a good general approach to prepare SF 5 heterocycles we want ed to extend this method to synt hesi ze SF 5 thiophene, which might also have great potential for application since thiophene and its analog s have been extensively used in materials science. Figure 2 1 7 C onstruction of thiophene from thi a zole building bl ock Inspired by the previous example of preparing SF 5 furan from oxazole building blocks, we tried to apply the same strategy to prepare SF 5 thiophene since it only require s one step to achieve the target molecule compared to a possible 1,3 dipolar cycloa ddition approach. Therefore we prepared compound 2 18 which was first found by Ye and his coworkers 34 to undergo Diels Alder reaction to build thiophene structure s (Figure 2 1 7 ) However when the SF 5 alkyne was mixed with thia zole, no desired product was found and all the starting materials decomposed mainly due t o the

PAGE 41

41 required extremely high reaction temperature. The attempt to lower the temperature did not provide any positive result s Figure 2 1 8 C onstruction of thio phene 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 c ompound 2 19 first invented by Sakurai, 35 was an excellent ylide precursor (Figure 2 1 8 ) with g enerally w ide substrate scope and mild reaction condition s 36 Table 2 4. The preparation of SF 5 thiophene When mix ing the readily prepared 2 19 with SF 5 alkyne and initiating with cesium fluoride in acetonitrile at RT, to our delight the reaction proceeded smoothly to give moderate c onversion. After optimiz ing the condition s we found TBAF/THF was a better activat ing system. However the next oxidation step proved to be considerably

PAGE 42

42 challeng ing Various oxidants were screened for the reaction such as DDQ, CuBr 2 NBS, etc., and finally SO 2 Cl 2 was found effective for the oxidizing the aromatic substituted substrate s while aliphatic substrates still remained a challenge. Nonetheless, many aromatic substituted SF 5 alkyne s could proceed in this pathway and thus provided the desired product with good yields over two steps. 2.4.2 Structure Characterization Figure 2 1 9 1 H NMR of 2 20d

PAGE 43

43 Figure 2 20 1 H NMR of 2 21d Figure 2 21 19 F NMR of 2 20d and 2 21d

PAGE 44

44 In Figure 2 19, the appearance of characteristic peaks for the p to l uene group (2.33ppm for CH 3 and 7.04, 7.15ppm for the AB system) and two sets of CH 2 signals (3.97, 4.30ppm) unambiguously conf i rm ed the ring formation. Interestingly, one of the CH 2 group s gave a si n glet peak, while the other was a triplet with a coupling constant of 4.6Hz, which might be attributed to coupling with the SF 5 group. In Figure 2 20 t he disappearance of the signal for the two CH 2 groups accomp an ied by the appearance of two new peaks in the aromatic region proved the achievement of oxidation by SO 2 Cl 2 The 19 F NMR spectrum was also use d to characterize the product. The SF 5 group of compound 2 20d gives the doublet peak at 66.8ppm with a coupling constant 149 Hz. 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 (SF 5 ) group were previously unknown. Utilizing the cycloaddition react ion of azomethine ylide s with SF 5 alkyne s a series of SF 5 pyrrole carboxylic acid ester s were prepared in good yield. Further the smooth reaction of SF 5 alkyne with N b enzyl N (methoxymethyl) N (trimethylsilylmethyl)amine initiated by triflic acid demonst rated that 1,3 dipolar cycloaddition s are a good general approach to construct heterocyclic compounds containing the SF 5 group. This chemistry was successfully extended to prepare SF 5 thiophene derivatives. 2. 6 Experimental Section All reagents and solve nts were purchased from commercial sources and used without further purification unless otherwise specified. Thin layer chromatography (TLC)

PAGE 45

45 was performed on SiO 2 60 F254 aluminum plates with visualization by UV light or staining. Flash column chromatograp hy was performed using Purasil SiO 2 mesh from Whatman. Melting points were uncorrected. 1 H, 19 F and 13 C NMR were recorded in CDCl 3 at 300 MHz, 282MHz and 75MHz respectively ESI TOF and DART TOF MS spe ctr um were recorded on an Agilent 6210 TOF spectrometer. CI MS spe c tr um were recorded on a Thermo Trace GC DSQ (single quadrupole) spectrometer. Elemental analyses were performed on a Carlo Erba 1106 instrument. SF 5 Cl gas was obtained from Airproduct s Compound 2 7 2 19 was prepared according to t he reported method. 27 36 Typical synthetic procedure for 2 2 : Into a round bottom flask equipped with a dry ice reflux condenser were adde d at 40 0 C, 20 m L of anhydrous hexane, alkyne (3 4 mmol) and SF 5 Cl (1.2 equiv). The solution was stirred at this temperature for 10min, and then Et 3 B (0.1 equiv., 1 M in hexane) was added slowly using a syringe. The solution was stirred for 1 h at 30 0 C, and then warmed to RT The mixture was hydrolyzed with aqueous NaHCO 3 and the organic phase was dried with MgSO 4 T he 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 MgSO 4 finally purified by column. 2 2b : ( 43% ) 1 H NMR(CDCl 3 ), 2.55 2.62 (m, 2H), 2.85 2.90 (t, J =10 Hz, 2H), 7.18 7.33 (m, 5H); 13 128.81, 139.20; 19 F (p, J = 158 Hz, 1F), 82.60 (d, J = 160 Hz, 4F).

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46 2 2 d : (45%). 1 H NMR(CDCl 3 ), 2.40 (s, 3H), 7.20 7.22 (d, J = 7.8 Hz, 2H), 7.44 7.47 (d, J = 7.8 Hz, 2H); 13 C 19 F (p, J = 162 Hz 1F), 88.05 (d, J = 177 Hz, 4F). 2 2e : (60%) 1 H NMR(CDCl 3 ), 7.18 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); 13 C NMR, 126.7, 129.8 (m), 134.0 (m) 19 F NMR 83.6 (m, 4F), 76.9 (m, 1F). Typical synthetic proc edure for 4a d A mixture of 2 7 (2.05 mmol, 3 eq), 2 2 (0.68 mmol, 1 eq) and 2.5 m L xylene was heated at about 135 o C for 24 h (monitor by 19 F NMR), when the reaction was over, purified 2 8 directly by flash column to re move the solvent and excess 2 7 Then 5 m L CCl 4 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 108 110 0 C 1 H NMR(CDCl 3 (s, 3H), 7.18 7.31 (m, 6H); 13 C (m), 122.70 (m), 126.93 (m), 127.39, 127.44, 130.12, 134.27, 135.20 (m), 163.93; 19 F (p, J = 153Hz, 1H), 75.40 (d, J = 153 Hz, 4H). HRMS, calcd.for C 16 H 18 F 5 NO 2 S, 383.0978; found, 383.0973. 2 9b : mp 115 117 0 C 1 HNMR(CDCl 3 (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); 13 C NMR, 59.97, 121.38 (m), 123.06 (m), 126.15, 127.10 (m), 128.51,

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47 128.61, 134.96 (m), 142.24, 163.59; 19 F (p, J = 150 Hz, 1H), 74.30 (d, J = 150Hz, 4 F ). HRMS, calcd.for C 18 H 22 F 5 NO 2 S, 411.1291; found, 411.1277. 2 9c : mp 41 44 0 C 1 H NMR(CDCl 3 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); 13 C NMR, (m), 122.67 (m), 128.12 (m), 134.86 (m), 163.70; 19 F (p, J = 155 Hz, 1H), 74.25 (d, J = 155 Hz, 4 F ). HRMS, calcd.for C 14 H 22 F 5 NO 2 S, 363.1291; found, 363.1316. 2 9d : mp 114 116 0 C 1 H NMR(CDCl 3 (s, 3H), 7.12 (s, 4H), 7.33 (s, 1H); 13 C ( m), 122.72 (m), 126.76 (m), 128.15, 129.95, 131.11, 135.29 (m), 136.99,164.08; 19 F (p, J = 152 Hz, 1H), 75.44 (d, J = 152 Hz, 4H). HRMS, calcd.for C 17 H 20 F 5 NO 2 S, 397.1135; found, 397.1120. Two drops of CF 3 SO 3 H was added to a flask equipped with 80 mg 2 9b and 2m L 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 165 167 0 C 1 HNMR(CDCl 3 ), 2.84 (dd, J = 8.1 & 4.2 H z, 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); 13 C (m), 122.02 (m), 126.19, 128.00 (m), 128.58, 128.61, 138.50 (m), 142.07, 161.26; 19 F (p, J = 148 Hz, 1 F ), 73.56 (d, J = 148 Hz, 4 F ). HRMS, calcd.for C 14 H 14 F 5 NO 2 S, 355.0665; found, 355.0648.

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48 G eneral procedure for preparation of pyrroles 4a f. Trifluoroacetic acid solution (0.9 m L 0.2 equiv, 1 M in CH 2 Cl 2 ) was slowly added to a mixt ure 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 m L CH 2 Cl 2 A fter addition, the reaction mixture was refluxed for 24 h, then cooled with an ice water bath. DDQ (4.7 mmol, 1.1 eq uiv) was carefully added to the light yellow solution. The mixture was stirred for another 2 h, the dark red mixture was diluted with 10 m L CH 2 Cl 2 and poured into saturated NaHCO 3 solution(20 m L ) The organic phase was separate d the solvent was evaporated T he 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 t o pyrrole 2 14e 2 13 : 1 H NMR(CDCl 3 ), 3.79 (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); 13 C NMR, 60.1, 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) 19 F NMR 83.9 (p, J = 164 Hz, 1F), 66.4(d, J = 166 Hz, 4F). 2 14a :(80%) 1 H NMR(CDCl 3 ), 5.05 (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); 13 C NMR, 54.3, 120.3, 121.8, 122.9, 127.3, 127.8, 127.9, 128 .7, 129.3, 130.1, 134.9, 135.9 19 F NMR 88.6 (p, J = 169 Hz, 1F), 76.2 (d, J = 163 Hz, 4F). HRMS:calcd for C 17 H 14 F 5 NS 359.0767; found, 359.0786.

PAGE 49

49 Anal. C alcd for C 17 H 14 F 5 NS : C, 56.82; H, 3.93; N, 3.90. Found: C, 56.47; H, 3.82; N, 4.01. 2 14b :(79%) 1 H N MR(CDCl 3 ), 2.93 (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); 13 C NMR, 28.6, 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 19 F NMR 89.6 (p, J = 164 Hz, 1F), 74.6(d, J = 161Hz, 4F). HRMS:calcd for C 17 H 18 F 5 NS 387.1080; found, 388.1153(M+H). Anal. C alcd for C 17 H 18 F 5 NS : C, 58.90; H, 4.68; N, 3.62. Found: C, 58.74; H, 4.29; N, 3.78. 2 14d : (88%) 1 H NMR(CD Cl 3 ), 2.43 (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); 13 C NMR, 21.4, 54.2, 120.1, 121.6, 122.8, 127.8, 128.6, 129.2, 129.9, 131.9, 135.9, 136.9 19 F NMR 88.6 (p, J = 160Hz, 1F), 76. 1 (d, J = 150 Hz, 4F). HRMS:calcd for C 1 8 H 1 6 F 5 NS 373.0923; found, 373.0921. Anal. C alcd for C 1 8 H 1 6 F 5 NS : C, 57.90; H, 4.32; N, 3.75. Found: C, 57.65; H, 4.35; N, 3.80. 2 14e : (96%) mp 69 71 o C. 1 H NMR(CDCl 3 ), 5.00 (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); 13 C NMR, 54.3, 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 19 F NMR 88.4 (p, J = 168 Hz, 1F), 75.7 (d, J = 163 Hz, 4F). HRMS:calcd for C 15 H 12 F 5 NS 2 365.0331; found, 365.0319. Anal. C alcd for C 15 H 12 F 5 NS 2 : C, 49.31; H, 3.31; N, 3.76. Found: C, 49.58; H, 3.25; N, 3.76. 2 14f : (78%) mp 37 39 o C. 1 H NMR(CDCl 3 ), 1.07 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); 13 C NMR, 12.6, 19.3, 53.8, 110.9 (m), 123.6 (m), 127.2, 128.4, 129.2, 129.4,

PAGE 50

50 136.5, 142.5 (m) 19 F NMR 89.4 (p, J = 164 Hz, 1F), 72.6 (d, J = 156 Hz, 4F). HRMS:calcd for C 20 H 30 F 5 NS Si, 439.1788; found, 440.1859(M+ H ) Anal. C alcd for C 20 H 30 F 5 NS Si: 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 m L, 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 m L ), extracted with CH 2 Cl 2 (5m L x 3), the solvent was removed and the residue was submitted to column. 0.12 g product was obta ined as colorless oil. (95%) 1 HNMR(CDCl 3 ), 5.04 (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); 13 C NMR, 54.2, 107.3 (m), 120.1 (m), 120.4, 127.6, 128.6, 129.2, 136.2 19 F NMR 87.6 (p, J = 162 Hz, 1F), 70. 8 (d, J = 163 Hz, 4F). HRMS:calcd for C 11 H 10 F 5 NS 283.0454; found, 283.0458. Anal. C alcd for C 11 H 10 F 5 NS : 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 dihydr o pyrrole( 2 16 ): 1 C hloroethyl 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 m L CH 2 Cl 2 at 0 C with stirring

PAGE 51

51 T the mixture was concentrated after 30 min, and dissolved in methanol (2 m L ) then stirred overnight. The solvent was r emoved and the residue was submitted to column. A colorless oil ( 102mg ) was obtained. (68%) 1 H NMR(CDCl 3 ), 2.17 (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); 13 C NMR, 56. 9 (m), 59.8, 125.2 (m), 125.7, 127.5, 132.2, 139.1 (m), 47.1 (m) 19 F NMR 84.2 (p, J = 162 Hz, 1F), 67.4 (d, J = 164 Hz, 4F). 1 hydro 3 pentafluorosulfanyl 4 (3 thienyl) pyrrole( 2 1 7): DDQ (125 mg, 0.66 mmol) was added to a solution of 5 in CH 2 Cl 2 at 0 o C w ith stirring A fter standing for 2 hs, the mixture was submitted to column directly. A colorless oil ( 95 mg ) was obtained. (95%) 1 H NMR(CDCl 3 ), 6.67 (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); 13 C NMR, 117.4 (m), 119.4 (m), 123.2, 124.7, 129.6, 134.1, 136.6 (m) 19 F NMR 87.9 (p, J = 167 Hz, 1F), 75.5 (d, J = 163 Hz, 4F). HRMS:calcd for C 8 H 6 F 5 NS 2 274.9862; found, 274.9864. Anal. C alcd for C 8 H 6 F 5 NS 2 : C, 34.91 ; H, 2.20; N, 5.09. Found: C, 35.29; H, 2.25; N, 4.75. G eneral synthetic procedure for SF 5 thiphene TBAF (1.0 M in THF, 1.3 5 equiv) was added to a mixture of c hloromethyl trimethylsilylmethylsulfide (1.3 5 equiv) and SF 5 alkynes (1 equiv) in THF at RT After stirring for several hours (monitored by 19 F NMR), the reaction was quenched with water and submitted to column to give 2 20 as a white solid.

PAGE 52

52 A solution of 2 20 in DCM was cooled to 30 0 C S ulfury chloride ( 2 equiv) was added slowly over 10 min. A fter stirring the mixture for another 30 min, the reaction was quenched with water and the organic phase was dried by Na 2 SO 4 T he solvent was Evaporated and the residue was purified by column to give 2 21 as white solid or c olorless oil. 3 pentafluorosulfanyl 4 p tolyl dihydrothiophene (2 20d) : 1 H NMR(CDCl 3 ), 2.36 (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); 13 C NMR, 21.43, 39.68, 44.09, 126.86, 129.12, 132.40, 138.34, 145.50, 148.34 (m) 19 F NMR 83.12 (p, J = 153 Hz, 1F), 67.05 (d, J = 163 Hz, 4F). 3 pentafluorosulfanyl 4 phenyl dihydrothiophene (2 20a) : 1 H NMR(CDCl3), 3.99 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); 13 C NMR, 39.74, 44.10, 127.00, 128.36, 135.51, 145.32, 148.62 (m) 19 F NMR 83.0 0 (p, J = 152 Hz, 1F), 66.11 (d, J = 163 Hz, 4F). 3 pentafluorosulfanyl 4 (3 thienyl) dihydrothiophene (2 20e) : 1 H NMR(CDCl 3 ), 3.96 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); 13 C NMR, 39.54, 43.23, 123.82, 125.94, 127.12, 134.22, 140.91 148.72 (m) 19 F NMR 82.97 (p, J = 161 Hz, 1F), 66.11 (d, J = 164 Hz, 4F). 3 pentafluorosulfanyl 4 p tolyl thiophene (2 21d) : mp 73 75 o C. 1 H NMR (CDCl 3 ), 2.40 (s, 3H), 7.07 ( m, 1H), 7.19 (s, 4H), 7.87 7.88 (d, J = 3.9 Hz, 1H); 13 C NMR, 21.43, 124.93, 127.90, 128.50, 129.64, 133.09, 137.85, 139.77, 150.65 (m) ; 19 F NMR 84.27 (p, J = 167 Hz, 1F), 72.55 (d, J = 162 Hz, 4F). HRMS:calcd for

PAGE 53

53 C 11 H 9 F 5 S 2 300.0066; found, 300.00 60. Anal. C alcd for C 11 H 9 F 5 S 2 : C, 43.99; H, 3.02. Found: C, 43.91; H, 3.06. 3 pentafluorosulfanyl 4 phenyl thiophene (2 21a) : 1 H NMR(CDCl 3 ), 7.10 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); 13 C NMR, 125.02, 127.80, 1 28.10, 129.81, 136.07, 139.80, 150.65 (m) 19 F NMR 84.11 (p, J = 161 Hz, 1F), 72.08 (d, J = 162 Hz, 4F). HRMS:calcd for C 10 H 7 F 5 S 2 285.9909; found, 285.9929. Anal. C alcd for C 10 H 7 F 5 S 2 : C, 41.95; H, 2.46. Found: C, 42.28; H, 2.49. 3 pentafluorosulfanyl 4 (3 thienyl) thiophene (2 21e) : 1 H NMR(CDCl 3 ), 7.07 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); 13 C NMR, 124.7, 125.3, 128.3, 129.3, 134.6, 135.3, 150.3 19 F NMR 84.0 (m, 1F), 72.1 (d, J = 162 Hz, 4F). HRMS:calcd for C 8 H 5 F 5 S 3 291.9474; found, 291.9504. Anal. C alcd for C 8 H 5 F 5 S 3

PAGE 54

54 CHAPTER 3 DIASTEREOSELECTIVE R EDUCTION OF GEM DIFLUOROCYCLOPROPENE D ACID 3 .1 Intro duction Bioactive molecules bearing fluorine atoms can greatly enhance properties compared to the non fluorinated compounds This leads to the wide spread use of fluorochemistry in pharmaceutical, agrochemical and fine chemical communities. 37 38 39 Highly stra ined gem difluorocyclopropane s unique member s of the fluor ine chemistry family, ha ve 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 straightfo rward method to construct difluorocyclopropane rings. Among those reagents, TFDA (trimethylsilyl 2 (fluorosulfonyl) 2,2 difluoroacetate), which readily react s 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 alkene s and all of them suffer ed a r ange of limitations which reduce d their application scope. 41a For example the most famous 3 ) is

PAGE 55

55 seldom used nowadays due to its high toxicity an d tedious preparation procedure The che apest commercial ly a vailable reagent sodium chlorodifluoroacetate (ClCF 2 COONa), which requires over 180 o C 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 dra wbacks of gas eous 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 di fluorocarbene 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 110 o C, 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 satisf actory yield; s econdly, the reaction is performed in common glassware u nder relatively mild condition s ; t hirdly, the catalytic amount of NaF makes the reaction almost homogeneous, which helps it to reach fu ll conversion in a short time; l ast but not least, it work s with a broad range of substrate s including many unreactive el ectron deficient alkenes. Figure 3 2 R eaction of TFDA with unsaturated ketones

PAGE 56

56 Although TFDA is a highly efficient reagent, its reaction with unsaturated ketones only provide d moderate yields, 42 probably due to t he 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 le d 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 s imple unsaturated ketone s or from Friedel Crafts reaction s But as to the substituted difluorocyclopropane ketone, the case still remains a challenge because the substituted unsaturated ketones did not react with TFDA at all 44 An alternative approach was used by the Chen group I n order to avoid the electron deficient substrate issue, the ketone group was protected prior to be ing treated with TFDA H owever, in the acetal hydroly sis step the product was dominated by formation of an unexpected monofluoro substituted furan in the case of electron rich substrates ( Figure 3 4 ). 44

PAGE 57

57 Figure 3 4. A ttempt to prepare of substituted difluorocyclopropane ketone s 3.2 The design of the reaction Although the dir ect reaction of substituted unsaturated ketone s with TFDA does not occur, when TFDA underwent reaction with substituted propynone s the reaction yielded the cyclopropen yl ketone s with high yield under mild conditions. 45 Figure 3 5 P reparation of difluoro cyclopropen yl ketone and its properties The chemical propert ies of cyclopropen yl ketones as determined by Chen group indicated that th ey w ere not stab l e and they tended to be attacked by nucleophile s in neutral or basic environment with generation of a n enolate ion. D uring the process of tautomerization from enolate to ketone, one HF molecule was eliminated, le ading to another monofluoro substituted cycloprepen yl ketone intermediate. This intermediate was even less stable and ending up losing a fluor ine ion to form a ring open ed product ( Figure 3 5 ). 46 On the contrary, a ring open ed product was obtained without los s of

PAGE 58

58 fluorine during the reaction of difluorocyclopropan yl ketone s with strong acid HBr in an i onic l iqu id ( Figure 3 6 ). 42 The mechanism was proposed to be SN 2 like in character. With the activation of ketone by protonation, the CH 2 group in the cyclopropane ring was attacked by bromide T his led to an enol intermediate which, interestingly, taut o merized to ketone with the two fluorine atoms remaining intact. Figure 3 6. R eactivity of difluorocyclopropyl ketone with HBr in Ionic Li q u id. Based on the above two very different results one can conclude that with fluorine atom s standing at position of a n enolate during the process of its tautomerization to ketone in basic environment, probably one HF molecule will be displaced while under acidic condition s the fluorine atoms will remain intact (Figure 3 7) Figure 3 7. Proposed tauto merization mechanism for difluoro enol s/enolates If this hypothesis is true, we could propose the following routes to solve the preparing problem of substituted difluorocycloprop yl ketone. Starting from readily available pr ecusor the difluorocyclopropen yl ketone s the carbonyl group is first activated by a a cid subsequent conjugated addition by a hydride donor lead s

PAGE 59

59 to an enol form which tautomerize to ketone under acidic condition s with the fluorine atoms remain ing intact (Figure 3 8) Figure 3 8. S ynthetic approach to substituted difluorocycloprop yl ketone s Therefore, the next issue to be concerned about is the cho ice of the correct hydride donor. Obviously, hydrogen and meta l hydride do no t 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 ha s been widely used as a hydride transfer reagent, usually catalyzed by a cid s under mild conditions ( Figure 3 9 ). 48 Figure 3 9. A pplication of HEH as hydride donor

PAGE 60

60 3.3 Results Table 3 1 Screen ing the conditions for the reduction of difluorocyclopropen yl ketones -a) RT, 20 h ; b) 2 equiv HEH; c) characterized by 19 F NMR ; d) no des ired products found; e) 0 o C, 20 h. The Hantzsch ester and gem d ifluorocyclopropene were prepared according to the literature methods. 45 47 T o initiate reduction, p toluen esulfonic acid w as chosen as the catalyst with 10% loading. In fact the reaction provided 60% conversion when simply mix ing the substrate with 2 equiv HEH in CH 3 CN at RT overnight (Table 2 3, entry 1)

PAGE 61

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 19 F NMR spectrum. Interestingly the cis isomer, which is believed to be th ermodynamically less stable than the trans isomer, dominated the products with a cis / trans ratio of 67:33. More common Br nsted a cid s were test ed and they all favored the cis product and ga ve similar conversion and selectivity. Using the catalyst pivalic acid ( BA 1d ), the solvent effect s were evaluated. Ether solvent THF did not lead to the desired product (entry 5) while m ore non polar solvents slow ed down the reaction but facilitated better selectivity. Dichloromethane provided the best combin ation 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 o C) did not enhance any selectivity based on the condition of entry 8. It is n oteworthy that the reaction was very sensitive to the acid ic enviro n ment E ven with using 2% of the catalyst, a good conversion was achieved (entry 10 ).

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62 Table 3 2 Screen ing conditions using bulky a cid s With the hope of increas ing the selectivity, more bulky benzoic acids were test ed As shown in Table 3 4, catalyst s BA 1e f and g gave similar selectivit ies 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 isoprop yl groups at the ortho position m ay not pla y 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 result s Further solvent optimization based on use of catalyst BA 1e which overall gave relative ly 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

PAGE 63

63 methyl t butyl ether also gave high selectivity but the conversion was not practical (ent ry 8) Figure 3 10 Reaction s of d ifluorocyclopropene with HEH c atalyzed by a cid To explore the limitation s of t his reaction, more substrates were prepared and tested ( Figure 3 10 ). Due to the relative ly slow r eaction rate 20% catalyst was applied, result ing in over 97% conversion in 4 days. The reaction had very broad substrate scope, including both electron deficient and elect ron rich substrates g i v ing almost quantitative NMR yields when the cis / trans isomer mixture was the product. It is noteworthy that m ost of the cis / trans isomers could be separated easily by column chromatography with the less polar trans isomer eluting first. Therefore, the yield s

PAGE 64

64 reported here are mainly for the isolated major cis isom er s While 2a was obtained with high dia stereo selectivity and excellent yield, a better result was expected with more steric ally demanding substrates. However, to our surprise, when more substituents were attached to the phenyl ring, the selectivity was sl ightly 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, th is compound cannot be prepared by other method s Also, the steric hindra nce 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 ca talytic reduction of difluorocyclopropen yl ketones

PAGE 65

65 The proposed mechanism for the catalytic cycle i s show n in Figure 3 11 The ketone is first activated by a cid follow ed by attack by HEH with the ketone functional group being transformed to its enol form. This enol form, which c an eliminate a n HF molecule under basic condition, tautomerize s back to ketone under acidic condition s, leaving the ring i ntact. During the tautomerization process, the a cid c an approach the enol from either the top face or the bottom face. However, due to the steric interaction between substituent s and the catalyst, the acid prefers attack on the top face which res ulted in the cis product being favored A control reaction was conducted wh ereby a pure cis product was treated under the standard reaction condition s N o trans isomer was detected by 19 F NMR, show ing 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 acid s were used a stronger steric interaction would occur between substituent s and the catalyst, resu lt ing in better selectivity Indeed the s electivity 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, catalyst s BA 1e f and g gave almost the same hig h selectivity while the apparently more bulky 2,4,6 triisoprop y benzoic ( BA 1h ) dramatically decreased the selectivity indicat ing that the substituent at the ortho position of benzoic acids do not have much influence on the transition state.

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6 6 However, the less bulky ortho substituted phenol catalyst ( BA 1i ) gave much better result s that from BA 1h probably due to the reduced size of the hydroxyl group compared with carboxyl moiety, shorten ing the distance between phenyl ring and the enol structure le adin g 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 prepar ing substituted gem d ifluocycloprop yl ketone in a reaction catalyz ed by a cid was designed based on the rationalized tautomerization mechanism of difluoro enolate The reaction, using HEH as a hydride transfer reagent, proved to be a general route to prepare substituted gem difluorocycloprop yl ketone s in high y ield. Moreover the reaction was dominated by formation of the cis product. Based on the proposed mechanism, the diastereoselectivity was improved by using more bulky a cid s under optimized conditions Further exploration of ena n tio selective prepar ation of gem difluorocycloprop yl ketones based on this research is on going in this lab and will be reported in due course 3. 6 Experimental section NMR spe ctr um were obtained in CDCl 3 using TMS and CFCl 3 as the internal standards for 1 H and 13 C NMR and 19 F NMR respectively; substituted propynone s 49 and TFDA 50 were prepared according to the previous literature, and all other chemicals were purchased from Aldrich, Alfa, or Fisher without further purification. Procedure for p reparation of gem d ifluorocyclopropen yl k etone s : A mixture of substituted propynone (3.55 mmol), NaF (10%mol), Diglyme (2 ml) was heated to 120 o C under the flow of N 2 TFDA was then added dropwise (about 40 min), with stirring at this

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67 temperature for 1 h, the solution was cooled and submitted to column for purification directly with h exane/ d ichloromethane. 1b : (87%). 1 H 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). 19 FNMR: 104.3 (s, 2 F). 1c : (89%). 1 H 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). 19 F 104.3 (s, 2 F). 1d : (91%). 1 H NMR: 2.41 (s, 6 H), 7.25 (s, 1H), 7.65 (m, 5 H), 8.16 (m, 2 H). 19 F NMR: 104.4 (s, 2 F) 1e : (88%). 1 H 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). 19 FNMR: 104.1 (s, 2 F). 1f : (86%). 1 H 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). 19 F NMR: 104.3 (s, 2 F). 1g : (85%). 1 H NMR: 7.60 (m, 2 H), 7.72 (m, 3H), 7.89 (m, 2 H), 8.14 (m, 2 H). 19 F NMR: 104.1 (s, 2 F). 1h : (75%). 1 H NMR: 2.59 (s, 1 H), 7.56 (m, 3H), 7.86 (m, 2 H). 19 F 107.7 (s, 2 F). 1 i : (90%). 1 H 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). 19 F NMR: 104.2 (s, 2 F). 1j : (55%). 1 H 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). 19 F NMR: 102.2 (s, 2 F). Procedure for Reduction of gem Difluoro cyclopropenyl Ketone with HEH: a cid (20% mol) was added to a mixture of gem d ifluorocyclopropenyl k etone (100 mg), HEH ( 2 equiv), toluene (1m L ) in round bottom flask at RT, the solution was stirred until

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68 the ketone was consumed (monitored by TLC or 19 F NMR), then the mixture was purified by column chromatograph y 2a : (79%). 1 H 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). 13 .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. 19 F NMR: 115.7 (dt, J = 155 and 14 Hz, 1F), 147.4 (d, J = 155 Hz, 1F). HRMS: calcd for C 16 H 12 F 2 O[ M+Na] + 281.0748; found, 281.0759. 3a : 1 H 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). 13 (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. 19 F NMR: 132.55 (m). HRMS: calcd for C 16 H 12 F 2 O[M+Na] + 281.0748; found, 281.0755. 2b : (72%). 1 H 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). 13 (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. 19 F NMR: 115.6 (dt, J = 155 and 14 Hz, 1F), 147.4 (d, J = 156 Hz, 1F). HRMS: calcd for C 17 H 14 F 2 O[M+Na ] + 295.0905; found, 295.0913. 2c : (70%). 1 H 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). 13 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. 19 F NMR: 115.7 (dt, J = 155 and 11 Hz, 1F), 147.4 ( d J = 155 Hz, 1F). HRMS: calcd

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69 for C 17 H 14 F 2 O[M+Na] + 295.0905; found, 295.0 918. Anal. Calcd for C 17 H 14 F 2 O: C, 74.99; H, 5.18. Found: C, 74.94; H, 5.57. 2d : (69%). 1 H 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). 13 21.51, 3 3.12 (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), 1 27.5, 128.3, 128.9, 129.4, 129.7, 133.5, 137.9, 138.2, 190.3. 19 F NMR: 115.6 (dt, J = 155 and 14 Hz, 1F), 147.4 (d, J = 156 Hz, 1F). HRMS: calcd for C 1 8 H 16 F 2 O[M+Na] + 309.1061; found, 309.1072. 2e : (68%). 1 H 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). 13 (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. 19 F NMR: 115.7 (dt, J =155 and 11 Hz, 1F), 147.9 (d, J = 156Hz, 1F). HRMS: calcd for C 24 H 28 F 2 O[M+Na ] + 393.2000; found, 393.2009. Anal. Calcd for C 24 H 28 F 2 O: C, 77.81; H, 7.62. Found: C, 77.51; H, 8.09. 2f : (81%). 1 H 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). 13 (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. 19 F 115.8 (dt, J = 155 and 11 Hz, 1F), 147.5 (d, J = 154 Hz, 1F). HRMS: calcd for C 20 H 20 F 2 O[M+Na] + 337.1374; found, 337.1382. 2g : (75%). 1 H 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). 13 (dd, J = 9 and

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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. 19 F 116.1 (dt, J = 155 and 14 Hz, 1F), 147.5 (d, J = 155 Hz, 1F). HRMS: calcd for C 16 H 11 BrF 2 O[M+Na] + 358.9854; found, 358.9855. Anal. Calcd for C 16 H 11 BrF 2 O: C, 57.00; H, 3.29. Found: 57.31; H, 3.29. 2h : (61%). 1 H 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). 13 (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. 19 F NMR: 116.6 (d, J = 160 Hz, 1F), 144.9 (d, J = 164 Hz, 1F). HRMS: calcd for C 11 H 10 F 2 O[M+Na] + 219.0592; found, 219.0599. Anal. Calcd for C 11 H 10 F 2 O: C, 67.34; H, 5.14. Found: C, 67.06; H, 5.46. 2i : (80%). 1 H 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). 13 (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. 19 FNMR: 115.9 (dt, J = 155 and 14 Hz, 1F), 147.4 (d, J = 156 Hz, 1F). HRMS: calcd for C 20 H 20 F 2 O[M+Na] + 337.1374; found, 337.1388. Anal. Calcd for C 20 H 20 F 2 O: C, 76.41; H, 6.41. Foun d: C, 76.17; H, 6.61. 2j ( cis / trans mixture) : (95%). 1 H 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). 19 F NMR: 115.9 (dt, J = 152 and 14 Hz, 1F), 134.7 (m, 2F) 147.4 (d, J = 152 Hz, 1F).

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71 CHAPTER 4 FACILE PREPARATION O F SF 5 CONTAINING POLYMERS BY RING OPENING METATHESIS POLYMERIZ ATION (ROMP) AND PRO DUCT CHARACTERIZATIO N 4.1 Introduction Polymers containing fluorine atom(s) usually exhibit unique proper ties such as excellent thermal and chemical resistance, low dielectric constants, low surface energ ies etc. Hence, fluoropolymer s ha ve received considerable attention from fundamental research to industrial application. 51 While polyethylene with differen t fluorine content, poly(vinyl fluoride) (PVF), poly(vinylidene fluoride) (PVDF), poly(ethylene tetrafluoroethylene) (PETFE), ha ve been well known for their high performance, 52 recent research has also show n that fluoropolymer s can be potentially used in advance d materials area such as optic material, 53 anti fouling coating s 54 and supercapac itor s 55 The p entafluorosulfa nyl (SF 5 ) group, an appealing trifluoromethyl alternative has attracted much interest since it is more electronegative, has larger steri c size, and has better chemical stability. Although SF 5 chemistry was first studied almost a half century ago this group ha d n o t been well explored until several breakthroughs in its synthetic methodology occurred during last decade. T hese dramatically fa cilitate d the application of SF 5 chemistry to the organic, pharmaceutical, material, and agrochemical fields For example, Et 3 B was discovered as an excellent radical initiator for the introduc tion of commercial ly available SF 5 Cl int o aliphatic substrate s thereby avoiding need for an autoclave reactor T he continu ally active area of synthetic development of SF 5 benzene has allowed it to become an affordable building block for medic inal chemistry. While small molecules bearing the SF 5 group were well devel oped, macromolecules modified with the SF 5 moiety had potentially interesting properties for

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72 the application as lubricants, surface active reagents, optical materials, and protective coatings. 56 Although numerous SF 5 containing monomers were prepared, the s ynthesis of polymer s with the SF 5 group directly attached to the polymer main chain still remains a challenge. T his may be explained in several ways : First, only a few SF 5 based reagents such as SF 5 Cl or SF 5 benzene are commercial ly available; s econdly, few synthetic method s were available for the incorporation of the SF 5 moiety in to the monomer; t hirdly, the steric and electronic propert ies of the SF 5 substituent dramatically affects the polymerization process For example, Ameduri et al reported th at SF 5 substituted ethylene would not undergo radic al initiated homopolymerization. Even in the case of terpolymerization with vinyl denefluoride (VDF) and hexafluoropropene, the polymers contained only a low percentage of the SF 5 unit s (<1%) or had very low mac romolecular weight (Mn = 600). 57 Hence, we thought it would be valuable to prepare the polymer with an SF 5 group directly attached to the backbone to further study its structure propert y relationship s Inspired by the well established Ring Opening Metathes is Polymerization (ROMP) method, 58 59 which is a powerful tool to prepare functionized polyethylene, we designed SF 5 substituted cyclooctene monomers for polymerization s initiated by ruthenium based catalyst and subsequent hydrogenation (Figure 4 1) 4.2 Results and Discussion 4.2.1 Monomer synthesis Based on the Et 3 B initiation methodology, SF 5 Cl was readily added to 1,5 cyclooct a diene with high yield at low temperature after two hours. A satisfactory purity of M1 was obtained by vacuum distillation fo llow ed by flash column chromat og raphy. Ne ither method alone provide d clean spe c trum The byproduct could derive from the

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73 reaction of the second double bond with excess SF 5 Cl gas, or a possible intramolecul ar 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 SF 5 chemistry CH 3 ONa/CH 3 OH did not work at all for this reaction. 4.2.2 Polymer Synthesis and Structure Characterization The firs t attempt to prepar e P1 failed with a substrate/solvent ratio of 1 g/10 m L W e 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 CH 2 Cl 2 just enough to dissolve the catalyst, light yellow rubber like P1 was attained in high yield. The 1 H NMR spectr um (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 hydrogen s (5.2 and 4.3 ppm) on the substituted carbon s moving upfield (4.6 and 3.8 ppm). Initially hydrogenation of P1 w ith p toluenesulfonhydrazi de/tributylamine in xylene did not lead to the desired product 58 I nstead all the starting materials decomposed. Figure 4 1. Synthetic route toward SF 5 polymers

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74 Luckily, without using tributylamine, the same condition s gave clean conversion after reflux ing for two hours. The olefin proton peak (5.4 ppm) noticeably disappeared in the P2 NMR spectrum M2 was also polymerized under identical condition s Figure 4 3 unambiguously show s 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 spectr um indicate d its successful hydrogenation. Figure 4 2. 1 H NMR of M1 P1 and P2

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75 Figure 4 3 1 H NMR of M2 P3 and P4 The molecul ar weight s and polydispersity index (PDI) of all products ex cept P3 which was not very soluble in any known solvent s were further characterized by gel permeat ion chromatography (GPC). The results w ere consistent with the well established ROMP reaction products (Table 4 1) Although the molecul ar weight of P1 dropp ed down after hydrogenation to P2 Coughlin et al proposed that this may be due to an increase in t he degree s of freedom after reduction of the double bonds, possibly lead ing to a more compact conformation with d iminished hydrodynamic radius. 59 Table 4 1 Preparation and properties of SF 5 containing Polymers ----

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76 Figure 4 4 The 19 F NMR spectrum of monomers and polymers Fluorine NMR was also used to monitor the reactions. Since four fluorine atoms are equatorial, and one axial, 19 F NMR spectrum of all SF 5 containing compounds in Figure 4 4 showed characteristic double t, around 54 58 ppm and pentet, with fine structure at 85 87 ppm (AB4 system). The expanded area of the spectrum demonstrat e s the clean and clear transformation of each step. 4.2. 3 Thermal Properties Characterization Figure 4 5 T hermogravimetric Analys i s for SF 5 polymers Thermogravimetric Analys i s (TGA) showed the unsaturated and hydrogena ted polymers to have similar thermal behavior such as close T d ( 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 SF 5 group. Interestingl y, The T d of P3 and P4 are about 90 o C higher than those of P1 and P2 indicating that the

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77 presence of chlorine atom s decrease s the thermal stability probably due to the elimination of HCl at high temperature. Figure 4 6 The Differential Scanning C alorimetry of SF 5 polymers Differential Scanning Calorimetry (DSC) was also used to characterize the thermal profile of the polymers. A T m was not observed due to the lack of regularity in the microstructure (mainly because of head tail, head head, tail t ail mixture). Though P3 and P4 have higher T d than P1 and P2 Table 4 1 show s that the la t ter pair has higher glass transition temperature s (T g ) indicating that the presence of double bonds has more impact on Tg than the chlorine atom s With the introd uction 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 T g This effect can also explain the higher Tg of P1 compared to P2 59

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78 4. 3 Conclusions W e have successfully established a facile method to prepare two polymers with SF 5 group directly attached to the backbone using ring opening metathesis polymerization of SF 5 substituted cyclooctene s follow ed by hydrogenation. The microstructure s of these novel polymers were characterized by 1 H NMR, GPC and 19 F NMR. TGA and DSC experiments show ed the unsaturated polymers and their hydrogenated derivatives have similar thermal profiles Polymers P3 and P4 wit hout 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 perf ormed 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. Thermogr avimetric analyses (TGA) were carried on a Perkin Elmer 7 series thermal analysis system with a heating rate of 10 o C per min, sweeping temp eratures ranging from 25 to 700 o C under inert atmosphere. Differential scanning calorimetry (DSC) measurements were p erformed on a DSC Q1000 V9.6 Build 290 with a heating rate of 10 o C per min from 25 to 250 o C. Preparation of M1. Into a three neck round bottom flask equipped with a dry ice reflux condenser were added at 40 0 C, 50 m L of anhydrous hexane 5 g 1,5 cyclooct a diene and 11.5 g SF 5 Cl (1.2 equiv). The solution was stirred at this temperature for 10 min, and 5 m L Et 3 B (0.1 equiv., 1 M in hexane) was added slowly using a syringe. The solution was stirred for 1 h at 30 0 C, and then warmed to rt. The mixture was

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79 hy drolyzed with aqueous NaHCO 3 and the organic phase was separated and dried with MgSO 4 After evaporated the solvent, the crude product was first purified by vacuum distillation and then submitted to column chromatography with hexane as eluent. ( 78 %) 1 H NMR(CDCl 3 ), 2.28 ( m 5 H), 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) ; 13 C NMR, 21.65, 22.85, 29.27, 36.69, 60.95, 89.23, 128.39, 132.03 19 F NMR, 85.81 (p, J = 138 Hz, 1F), 54.41 (d, J = 1 41 Hz, 4F). HRMS: calcd for C 8 H 12 ClF 5 S 270.0268 ; found, 270.0267 Preparation of M2. Into a round bottom flask, 1.62 g LiOH.5H 2 O was slowly added to a DMSO (21 m L ) 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%). 1 H NMR (CDCl 3 ), 2.46 ( m 6 H), 2. 8 8 ( m 2 H), 5.59 (m, 2H), 6.51 ( m 1H); 13 C NMR, 26.21, 27.69, 27.95, 28.89, 128.27, 128.61, 134.34, 157.07 19 F NMR, 7.53 (p, J = 1 47 Hz, 1F), 5 6.88 (d, J = 1 4 7 Hz, 4F). HRMS: calcd for C 8 H 11 F 5 S 234.0502 ; found, 234.0490 General proc edure for polymerization. Under nitrogen atmosphere, a highly concentrated CH 2 Cl 2 ([M]/[C] = 500) was added to a sealed tube filled with monomer via syringe. The mixture was stirred at 40 o C overnight. Then the oil bath was removed, 1 m L vinyl ether and 5 ml chloroform was added to solidified solution, after stirring for 2 h, the orange solution was poured in to 200 ml meth an ol and white solid was precipitated. The product was collected and dried overnight by vacuum.

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80 P1 : ( 89 %). 1 H NMR (CDCl 3 ), 1.84 ( bm 3 H), 2.21 2.34 ( bm 5 H), 3.90 ( b 1 H), 4.57 ( bm 1H) 5.46 (b s 2H) 19 F NMR, (p, J = 147 Hz, 1F), 58.03 (d, J = 1 44 Hz, 4F) P3 : ( 85 %). 1 H NMR (CDCl 3 ), ( bs 3 H), 2.17 ( bs 5 H), 2.46 (bs, 2H), 5.44 ( bs 2 H ), 6.26 (bm, 1H) 19 F NMR, 7.05 (p, J = 1 52 Hz, 1F), 57.91 ( d, J = 1 4 7 Hz, 4F) General procedure for hydrogenation. The 0.25 g P1 was added to a flask filled with 8 m L o xylene, the flask was heated to 80 o C to dissolve the solid and then cool ed to RT. p T oluenesulfonhydrazide (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. T he polymer precipitated as light orange solid, which was filtered and dried over vacuum. P 2 : ( 83 %). 1 H NMR (CDCl 3 ), 1. 38 1.8 0 ( bm 10 H), 2. 27 ( bm 2 H), 3.90 ( b s 1 H), 4.5 8 ( bm 1H) 19 F NMR 85. 73 (p, J = 14 1 Hz, 1F), 57.57 (d, J = 1 44 Hz, 4F) P4 : ( 80 %). 1 H NMR (CDCl 3 ), 1.3 4 1. 48 ( bm 8 H), 2. 13 ( b s 2 H), 2.41 ( bs 2 H), 6.25 ( b s 1H) 19 F NMR 8 7.63 (p, J = 14 7 Hz 1F), 5 8.07 (d, J = 1 4 7 Hz, 4F)

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81 APPENDIX NUCLEAR MAGNENETIC R ESONANCE (NMR) SPECTRUM Figure A 1 1 H and 13 C NMR assignment of compounds 2a (B) and 3a (A) by Dr. Ghiviriga

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82 Figure A 2 1 H NMR spectrum of 3 3a Figure A 3 1 H NMR spectrum of 3 3a ( expanded in aromatic region)

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83 Figure A 4 1 H NMR spectrum of 3 3a ( expanded in aliphatic region) Figure A 5 19 F NMR spectrum of 3 3a

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84 Figure A 6 g HMQC spectrum of 3 3a

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85 Figure A 7 g HMQC spectrum of 3 3a ( expanded in aromatic region) Fi gure A 8 1 H NMR spectrum of 3 2 a

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86 Figure A 9 1 H NMR spectrum of 3 2 a ( expanded in aromatic region) Figure A 10 1 H NMR spectrum of 3 2 a ( expanded in aliphatic region)

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87 Figure A 11 19 F NMR spectrum of 3 2 a Figure A 12 g HMQC spectrum of 3 2 a

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88 Figure A 13 1 H NMR spectrum of M1 Figure A 14 1 3 C NMR spectrum of M1

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89 Figure A 15 19 F NMR spectrum of M1

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90 Figure A 16 1 H NMR spectrum of M 2 Figure A 1 7 1 3 C NMR spectrum of M 2

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91 Figure A 1 8 19 F NMR spectrum of M 2 Figure A 1 9 1 H NMR spectrum of P1

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92 Figure A 20 19 F NMR spectrum of P1 Figure A 21 1 H NMR spectrum of P2 Figure A 22 19 F NMR spectrum of P2

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93 Figure A 23 1 H NMR spectrum of P3 Figure A 24 19 F NMR spectrum of P3

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94 Figure A 25 1 H NMR spectrum of P4 Figure A 26 19 F NMR spectrum of P4

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99 BIOGRAPHICAL SKETCH received his B.S. degree from Nanjing Normal University in 2003 and his M.S. de gree 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 D epartment of C hemistry, University of In the fall of 2012, h e received his Ph.D. from the University of Florida. Zhaoyun and his wife, Lijuan Yue, have one lo vely daughter, Fiona Haoting Zheng.