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A new radical trifluoromethoxylation strategy and investigation on the fluorination of boronic acids… Binayeva, Meruyert 2015

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  A NEW RADICAL TRIFLUOROMETHOXYLATION STRATEGY AND INVESTIGATION ON THE FLUORINATION OF BORONIC ACIDS USING ELECTROPHILIC N-F REAGENTS   by Meruyert Binayeva  B.Sc., M. Auezov South Kazakhstan State University, 2012   A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF  MASTER OF SCIENCE in  THE FACULTY OF GRADUATE AND POSTDOCTORAL STUDIES (Chemistry)  THE UNIVERSITY OF BRITISH COLUMBIA (Vancouver)  December 2015 © Meruyert Binayeva, 2015 	   ii	  Abstract  Fluorine-containing motifs are important components in pharmaceuticals and agrochemicals. Upon incorporation of fluorinated moieties, many small molecules show enhanced bioavailability, lipophilicity and metabolic stability. Despite their industrial importance, many fluorinated motifs remain a significant synthetic challenge. This thesis describes the investigation and development of new radical fluorination methods for the synthesis of two important, and synthetically challenging fluorinated motifs: trifluoromethoxyarenes and aryl fluorides.  Chapter 1 provides a literature survey on the importance of fluorinated small molecules and outlines current methods to synthesize them. The chapter begins with a historic overview of fluorinated pharmaceuticals. Common fluorination reagents are then summarized, including anionic, cationic, and radical sources of fluorine. The chapter concludes with a brief survey of the application of 18F-fluorinated molecules in Positron Emission Tomography (PET).  Chapter 2 outlines work towards the development of a radical fluorodecarboxylation methodology for the synthesis of trifluoromethoxy ethers. The chapter begins with a review of synthetic methodologies to access trifluoromethoxylated molecules that have been developed over the last few decades. Next, a novel methodology based on a radical fluorodecarboxylation method will be presented along with substrate scope studies. XeF2 was used both to induce decarboxylation and as atomic fluorine source. The reaction afforded good yields for electron-rich substrates, whereas electron-deficient substrates and naphthol derivatives produced lower yields.   Chapter 3 outlines work for the fluorination of aryl boronic acid and boronated derivatives using Selectfluor®. The chapter starts with a brief overview of known methodologies in fluorination of boronic acid derivatives. Studies towards synthesizing aryl fluorides from a number of boronic acid and boronate ester derivatives will then be described. Preliminary results of this transition metal-free method showed that the reaction is substrate dependent, and the general product yields were low. 	   iii	  Preface Chapter 2 is based on research performed in the Sammis group with my colleagues Claire Chatalova Sazepin and Maxim Epifanov. Difluoroaryloxyacetic acid derivatives 227, 228, 229, 230, 231, 232, and 233 were prepared and characterized by C. Chatalova Sazepin. I performed all other syntheses, characterizations and experimental work in this chapter.   Chapter 3 is based on research performed in the Sammis group with my colleague Maxim Epifanov. Substrate 263 was prepared and characterized by M. Epifanov. I carried out all experimental work in this chapter, as well as the synthesis and characterization of all compounds.                	   iv	  Table of Contents  Abstract…………………………………………………………………………………        ii Preface…………………………………………………………………………………..       iii Table of Contents…………………………………………………………………...….        iv List of Tables…………………………………………………………………...……….       vi List of Figures………………………………………………………………...…………  vii List of Schemes……………………………………………………………...………….. viii List of Abbreviations and Symbols…………………………………………………….     x Acknowledgements……………………………………………………………...………    xiii 1 Introduction……………………………………………………………...…………...    1 1.1 Fluorine incorporation in small molecules: a brief historic overview.……….........    2 1.2 Medicinal benefits of fluorinated small molecules…………………...………........    3 1.3 Synthetic fluorination strategies…………………………………...………………     4 1.3.1 Nucleophilic fluorine methodologies…………………………………...…...    5 1.3.2 Electrophilic fluorine sources………………………………...………...........     6 1.3.3 Radical-based fluorination methodologies …………………………………      8 1.4 Positron Emission Tomography imaging……………………………………...…...   12 2 Introduction to trifluoromethoxylation………………………………………….…   14 2.1 Properties and structure of trifluoromethoxy moieties…………………………..     15 2.2 Traditional methods for the synthesis of aryl trifluoromethyl ethers……………     19 2.3 Decarboxylative fluorination strategies………………………………..…...………   30 	   v	  2.4 Results and discussion……………………………………...…………...…………   38 2.4.1 Initial studies toward the synthesis of trifluoromethoxy arenes……………..   39 2.4.2 The synthesis of trifluoromethoxy arenes through fluorodecarboxylatons of difluoroaryloxyacetic acids ……………………………...………………….……………   39 2.5 Conclusion……………………………...………………………………................   42 2.6 Experimentals…………………………...…………………………………............   43 2.6.1 General experimental………………………………………………………...   43 2.6.2 Synthesis of ethyl difluorophenoxy acetates…...…………………………....   44 2.6.2.1 General ethyl difluorophenoxy acetate synthesis procedure………......   44 2.6.2.2 Synthesis of esters 246-253………………...……………………….....   44 2.6.3 Synthesis of α,α-difluorocarboxylic acids…………………………...............   48 2.6.3.1 General α,α-difluorocarboxylic acid synthesis procedure……………..   48  2.6.3.2 Synthesis of acids 254-261…………………………………………….   49 2.6.4 Synthesis of trifluoromethoxyarenes………………………………….……...   53       2.6.4.1 General trifluoromethoxyarene synthesis procedure ……………..……  53       2.6.4.2 Synthesis of trifluoromethoxyarenes 227-240 …………………..…….   53 3 Fluorination of boronic acid derivatives………………………….…..……….……..     60 3.1 Generation of aryl radicals from deborylation of arylboronic acids……..……….    60 3.2 Results and discussion: metal-free fluorination of aryl boronic acids …………....   62 3.3 Conclusion……………………………………………………….…………...……  69 4 Conclusions and future work………………………………………………....……….    70 Bibliography…………………………………………………………….………………...   73  Appendix Selected spectra for Chapter 2…………………………………………….…   80  	   vi	  List of Tables   Table 1.1. Properties of common elements and their bonds to carbon…………………..…   4 Table 1.2. Selected nucleophilic fluorinating reagents…………………………………..…   5 Table 1.3. Selected electrophilic fluorinating reagents……………………………….....…    7 Table 2.1. Coupling constants data from 1H and 13C NMR spectroscopies……………….   16 Table 2.2. Effect of a substituting a CF3 group for methyl on different heteroatoms……..   17 Table 2.3. Lipophilicity Increment π as assessed for mono-substituted benzenes H5C6-X..   18 Table 3.1. Fluorination of 4-methylbenzene boronic acid………………………………..    64 Table 3.2. Fluorination of pinacol phenylboronate………………………………………..   65  Table 3.3. Fluorination of (3-pyridinyl) boronic acid……………………………………    67 Table 3.4. Fluorination of 4-methylphenylboronic acid pinacol ester………………..….     68 Table 3.5. Fluorination of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-o-xylene…..     68 Table 4.1. Radical fluorodecarboxylation, results summary………………………..……     72 Table 4.2. Radical fluorination, results summary…………………………………………   74        	   vii	  List of Figures  Figure 1.1. Selected commercially available fluorine containing pharmaceuticals…………  1 Figure 1.2. Structures of fludrocortisone and 5-fluorouracil………………………………..  3 Figure 1.3. Comparison of the redox potential of crystalline, bench-top stable fluorinating reagents………………………………………………………………………………………  8 Figure 1.4. Trifluoromethylhypofluorite………………………………….………………… 9 Figure 1.5. Xenon fluorides…………………………………………………………………. 9 Figure 1.6. Selected key 18F tracers…………………………………………………...…… 12 Figure 2.1. Selected OCF3-containing a) pharmaceuticals, and b) agrochemicals………...  14 Figure 2.2. Mesomeric structures of the OCF3-group……………………………………...  15 Figure 2.3. Molecular structures of 49, 50 and 51…………………………………………  15 Figure 2.4. Structure of tris(dimethylamino)sulfonium (TAS) trifluoromethoxide………..  16 Figure 2.5. Structure of 51………………………………………………………………...   17 Figure 2.6. Conformational preference of the trifluoromethoxy group on aryl rings……… 18 Figure 2.7. Electrophilic trifluoromethylation reagents……………………………………  22 Figure 3.1. Boronic acid substrates for fluorination reactions…………………………….   63 Figure 3.2. Electron dense boronic acid derivatives………………………………………   69 Figure 4.1. Difluoroacetic acid substrates for trifluoromethoxylation……………………..  71     	   viii	  List of Schemes  Scheme 1.1. Ionic and radical fluorine incorporation………………………………………   8 Scheme 1.2. Fluorodecarboxylation reactions……………………………………………… 10 Scheme 1.3. Two distinct mechanisms for the formation of fluoroalkenes………………... 11 Scheme 2.1. Traditional approaches to access trifluoromethoxy arenes………………...…  19 Scheme 2.2. Synthesis of trifluoromethyl aryl ethers………………………………………  20 Scheme 2.3. Synthesis of trifluoromethyl aryl ethers………………………………………  20 Scheme 2.4. Synthesis of trifluoromethyl aryl ethers via an in situ chlorination/fluorination sequence………………………………………………………….…………………………  21 Scheme 2.5. Synthesis of trifluoromethyl ethers via fluoroformates………………………  21 Scheme 2.6. Synthesis of trifluoromethyl aryl ethers via fluorodesulfurization of aryl xanthates……………………………………………………………………………………. 22 Scheme 2.7. Synthesis of trifluoromethyl ethers through O-(trifluoromethyl)dibenzofuranium reagent………………………………………………………………………………………. 23 Scheme 2.8. Synthesis of trifluoromethyl ethers through Togni reagent…………………... 24 Scheme 2.9. Synthesis of trifluoromethoxybenzene…………………………………….…  24 Scheme 2.10. Synthesis of trifluoromethyl ethers via aryne intermediate…………………  25 Scheme 2.11. Ag-mediated trifluoromethoxylation of aryl stannanes……………………..  25 Scheme 2.12. Ag-mediated trifluoromethoxylation of arylboronic acids………………….  26 Scheme 2.13. Aryl trifluoromethoxylation by OCF3 group migration……………………..  26 Scheme 2.14. Selected examples of the OCF3-migration reaction…………………………  27 Scheme 2.15. Evidence for the proposed reaction mechanism…………………………….  28 Scheme 2.16. Trifluoromethoxylation of olefins with CF3OF……………………………..  29 Scheme 2.17. Initiation,propagation and termination steps of the radical chain mechanism.29 	   ix	  Scheme 2.18. Radical mechanism of the addition of CF3OF to aromatics in the presence of CF3OCF=CF2 as free radical initiator………………………………………………………. 30 Scheme 2.19. Decarboxylative radical fluorination of alkylperoxoates……………………  31 Scheme 2.20. Photodecarboxylative radical fluorination of aryloxycarboxylic acids…..…  32 Scheme 2.21. Mechanistic model of photodecarboxylative fluorination…………………..  33 Scheme 2.22. Photodecarboxylation of aryloxyacetic acid derivatives and photoredox catalyzed system…………………………………………………………………………….  33 Scheme 2.23. Catalytic photoredox decarboxylative fluorination………………………….  34 Scheme 2.24. Decarboxylative radical fluorination of aliphatic carboxylic acids…………  35 Scheme 2.25. Decarboxylative fluorination for the synthesis of tri- and difluoromethyl  ethers………………………………………………………………………………………... 36 Scheme 2.26. Decarboxylative fluorination of γ-butyrolactones…………………………...  37 Scheme 2.27. Decarboxylative fluorination aliphatic carboxylic acids……………………   38 Scheme 2.28. Synthetic methods to access trifluoromethoxy arenes and decarboxylative-fluorination………………………………………………………………………………….  39 Scheme 2.29. Fluorodecarboxylation reaction scope for α, α- difluoroaryloxyacetic acid derivatives…………………………………………………………………………………..  40 Scheme 2.30. Fluorodecarboxylation reaction scope for α, α- difluoroaryloxyacetic acid derivatives…………………………………………………………………………………..  41 Scheme 2.31. Proposed mechanism of fluorodecarboxylation of difluoroaryloxyacetic  acids………………………………………………………………………………………...  42 Scheme 3.1. Synthesis of simple fluoroarenes………………………………..……………  60 Scheme 3.2. Aryl radical reactions utilizing boronic acids and Mn(III) …………………..  61 Scheme 3.3. Conversion of aryl boronic acid into fluorobenzene using Selectfluor®……..  62 Scheme 3.4. Fluorination reaction with Selectfluor®……………………………………...   62 Scheme 3.5. Conversion of aryl boronic acid into fluorobenzene…………………………  63 Scheme 3.6. Proposed SET mechanism of fluorodeborylation…………………………….  66 Scheme 4.1. Studies performed in thesis work……………………………………………..  70 Scheme 4.2. Proposed synthesis of difluoromethyl ethers through fluorodecarboxylative fluorination……………………………………………………………………………….....  71 	   x	  List of abbreviations and symbols	   δ   chemical shift ° C  degree Celsius 18-crown-6 1,4,7,10,13,16-hexaoxacyclooctadecane 5-FU  5-fluorouracil Å  angstrom BHT  butylated hydroxytoluene CETP  cholesteryl ester transfer protein  CSD  Cambridge Structural Database  d  doublet DAST  (diethylamino)sulfur trifluoride DBH  1,3-dibromo-5,5-dimethylhydantoin DBU  1,8-diazabicyclo(5.4.0)undec-7-ene DDQ  2,3-dichloro-5,6-dicyano-1,4-benzoquinone Deoxofluor bis(2-methoxyethyl)aminosulfur trifluoride DFT  density functional theory DMF  N,N-dimethylformamide DTBP  di-tert-butyl peroxide  E  redox potential eq.   equation 	   xi	  equiv.  equivalents ESI  electrospray ionization Freon  chlorofluorocarbon  h  hour HRMS high resolution mass spectra hν  light IR  infrared J  coupling constant kcal  kilocalories m  multiplet Me  methyl min  minute MLCT metal-to-ligand charge transfer mmol  millimole mol  mole MOST 4-morpholinosulfur trifluoride NFSI  N-fluorobenzenesulfonimide NMO  N-methylmorpholine-N-oxide  NMR  nuclear magnetic resonance π  lipophilicity Increment PET  positron imaging tomography 	   xii	  ppm  parts per million q  quartet R  undefined portion of a molecule r.t.  room temperature s  second or singlet SET  single electron transfer t  tert t  triplet TAS+CF3O- tris(dimethylamino)sulfonium trifluoromethoxide TBAF  tetrabutylammonium fluoride THF  tetrahydrofuran  TLC  thin layer chromatography TMAF tetramethylammonium fluoride UV  ultraviolet X  undefined halogen       	   xiii	  Acknowledgements  I would like to express my gratitude to my supervisor, Professor Glenn Sammis, whose patience, experience, guidance and understanding helped me considerably throughout my graduate school. I deeply appreciate his commitment to chemical education and research. I would also like to thank all of my committee members for reading my thesis. Financial support was provided by Kazakhstani government through Bolashak International Scholarship, who founded 2 years of my graduate studies.   My graduate research was possible with the support from the staff in the Department of Chemistry. I wish to thank Marshall Lapawa at the mass spectroscopy lab, Maria Ezhova at the NMR lab, and Sheri Harbour. I also want to thank Dr.Jay Wickenden, Dr.Christine Rogers, Anne Thomas and Ben Herring for helping me with teaching assistant role.  I would specially like to thank past and present members of the Sammis research group: Dr. Montserrat Rueda-Becerril, Claire Chatalova Sazepin, Wei Zhang, Maxim Epifanov, Ben Boswell, Max Wurzenberger, Carolyn Amador, Paul Foth. I am grateful for the support and friendship of my group.  Thank you to my friends, my Vancouver family: Aigerim, Zhansulu, Aida, Zarina, Aigul, Aizhan, Nada, Huda, Alla, Yerzhan, Danil, Gaziz. Thanks for your friendship and helping me with your positive attitudes.  Finally, I wish to thank my mom Gulnur and my grandmother Raikhan. Thank you mom for your endless support throughout every step of my life, for teaching me patience and for letting me go overseas to find my own path. Grandmother, thanks for your protective concerns whenever I go and for your teaching me how to live honest live.        1 Chapter 1. Introduction    Fluorine containing organic molecules have become increasingly important in both the pharmaceutical industry and in positron imaging tomography (PET) technology over the past 60 years.1,2 Currently, more than 20% of all pharmaceuticals contain fluorine,3,4 including the top-selling Prozac (antidepressant fluotexine) (1)5, Lipitor (cholesterol lowering drug) (2) 6 and Ciprobay (antibacterial ciprofloxacin) (3) (Figure 1.1).7 The fluorine atom has unique characteristics, such as high electronegativity and a small size, which can provide many beneficial properties when incorporated into a molecule. Fluorine can enhance the pharmacological features of a compound, such as solubility, metabolic stability, liphophilicity and biological availability.1,8    Figure 1.1. Selected commercially available fluorine containing pharmaceuticals  A number of ionic methods have been developed over the last few decades to introduce fluorine, through the use of either nucleophilic or electrophilic fluorine sources. Radical fluorination using atomic sources of fluorine is a complementary approach; however, it has been limited due to the lack of selectivity and high reactivity of the known sources of atomic fluorine.  The Sammis group primarily focuses on the development of radical methods and is particularly interested in radical fluorination. In 2012, our group demonstrated that the electrophilic fluorine sources N-fluorobenzenesulfonimide (NFSI) and Selectfluor® can effectively fluorinate alkyl radicals.9 These radical-based synthetic methodologies could provide a simple yet synthetically useful approach to access fluorinated compounds.  NOFNHNONHFF FH ClNONHOH OHOO1/2 Ca2+OHOCl HProzac LipitorFCiprobay1 2 3 2 In this section, a brief account on the history of fluorine, traditional fluorinating reagents (nucleophilic and electrophilic), along with radical fluorine sources will be described. In addition, 18F tracers in Positron Emission Tomography (PET) will be briefly reviewed.   1.1 Fluorine incorporation in small molecules: a brief historic overview   The latin noun fluo means “flow or stream of water”. The name derives from the fluorine containing mineral fluorspar, used as a flux in iron smelting. In 17th century, it was discovered that the treatment of flluorspar with sulphuric acid formed a gas that etched glass.10 This acid was fluoric acid. In 1810, André-Marie Ampére proposed that fluoric acid contained hydrogen and an unknown element that was similar to chlorine.11 In 1886, French chemist Henri Moissan isolated fluorine (F2),12-14 for which he was awarded a Nobel Prize in Chemistry in 1906.15   The significant scientific foundations in fluorocarbon chemistry began in 1890 primarily by the Belgian chemist S. Swarts.11 Over 25 to 30 years, Swarts developed systematic methods to synthesize polyfluorinated compounds. One of his primary contributions to fluorine chemistry is the discovery of halogen exchange reaction, in which the chlorocarbon chlorines can be substituted for fluorines by hydrogen fluoride under catalysts. This fluorination reaction is named after Swarts, and the process is currently used in industrial fluorocarbon production.11 Further development of fluorine chemistry in the 20th century witnessed some significant discoveries: the discovery of freons with refrigerant properties in the 1930s,16 the discovery of polytetrafluoroethene with dielectric properties in 1938,17 and fluorinated non-flammable anesthetics in the 1950s.18  In late1940-1950s, the application of fluorine was limited to only military and special materials. The idea of incorporating fluorine into molecules of natural products was unconceivable until the discovery of fludrocortisones in 1953.19 Fludrocortisone (Figure 1.2, 4), the first fluorine-containing pharmaceutical, was found to possess a remarkable glucocorticoid activity. Subsequently, 5-fluorouracil (5-FU) (5) was demonstrated to have  3 tumor-inhibiting activity.20 These two drugs have fundamentally changed a view of fluorine in pharmaceutical-related research.   Figure 1.2. Structures of fludrocortisone and 5-fluorouracil   This breakthrough in medicinal chemistry demonstrated that the role of fluorine in the design and development of biologically active compounds would ever increase. The next section will describe some beneficial biological properties of molecules upon introduction of fluorine or fluorine containing moieties.   1.2 Medicinal benefits of fluorinated small molecules   Fluorine substituents have become widespread in modern medicinal chemistry. Fluorine incorporation into small molecules often leads to enhanced properties, such as biological availability, metabolic stability, binding affinity, lipophilicity, blood-brain-barrier penetrability and protein-ligand interactions.2 As the most electronegative element, fluorine can modify the pKa of nearby functional groups, such as amines.21 This is beneficial because protonation of these residues at physiological pH can hinder a pharmaceutical’s membrane permeability.21 Fluorination of arenes leads to increased lipophilicity compared to their nonfluorinated counterparts.22 The blood-brain barrier permeability and bioavailability of a drug can be increased upon incorporation of fluorinated moieties, such as CF3, OCF3 and SCF3.23 Another established effect of fluorine is the modulation of metabolic stability of a compound; replacing hydrogen with fluorine on aromatic rings significantly slows down the oxidative metabolic step of a drug by Cytochrome P450 monooxygenases.24 HOHOOH O OHHFHNNHOFOFludrocortisone 5-Fluorouracil4 5 4 Table 1.1. Properties of common elements and their bonds to carbon25  H F O N C Cl Br Van der Waals radius (Å) 1.20 1.47 1.52 1.55 1.70 1.75 1.85 Pauling electronegativity 2.1 4.0 3.5 3.0 2.5 3.2 2.8 Length of bond to carbon (Å) 1.09 1.40 1.43 1.47 1.54 1.77 1.97 Strength of bond to carbon (kcal mol-1) 98 105 84 70 83 77 66  Moreover, due to high electronegativity of fluorine (Table 1.1), the C-F bond is highly polarized. Hence, there are coulombic interactions between the carbon and fluorine atoms through the polarized covalent bond.26 This large bond polarization contributes to an attractive interaction of the C-F with hydrogen-bond donors,27,28 other fluorine-containing compounds,121 and polar functional groups (carbonyl groups).29 As a result of the fluorine’s pharmacological impact on efficacy and selectivity, the number of fluorinated pharmaceuticals and agrochemicals has been steadily increasing. Therefore, there is a high demand for the development of novel, more efficient, and safer fluorinating methodologies. The following section summarizes nucleophilic, electrophilic and radical methods to incorporate fluorine in small molecules.   1.3 Synthetic fluorination strategies  The isolation of fluorine gas (F2) by Henri Moissan12-14 and its subsequent taming have allowed the development of electrophilic fluorination. Consequently, safer and easier to handle electrophilic sources of fluorine were synthesized.30 There have been impressive advances in nucleophilic fluorination reactions. This section provides an overview of the traditional fluorinating methods followed by more recent radical-based approaches.       5 1.3.1 Nucleophilic fluorine methodologies  Fluoride is the smallest anion. Therefore, the high charge density of fluoride causes the unsolvated anion to be strongly basic. Fluorine can form strong hydrogen bonds,31 and solvation can significantly decrease its nucleophilicity by forming stable solvation shells. Alkali fluorides, such as LiF, NaF, KF and CsF, can be used as nucleophilic fluorination reagents (Table 1.2).32 Due to its high ionic strength, LiF is the least reactive fluorination reagent among the alkali metal fluorides; the increased ionic strength decreases the nucleophilicity and solubility of fluoride in organic solvents. A solution to this problem is the use of crown ethers, such as KF-18-crown-6, with alkali metal fluorides that can increase fluoride’s solubility and, thus, reactivity.33   The application of tetraalkylammonium ions as counterions for fluoride increases solubility in organic solvents and lessens the ionic bond strength.34 The most widely used fluoride quaternary ammonium salt is tetrabutylammonium fluoride (TBAF) (9). The nucleophilicity of fluoride in TBAF can be diminished by the presence of water as it can hydrogen bond with fluoride. Thus, the synthesis of anhydrous TBAF was developed.35 Tetramethylammonium fluoride (TMAF) (10) is also commonly used tetraalkylammonium fluoride derivative.36 Sulfur-based reagents can also serve as nucleophilic sources of fluoride. While SF4 is too toxic and volatile for facile synthetic handling, the safer analog, (diethylamino)sulfur trifluoride (DAST) (11), has found widespread use in organic synthesis.37 Even safer and more thermally stable derivatives have been synthesized, such as 4-morpholinosulfur trifluoride (MOST) (12) and bis(2-methoxyethyl)aminosulfur trifluoride (Deoxofluor) (13).38   Table 1.2. Selected nucleophilic fluorinating reagents Nucleophilic fluorinating reagents (F-) Alkali metal fluorides      NaF KF CsF6 7 8 6 Table 1.2 (cont.). Selected nucleophilic fluorinating reagents Tetraalkylammonium fluorides  DAST and its derivatives  DAST (diethylamino)sulfur trifluoride, Deoxofluor bis(2-methoxyethyl)aminosulfur trifluoride, MOST 4-morpholinosulfur trifluoride.   1.3.2 Electrophilic fluorine sources  Most early electrophilic fluorinating reactions utilized fluorine gas. Not only is molecular fluorine the strongest elemental oxidant, but it is also very dangerous to handle. While significant progress has been made on alternative reagents, such as, hypofluorites, fluoroxysulfates, perchloryl fluoride, and XeF2, these reagents are still powerful oxidants and limited the scope of substrates that could be synthesized.30 In the early 1990’s, the development of bench-stable, crystalline fluorinating reagents, such as N-fluorobis(phenyl)sulfonimide (NFSI) (Table 1.3, 18),39 N-fluoropyridinium salts (14, 15, 16),40,41 and 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (Selectfluor®, F-TEDA-BF4) (20)42 reinvigorated electrophilic fluorination development. These reagents can proceed through SN2-type displacement with nucleophilic attack at the fluorine atom.     NFTBAFNFTMAF9 10NSF3DASTNSF3MOSTONSF3DeoxofluorOMeMeO11 12 13 7 Table 1.3. Selected electrophilic fluorinating reagents Electrophilic fluorinating reagents (F+) N-Fluoropyridinium salts  N-Fluorosulfonamide and its derivatives  Selectfluor® and a derivative  F-TEDA-BF4, Selectfluor® 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate), NFSI N-fluorobis(phenyl)sulfonimide.      The reactivity of N-F fluorinating reagents can be adjusted by substitution patterns.30 Selectfluor® (Figure 1.3, 20) has the highest reduction potential (E = -0.04 V). Fluoropyridinium salts (22, 23) can have differing oxidation potentials depending on the substituent of the pyridine heterocycle, and the redox values suggest that the salts have less oxidizing characteristics than Selectfluor®. Among these N-F fluorinating reagents, NFSI (20) has the lowest value (E = -0.78 V).30  NF BF4NF BF4NF BF4Cl Cl14 15 16NFSS CF3O OF3CO ONFSS PhO OPhO ONFSIN FSOO17 18 19NN ClF2 BF4F-TEDA-BF4NNF2 TfO20 21 8  Figure 1.3. Comparison of the redox potential of crystalline, bench-top stable fluorinating reagents30  1.3.3 Radical-based fluorination methodologies   Radical fluorination strategies represent a complementary approach to traditional ionic methodologies (Figure 1.4). This section gives a brief summary of the radical fluorine (F•) sources: molecular fluorine,43 trifluoromethyl hypofluorite,10 XeF244 along with recently discovered NFSI and Selectfluor®.9       Scheme 1.1. Ionic and radical fluorine incorporation9  The earliest known source of atomic fluorine is molecular fluorine (F2).10 Due to the high heats of formation of C-F and H-F bonds (108.91 kcal mol-1,45 and 133.75 kcal mol-1 respectively),46 F2 reacts with hydrocarbons exothermically. Hydrocarbons can be directly fluorinated using F2 in a non selective fashion, and the typical products correspond to compounds where the carbon backbones are saturated with fluorine atoms, which in most cases, proceed through a radical mechanism.47-49 However, F2 has extreme reactivity and possesses dangers associated with its use that has limited its synthetic utility.4,50 Trifluoromethyl hypofluorite (Figure 1.4, 24) is a toxic gas, and it is a slightly safer alternative to fluorine gas.10 Trifluoromethyl hypofluorite is synthesized by treatment of OTf OTfN-fluoropyridinium salts -0.73                     -0.47 VN-fluorobenzenesulfonimide                 -0.78 Vincreasing reduction potentialNFSS PhO OPhO O18NFNF22 23NN ClF2 BF4F-TEDA-BF4     -0.04 V20[R-][R+]R-F "F " source [R ]"F+" source"F-" sourcenucleophileelectrophile alkyl radical 9 elemental fluorine with methanol or carbon monoxide in the presence of a silver difluoride catalyst.51 The reactivity of trifluoromethyl hypofluorite is a result of the weak O-F bond (DO-F = 44.8 ± 0.8 kcal mol-1),52 and both electrophilic and radical reactions have been reported.53,54 Trifluoromethyl hypofluorite can act as an electrophilic fluorine source under reaction conditions similar to those which promote an electrophilic mode of reactivity for F2.53,54 Alternatively, trifluoromethyl hypofluorite can be used as a source of atomic fluorine under reaction conditions that favor the generation of radicals, such as photochemical processes and gas phase reactions.55    Figure 1.4. Trifluoromethylhypofluorite52   Another common F• source is xenon difluoride (XeF2) (Figure 1.5). XeF2 is commercially-available, and has been thoroughly investigated.44 It is a dense, crystalline solid stable in air at room temperature and significantly more stable than molecular fluorine.44 XeF2 is prepared via the reaction of F2 with xenon gas under ultraviolet irradiation.56 The ease of synthesis is exemplified by the procedure of exposing a pyrex glass bulb containing 1:1 mixture of the two gases to sunlight,57 upon which condensation of solid XeF2 to the glass walls is observed.57    Figure 1.5. Xenon fluorides  As radical and electrophilic source of fluorine, XeF2 reacts with alkenes to produce vicinal and geminal alkyl fluorides.58 Later, it was observed that reactions proceeded faster when the alkene had a lower ionization potential, which suggested an SET process is involved in the mechanism.59 It was also reported that XeF2 can selectively fluorinate C OFF FF24F Xe FXenon difluorideXe FXenon fluoride       cationF Xe FXenon difluoride  radical anionXe FXenon fluoride      radical25 26 27 28 10 enolates.60 In a similar fashion, a number of investigations were conducted to assess the reactivity of xenon difluoride. Patrick and coworkers reported the reaction of carboxylic acids with XeF2 (Scheme 1.1).61,62 Analogous to silver-mediated Hunsdiecker’s reactions,63 the treatment of a carboxylic acid with XeF2 and a catalytic amount of hydrofluoric acid in dichloromethane afforded the corresponding fluoroalkanes in 54 – 84% yield. The primary, tertiary, α-aryloxy and benzylic alkyl fluorides underwent decarboxylative fluorination. Double fluorodecarboxylation was also performed to give difluoroalkene in good yields.     Scheme 1.2. Fluorodecarboxylation reactions61,63  The fluorodecarboxylation reaction can proceed through both ionic and radical pathways (Scheme 1.2).44 The reaction of a carboxylic acid with XeF2 generates a mixed fluoroxenon ester (33), which can either proceed further in ionic or radical pathways to generate the corresponding fluorinated compound 34. The first possible route is ionic, in which fluoroxenon ester (33) is attacked by a fluoride to produce the corresponding fluoroalkene, CO2, xenon gas and fluoride anion (eq. 1.1). The second feasible pathway is Hunsdiecker-like radical decarboxylation (eq. 1.2), in which fluoroxenon ester (33) undergoes radical decarboxylation. The formed alkyl radical (36) then can either react with radical fluorine or can undergo single electron-transfer step to generate a carbocation (37) that forms fluoroalkene (34) upon reaction with a fluoride anion.   R OOAgX2CCl4XRX = Br, ClHunsdiecker reactionR OHOXeF2, HFCH2Cl2FRPatrick's fluorodecarboxylation reaction29 3031 32 11  Scheme 1.3. Two distinct mechanisms for the formation of fluoroalkenes44    The existing sources of radical fluorine are all strong oxidants, and, thus, limit the possibilities of radical methodologies to access fluorinated compounds. Therefore, the development of safer atomic fluorine sources was necessary. Recently, our group has demonstrated a novel, safe radical approach to form C-F bonds via decomposition of peresters and diacylperoxides.9,64 DFT calculations showed that the N-F bond strength of electrophilic N-F fluorinating reagents, such as NFSI, Selectfluor®, N-fluoropyridinium salts, was on the order of 60 kcal mol-1, which is sufficiently low to allow radical atom transfer reactions. The methodology was successfully applied to fluorinate a broad range of alkyl radicals, including primary, secondary, tertiary, benzylic and heteroatom-stabilized radicals. This method, which utilizes NFSI and Selectfluor® as fluorine transfer reagents, represents a novel and safer approach for synthetic radical fluorination.  In the past decade, numerous new transformations have been developed that utilize either NFSI or Selectfluor® as radical transfer reagents65 for fluorination reactions. With these selective radical fluorination methodologies available, the field has experienced a renaissance as a new method for fluorine incorporation. Hence, radical fluorination processes represent a practical and efficient way to construct C-F bonds.     Fluorinated molecules have become important not only in pharmaceuticals and agrochemicals, but also in imaging technologies. The next section will briefly summarize the application of 18F-fluorinated molecules in Positron Emission Tomography (PET), including a general overview of PET imaging and key 18F tracers.     R OHOXeF2 R OOFXe F HF R-F CO2 Xe0 F- (1.1)R OOXe F R OOXe0 F R CO2XeF2 RF-R-FFXe  or F(1.2)3333343435 36 37 12 1.4 Positron Emission Tomography imaging   Positron Emission Tomography (PET) is an in vivo molecular imaging processes through the detection of positron decay of radioactively tagged molecules called radiotracers.1,66,67 PET imaging has been progressively employed as an important clinical diagnostic and research tool in drug development, neurology, oncology, and cardiology.67,68 A small amount of radioactive material (tracer) is injected through a vein, and it generates images of the body by detecting pairs of gamma rays emitted from radioactive substances. Radiotracers are biologically active molecules tagged with radioactive isotopes, such as carbon-11, fluorine-18, oxygen-15, or nitrogen-13, and they are used as radioactive substances.1    Fluorine-18 labeled radiotracers have been one of the primary reagents in PET imaging for several reasons: it has a convenient half-life time of 110 minutes,67 it is prevalent in organic molecules and drugs,2 it has a high isotopic purity, and very low positron emission energy is required to achieve very high resolution.69 Currently, among the most significant 18F PET radiotracers are tumor tracers  [18F]fluorothymidine ([18F]FLT) (38),70 dopamine receptor tracers [18F]fallylpride (39),71 [18F]haloperidol (40),72 [18F]spiperone (42),73 hypoxia tissue tracers [18F]fluoroazomycinarabinofuranoside ([18F]FAZA) (43)74 and [18F]Fluoromisonidazole ([18F]FMISO) (41) (Figure 1.6).75   Figure 1.6. Selected key 18F tracers76 NNHOOO18FHOOCH3OCH318F NHON[18F]fallylpride[18F]FLTClHO O18F[18F]haloperidolNNHONO18F[18F]spiperoneN18FOHNO2N[18F]FMISONOOH18F OHNNO2[18F]FAZA38 39 4041 42 43 13 The application of 18F-fluoride ion in PET imaging is still a major challenge, as most peptides and other biomolecules are soluble in water or mixed aqueous solvents while anionic 18F-fluoride is generally unreactive due to its high solvation energy.69 Furthermore, due to the short half-life, the introduction of fluorine-18 into molecules should occur at the last step or at the latest stage of the radiotracer synthesis. The ideal time used to prepare, purify and formulate radiotracers for injection has to be less than two half-life cycles. Therefore, a 103- or 104-fold excess of the unlabeled precursor is employed in order to obtain picomolar amounts of radiotracers. The general synthesis of fluorine-18 proceeds via bombardment of oxygen-18-labelled water with protons to give wet 18F-fluoride in high specific activity (18F/19F is > 100:1). Due to strong hydrogen bonding interaction of the fluoride with water,31 the process of desolvation of wet 18F-fluoride is difficult, preventing the application of anhydrous 18F-fluoride for PET chemistry. The theoretical maximum yield with high specific activity fluorine-18 is 100%. In addition, 18F-fluoride can be diluted with 19F-fluorine gas to give an 18F-enriched electrophilic fluorinating reagent, but it would afford low specific activity reagent due 18F dilution with 19F. Reactions with high specific activity 18F are hence more favored.                   14 Chapter 2. Introduction to trifluoromethoxylation  Trifluoromethoxy moieties (OCF3) are of current interest in pharmaceuticals and agrochemicals due to their unique electronic and structural features, which induce useful physiochemical properties in organic molecules (Figure 2.1).77 The incorporation of an OCF3 group into organic molecules can lead to increased lipophilicity and conformational changes of the compounds. For instance, the highly lipophilic OCF3 group affects in vivo uptake and transport of the drug in biological systems. Additionally, trifluoromethoxy substituents adopt an orthogonal orientation with regard to the arene plane that leads to conformational changes that can be beneficial for obtaining additional binding affinity.78    Figure 2.1. Selected OCF3-containing a) pharmaceuticals, and b) agrochemicals77  The chapter presents a novel, radical trifluoromethoxylation strategy that has been discovered in our group along with substrate scope studies. This chapter begins with an overview of the properties and structural characteristics of the trifluoromethoxy group. The known synthetic trifluoromethoxylation methodologies that have been developed previously will then be discussed followed by a discussion of the new trifluoromethoxylation methodology that has been developed in our laboratory.   NOOF3COHOCelikalimF3COHN NNN NMeNH2ONN MeNMS-P937NS OCF3H2NRiluzoleBrOCF3BrHNONSCF3MeThifluzamideOCF3SONONONNOCH3ONaMeFlucarbazone-sodiuma)b)44 45 4647 48 15 2.1 Properties and structure of trifluoromethoxy moieties  What makes the incorporation of OCF3 moiety into biologically active molecules particularly interesting is its unique electron distribution. As outlined in Figure 2.2, the geminal combination of an alkoxy or aryloxy groups with a fluorine atom results in bonding and non-bonding resonance, which can be characterized by superposition of a covalent and an ionic limiting structure (Figure 2.2).77      Figure 2.2. Mesomeric structures of the OCF3-group77  Anomeric effects can also be introduced into molecules upon trifluoromethoxylation, which is expressed as lengthening of the acceptor C-F bonds and the shortening of the C-O donor bonds.77 Several molecules have been studied to observe this trend, such as tris(dimethylamino)sulfonium trifluoromethoxide (TAS+CF3O-) (49), 1,1-difluorinated 2,3,4,6-tetra-O-acetyl-1-deoxy-D-glucopyranose (50), and 2,2,3,3-tetrafluoro-2,3-dihydro-1,4-benzodioxine (51) (Figure 2.3).   Figure 2.3. Molecular structures of 49, 50 and 51  X-ray analysis of the TAS+CF3O- (49) molecule’s structure led to the following observations:79 the three C-F bonds are elongated by almost 0.07 Å, whereas the C-O bond is shortened by 0.09 Å compared to trifluoromethanol80 and by approximately 0.21 Å with regard to methanol. The C-F bond lengths (1.390 and 1.397 Å) are extraordinarily long and the C-O bond length (1.227 Å) is reasonably short (Figure 2.4).79   RO C FFFRO CFFFN SNNOCF3OFFOAcAcOAcOOAcOOF FFF12345649 50 51 16  Bond distances in Å. Figure 2.4. Structure of tris(dimethylamino)sulfonium (TAS) trifluoromethoxide79,80  Similarly, 13C NMR spectroscopy reveals differences through coupling constants that may be taken as a first evidence for anomeric effects in the 1,1-difluorinated 2,3,4,6-tetra-O-acetyl-1-deoxy-D-glucopyranose (Table 2.1, 50). 1JF,C, 2JF,C and 3JF,C coupling constants increase due to the increasing electronegativity of the axial halogen at the anomeric carbon, while 3JF,H decreases, hence it shows that the molecule has non-identical C-F bond lengths in pyranose derivative.81      Table 2.1. Coupling constants data from 1H and 13C NMR spectroscopies  H-1    H-2     H-3      H-4     H-5    H-6    H-6’ J1,2      J2,3       J3,4       J4,5       J5,6      J5,6’     J6,6’ C-1     C-2       C-3      C-4     C-5    C-6    C-O 1JF,C     2JF,C       3JF,C                  3JF,C     -       -           9 2        9.2        -       4 3      13.3 -256.0   30.6     9.4                  2.8               -271.7   30.6                            4.0                 Likewise, the structure of 2,2,3,3-tetrafluoro-2,3-dihydro-1,4-benzodioxine (51) (Figure 2.5)82 shows a similar trend. This benzodioxine derivative has a half-chair conformation with different C-F bond lengths: the lengths of quasi-axial and quasi-equatorial fluorine atoms are 1.355 Å and 1.330 Å, respectively.    N SNN OFFF1.2271.3901.39749OFFOAcAcOAcOOAc 12345650 17  Bond distances in Å. Figure 2.5. Structure of 51 82  The effect of replacing a methyl group by a trifluoromethyl moiety on bond length is dependent upon the electronegativity of the atom to which the substituent is attached.77 As outlined in Table 2.2, the shortening of the donor bond and lengthening of the acceptor bond are small when a methyl was replaced by an trifluoromethyl group; O-CH3 has 1.416 Å and O-CF3 has 1.369 Å lengths (Table 2.2).   Table 2.2. Effect of a substituting a CF3 group for methyl on different heteroatoms77 C-Y bond length in Å Atom/group Y-CX3 (X = H, F) X = H X = F P-(CX3) 1.844 1.904 H-(CX3) 1.099 1.102 I-(CX3) 2.139 2.138 S-(CX3) 1.805 1.819 Se-(CX3) 1.945 1.980 Br-(CX3) 1.939 1.923 Cl-(CX3) 1.781 1.752 N-(CX3) 1.458 1.426 O-(CX3) 1.416 1.369 F-(CX3) 1.385 1.319  Replacing a methyl group by a trifluoromethoxy moiety in aryl rings can also lead to conformation changes.78 For instance, investigations of anisole and trifluoromethoxybenzene structures show that their substituents orient themselves differently; simple anisoles derivatives adopt a planar conformation, while trifluoromethoxylated arenes have the OCF3 moiety orthogonal to the plane.78 As a consequence, lone-pair electrons on oxygen can only weakly delocalize into the ring, which renders OCF3 to be an electron-withdrawing group (Figure 2.6).78  OOFFFF1.3551.33051 18  Figure 2.6. Conformational preference of the trifluoromethoxy group on aryl rings78  These conformational changes in trifluoromethoxylated molecules can have significant consequences in biologically active molecules. Since aryl rings adopt different conformation upon trifluoromethoxylation, the OCF3 is not only a simple an isostere of an OCH3 group, but can also lead to stabilization of bioactive molecules.83 Massa and coworkers studied inhibitors of cholesteryl ester transfer protein (CETP) bearing 3-tetrafluoroethoxy substituents.83 It was found that the steric and electronic properties of Ph-OCF2CF2H are analogous to 2-phenyl-furan, which has a nonplanar structure. This finding is interesting for medicinal chemistry as mono-substituted furans are generally viewed to be undesirable groups due to their metabolic instability and potential to generate reactive metabolites.83  The trifluoromethoxy group has electronic properties similar to chlorine or fluorine atom,84 but it is more electron withdrawing and lipophilic than the methoxy analogue (Table 2.3).77 Both trifluoromethyl and trifluoromethoxy substituents invariably increase lipophilicity, whereas the incorporation of single fluorine atom may alter this trend in either direction. The OCF3 moiety is more lipophilic (π = +1.04) than most other halogens,77 and lies between a CF3 (π = +0.88) and  a SCF3 (π = +1.44) groups.   Table 2.3. Lipophilicity Increment π as assessed for mono-substituted benzenes H5C6-X85 Substituent Pauling electronegativity π85 H 2.1 0.00 F 4.0 0.14 Cl 3.0 0.71 I 2.5 1.12  ORβR = CH3   β = 18 0R = CF3    β = 90 0O R 19 Table 2.3 (cont.). Lipophilicity Increment π as assessed for mono-substituted benzenes H5C6-X85 Br 2.8 0.86 CH3 2.3 0.56 CF3 3.5 0.88 OCH3 2.7 -0.02 OCF3 3.7 1.04 SCF3 - 1.44 SF5 - 1.23  Despite the biologically useful properties of trifluoromethoxy groups, their introduction into organic molecules remains a synthetic challenge. Most methodologies for the synthesis of trifluoromethoxyarenes have low functional tolerance due to the use of harsh reaction conditions, Lewis acids, or thermally unstable and reactive trifluoromethoxylating reagents.30 Considering this fact, we initiated a project to develop a novel and easy-to-perform strategy to access trifluoromethoxyarenes. The next section outlines a brief survey of known synthetic strategies to access trifluoromethoxylated molecules.     2.2 Traditional methods for the synthesis of aryl trifluoromethyl ethers  Trifluoromethoxylation has been accomplished by using three general strategies: nucleophilic displacement with fluoride (F-), electrophilic trifluoromethylation with trifluoromethyl cation (CF3+) and nucleophilic substitution and cross coupling with trifluoromethoxides (-OCF3) sources (Scheme 2.1). Each of these approaches will be described in more detail below.        Scheme 2.1. Traditional approaches to access trifluoromethoxy arenes  A) Nucleophilic fluorination of activated anisole derivatives. The first synthesis of aryl trifluoromethylethers was reported in 1955 by Yagupol’skii from substituted anisole FOF FAr"F-" source"CF3+" source"-OCF3" sourceAr O CX3Ar XAr OH 20 derivatives using two different fluorine sources in the presence of antimony pentachloride (SbCl5): anhydrous HF and antimony trifluoride (SbF3) (Scheme 2.2).86 This method required trichloromethoxybenzene derivatives (53) as precursor substrates; they were synthesized in 50-83% yield via the treatment of methoxybenzene derivatives (52) with PCl5 and dry Cl2. The trichloromethoxybenzenes were then treated with SbF3 and SbCl5 in a vigorous reaction. The reaction mixture was refluxed briefly, and distilled to produce phenyl trifluoromethyl ethers (54) in 20-80% yields.     Scheme 2.2. Synthesis of trifluoromethyl aryl ethers86  Similar to the Yagupol’skii’s protocol, Yarovenko and Vasil’eva reported the synthesis of trifluoromethoxylated arenes from trichloromethyl ethers as precursors (Scheme 2.3).87 Trichloromethoxybenzenes (57) were synthesized from easily formed, albeit highly toxic, aryl chlorothionoformates (56), which were prepared from phenols (55). These trichloromethyl ethers afforded trifluoromethoxy benzenes (58) in 71% yield, in a reaction with SbF3 and a catalytic amount of SbCl5. Unfortunately, this approach has limited applicability to industry due to the high toxicity of aryl chlorothionoformates.   Scheme 2.3. Synthesis of trifluoromethyl aryl ethers87  Feiring disclosed a simplified adaptation of nucleophilic fluorination in which the chlorination and fluorination sequence was carried out in one step (Scheme 2.4).88 Phenol derivatives (59) reacted with excess CCl4 and HF conditions. The reaction first produced OCH3RPCl5, Cl2190-200 ˚C, 6hOCCl3RHF orSbF3 + SbCl5OCF3R52 53 54OHCl ClSNaOHOSClCl2OCCl3SbF3 + SbCl5OCF355 56 57 58 21 trichoromethyl ethers in situ, which were subsequently converted into trifluoromethoxyarenes (60).  The reactions afforded a number of products bearing different substituents in 17-70%, and electron-withdrawing group substituted substrates, such as nitro, chloro or trifluoromethyl, afforded better yields. However, phenols with ortho substitution can hydrogen bond to the OH group (e.g., -OH, -NH2, or –NO2), and, hence, failed to give trifluoromethoxy ethers. Furthermore, stoichiometric amounts of CCl4 could lower the yield, and milder reaction conditions mainly afforded chlorodifluoromethoxylated products.   Scheme 2.4. Synthesis of trifluoromethyl aryl ethers via an in situ chlorination/fluorination sequence88  The nucleophilic fluorination of aryl trichloromethyl ethers and aryl chlorothionoformates are among the most frequently used strategies for the synthesis of trifluoromethoxyarenes. However, a general, practical and functional group tolerant trifluoromethoxylation is not yet available.30   B) Deoxyfluorination of fluoroformates. In 1964, Sheppard demonstrated a synthesis of aryl trifluoromethylethers using sulfur tertrafluoride (SF4).89 Aryl fluoroformates (62) reacted with SF4 and catalytic amount of HF; and purification of the product by means of distillation and a removal of HF with either sodium fluoride or a base wash, afforded the corresponding trifluoromethoxyarenes (63) in 50-80% yield (Scheme 2.5).89   Scheme 2.5. Synthesis of trifluoromethyl ethers via fluoroformates89   OHRCCl4HF/BF3150 ˚COCF3RHCl59 60OHRCOF2ORFOSF4/HF160 ˚COCF3RSOF261 62 63 22 C) Oxidative fluorodesulfurization-fluorination. A novel oxidative trfiluoromethoxylation method, discovered by Hiyama and coworkers, can be performed under milder reaction conditions compared to the previously developed strategies (Scheme 2.6).90 Aryl xanthates (64) reacted with excess HF-pyridine and 1,3-dibromo-5,5-dimethylhydantoin (DBH) (65), and the desired product was purified by means of chromatography or distillation. Both O-alkyl and O-aryl trifluoromethyl ethers were synthesized in 50-80% yield. Likewise, alkylated aromatics were formed in 50-58% yield and brominated aromatic rings were provided in 62% yield.90   Scheme 2.6. Synthesis of trifluoromethyl aryl ethers via fluorodesulfurization of aryl xanthates90  D) Electrophilic trifluoromethylation. Trifluoromethoxylations can also be accomplished using electrophilic trifluoromethoxylating reagents, such as 2-tert-butyl-o-(trifluoromethyl)dibenzofuranium hexafluoroantimonate and Togni reagents (Figure 2.7).30    Figure 2.7. Electrophilic trifluoromethylation reagents30  Umemoto and coworkers reported that simple phenol derivatives undergo trifluoromethoxylation with O-(trifluoromethyl)-dibenzofuranium salts in the presence of amine bases to give trifluoromethoxy ethers (Scheme 2.7).91 The reagent has to be generated prior to use by photochemical decomposition of the trifluoromethoxybiaryl diazonium salt at - 100 to - 90 °C to afford the active 2-tert-butyl-O-(trifluoromethyl)dibenzofuranium NNOOBrMeMe9 equiv (HF)9    pyridineCH2Cl2, 1h, 0 ˚ C50-80%Br64 65 66OROCF3RSSIOOF3CI OF3COt-BuCF3 SbF6Togni reagentsO-(trifluoromethyl)-dibenzofuranium salt67 68 69 23 hexafluoroantimonate (67). Phenols (70) were smoothly trifluoromethylated, and di(isopropyl)ethylamine was employed as an acid (HSbF6) trap. Similarly, trifluoromethoxyarenes bearing different substituents (71), such as bromo, alkyl, cyano and acetyl groups, were obtained in 74-85% yield.91    Scheme 2.7. Synthesis of trifluoromethyl ethers through O-(trifluoromethyl)dibenzofuranium reagent91  Although this methodology of trifluoromethoxylation with O-(trifluoromethyl)-dibenzofuranium salt showed the possibility of generating CF3+ species, there are some disadvantages of this methodology. The drawbacks of Umemoto’s trifluoromethoxylation with O-(trifluoromethyl)-dibenzofuranium reagent are in situ preparation of the trifluoromethoxyarenes at - 90 °C and the lack of recyclability.  Togni and coworkers reported a synthetic methodology to prepare hypervalent iodine trifluoromethylating agents, such as 1-trifluoromethyl-3,3-dimethyl-1,2-benziodoxole (Togni reagent, 68) and 1-trifluoromethyl-1,2-benziodoxol-3(1H)-one (Togni reagent II, 69) (Figure 2.7).92-95 These hypervalent trifluoromethyliodine derivatives are easy to handle and are stable in a freezer for several years. Moreover, the possible recyclability of these reagents makes them desirable for industrial applications. Togni and coworkers investigated O-trifluoromethylation of 2,4,6-trimethylphenol using Togni reagent II in the presence of 18-crown-6. The reaction afforded 1,3,5-trimethyl-2-(trifluoromethoxy)benzene (73) only in 15% yield along with other trifluoromethylation products (74, 75, 76, 77). 92  Ot-BuCF3 SbF6iPr2NEt     3h, -90 to -100 ˚C74-85%OCF3ROHR6770 71 24  Scheme 2.8. Synthesis of trifluoromethyl ethers through Togni reagent92  E) Nucleophilic trifluoromethoxylation. Kolomeitsev and coworkers reported the formation of a C(phenyl)-OCF3 and C(napthyl)-OCF3 bond when trifluoromethoxides were added to benzynes (Scheme 2.9 and 2.10).96 One of the successful substrates was o-trimethylsilylphenyl triflate (78), which upon reaction with trifluoromethanolate derivative afforded trifluoromethoxybenzene and fluorobenzene in 85:15 ratio. The mechanism begins with generation of benzyne (79) in situ. Subsequent treatment with a source of CF3O- led to a mixture of (trifluoromethoxy)benzene (80) and fluorobenzene (81) (85:15) in 72% yield (Scheme 2.9).96     Scheme 2.9. Synthesis of trifluoromethoxybenzene96   Another substrate, 1-trimethylsilylnapthyl 2-trifluoromethanesulfonate (82) was treated with CF3O- anion (83). Under the similar reaction conditions, the reaction afforded an 86:14 mixture of 2- and 1-(trifluoromethoxy)-naphthalenes (84 and 85) in 63% yield.96  ONa IOOF3C18-crown-6, 60 ˚COCF315%SOOOCF310%OCF32%OF3CCF35%IOOCF32%72 6973 74 7576 77OTfSiMe3 F--Me3SiF,   -TfO- CH3CN/ether (1:1)0 to 20 ˚CNNNMe2CF3O- OCF3F72% (85 : 15)78 79 80 81 25  Scheme 2.10. Synthesis of trifluoromethyl ethers via aryne intermediate96  F) Cross-coupling method of aryl stannanes with arylboronic acids. The first transition-metal-mediated cross-coupling method was disclosed by Ritter and coworkers in 2011 (Scheme 2.11).97 Treatment of aryl stannanes (86) with a stabilized trifluoromethoxide (94) and Selectfluor® in the presence of silver(I) hexafluorophosphate (AgPF6) afforded the corresponding aryl trifluoromethyl ethers (87) in 59-88% yield (Scheme 00).97 Several functional groups, such as alcohols, halogens, esters, ethers, alkenes, ketones and electron-rich, electron-poor, and ortho-substituted arenes can be tolerated.        Scheme 2.11. Ag-mediated trifluoromethoxylation of aryl stannanes97  Likewise, aryl trifluoromethyl ethers (97) can be accessed from arylboronic acids (95) in a two-step, one-pot procedure (Scheme 2.12).97 The reaction of arylboronic acids with sodium hydroxide and subsequent AgPF6 addition generated the corresponding aryl silver complexes (96). Subsequently, these complexes were transformed into aryl trifluoromethyl ethers in 63-76% yield upon addition of trifluoromethoxide and Selectfluor®.  SiMe3OTf NN NOCF31. 24h at -10 ˚C2. 4h at 20 ˚CMeCN/Et2O (1:1)OCF3OCF363% (β/α = 86/14 )82 83 84 85RSnBu3 2.0 equiv. TAS    OCF31.2 equiv. F-TEDA-PF62.0 equiv. AgPF6, 2.0 equiv. NaHCO3,THF/acetone (1:3), 2-4 h, -30 ˚CROCF3SNMe2NMe2Me2NOCF3OCF3PhOCF3BocN88% 72%MeO2CNHBoc75%OCF3OMeHHF3CO72%F3CONHONHBocCO2MePh67%OHONHOMeOHF3CO59%TAS   OCF386 8788 89 9091 92 9394 26  Scheme 2.12. Ag-mediated trifluoromethoxylation of arylboronic acids97   However, neither of Ag-mediated trifluoromethoxylation methods can tolerate basic functional groups, such as amines and pyridines. In addition, the two-step process from arylboronic acids and the use of toxic arylstannanes limits the application of this strategy.  G) Trifluoromethoxy group migration from anilines. Ngai and coworkers reported a two-step sequence synthesis of ortho-trifluoromethoxylated aniline derivatives (106) from N-aryl-N-(trifluoromethoxy)arenes (105).98 The key two steps are O-trifluoromethylation of N-aryl-N-hydroxylamine derivatives (104), followed by intramolecular OCF3 group migration (Scheme 2.13).98    Scheme 2.13. Aryl trifluoromethoxylation by OCF3 group migration98 RB(OH)2Ag-mediatedone-pot synthesis1.0 equiv. NaOHMeOH, 23 ˚C, 15 min2.0 equiv. AgPF60 ˚ C, 30 minRAgI   AgI2.0 equiv. TAS  OCF31.2 equiv. F-TEDA-PF6 2.0 equiv. NaHCO3THF/acetone (1:3)-30 ˚C, 2-4 hROCF3OCF3Ph72%OCF3MeO63%OCF3BocN76%OCF364%OCF3MeO2CMe65%OCF3F67%95969798 99 100 101102 103NHR1OHR CF3NHR1OCF3RNHOCF3R1Rheat104 105 106 27 In the first step, treatment of the N-hydroxylamine derivatives with Togni reagent II and catalytic amount of Cs2CO3, N-aryl-N-hydroxamic acids produced protected N-aryl-N-(trifluoromethoxy)amines (105) in 39%-96% yield. Next, protected trifluoromethoxyamines were treated with nitromethane (MeNO2) at 80 °C, leading to OCF3 group migration (Scheme 2.14).98 The reaction conditions tolerated a number of structurally and electronically diverse aromatics. Both electron-withdrawing and electron-donating groups can undergo trifluoromethoxylation under these reaction conditions, and product yields ranged from 59% to 91%.    Scheme 2.14. Selected examples of the OCF3-migration reaction98  As outlined in Scheme 2.15, the proposed mechanism of this trifluoromethoxylation method involves ionic intermediates. The heterolytic cleavage of the N-O bond of 105 produces an ion pair, nitrenium ion and trifluoromethoxide (A), which then recombines to NHOCF3R1RMeNO2 (1.0 M)80 0CNHR1OCF3RNH MeOOCF3NH MeOOCF3NH MeOOCF3NH MeOOCF3NH MeOOCF3NH MeOOCF3X X = H                91%       CN              63%      C(O)Me      90%      C(O)NMe2  71%X = F         88%       Cl        85%      Br        90%      I           71%F87%Br87%OMeF3C70%CF380%OMeO81%NH MeOOCF375%ClF3C105 106107-110 111-114115 116 117118 119 120 28 produce an intermediate B. A subsequent tautomerization of intermediate B afforded product 106. To test the proposed mechanism, reactions were performed in the presence and absence of BHT. As the yield for both reactions was similar, the formation of long-lived radicals is unlikely under this reaction conditions, indicating that ionic intermediates are viable. A carbocation intermediate trapping experiment was also conducted using 121, affording benzoxazole 123 via nitrenium ion C. This methodology is analogous to Kikugawa’s protocol of AlCl3-mediated intramolecular migration of OCH3 group in N-methoxy-N-phenylamides, that also proceeded through ionic intermediates.145 Kikugawa proposed a mechanism that is based on ion-pair formation through heterolytic cleavage of the N-O bond (Scheme 2.15).98, 99     Scheme 2.15. Evidence for the proposed reaction mechanism98,99  H) Addition of trifluoromethoxyl radicals to alkenes and arenes. In DesMarteau and coworkers seminal studies on radical trifluoromethoxylation, they demonstrated addition of simple, electron-deficient olefins and CF3OF.100 The reaction is thought to proceed via a free-radical mechanism yielding products with low stereo- and regioselectivity (Scheme 2.16).100 a) Proposed reaction mechanim: OCF3 migration by ion-pair formationNHR1OCF3RNHR1OCF3RNHR1RF3CONHOCF3R1Rb) OCF3 migration in the presence of a radical trapNH OCF3MeO MeNO2 (1.0 M)80 ˚C, 19h NHOCF3MeO     with BHT: 80%without BHT: 81%c) Benzoxazole formation through carbocation intermediate trappingNH OCF3PhOMeNO2 (1.0 M)120 ˚C, 20h NHOCF3PhOMeO2C MeO2C MeO2CNOPh79% yield 4% yieldN PhOMeO2Cpath aNHR1OCH3Rd) Kikugawa's work: Aluminum-promoted OCH3 migration by ion-pair formationAlCl3NHR1OCH3RNHR1RH3CONHOCH3R1RCl3Al105 A B 106105a 106a121 122 123 C 29  Scheme 2.16. Trifluoromethoxylation of olefins with CF3OF100  To support a radical mechanism, they conducted kinetic studies of the addition of CF3OF (134) to olefins.101 Using low temperature (from - 78 °C to - 105 °C), rate constants of the initiation, chain-propagation, and termination steps were determined. In the first step, homolytic cleavage of the O-F bond in the CF3OF molecule generated a CF3O• radical (136). Next, the CF3O• (136) radical attacks electron-poor olefins (133) in free radical chain-propagation steps (Scheme 2.17).101    Scheme 2.17. Initiation, propagation and termination steps of the radical chain mechanism.101  The trifluoromethoxylation of simple electron rich and electron poor aromatics, such as α,α,α-trifluoro-toluene, toluene, benzene, chloro-benzene, methoxybenzene, with CF3OF (134) was also studied in order to gain further understanding of the mechanism (Scheme F3CFC CF2CF3OFno solvent F3CF2C CF2OCF3 (CF3)2CFOCF32:1 (33% yield)ClH2CHC CH2CF3OFFreon 11 + 12CH2ClCHFCH2OCF3 CH2ClCH(OCF3)CH2F5:1 (50% yield)FHC CF2CF3OF CF3OCHFCF3 CF3OCF2CF2H2:1 (75% yield)124 125 126127 128 129130 131 132CF3OFk1FCF3O (1) initiationCF3Ok2OCF3(2) propagationCF3OFk3 CF3O (3) propagationOCF3 F3CO FR R k4 R R (4) termination133 134 135 136136 133 137137 134 138 136 30 2.18).102 The two selectivity pathways are possible at low temperature and in apolar solvent: one radical or electrophilic addition mechanisms.102 The reaction conditions were forced to follow preferentially one of the two possible pathways; addition of an electron-poor alkene, trifluoromethyl-trifluorovinyl-ether (139), increased the radical contribution. The olefin-induced radical mechanism increases the production of trifluoromethoxy radicals and hence the corresponding trifluoromethoxyarenes (145).    Scheme 2.18. Radical mechanism of the addition of CF3OF to aromatics in the presence of CF3OCF=CF2 as free radical initiator.102  Despite the significant synthetic advances in trifluoromethoxylation methodologies, the incorporation of OCF3 group into organic molecules still remains challenging. The next section provides a brief summary of radical fluorodecarboxylation methods, including radical decarboxylative fluorination methods that have recently been developed by the Sammis group for the synthesis of trifluoromethoxyarenes.   2.3 Decarboxylative fluorination strategies  The growing importance of fluorine containing compounds in medicinal chemistry has triggered the development of many powerful fluorination methods. Among these methods, fluorodecarboxylation strategies posses important characteristics, such as such as the use of CF3OF CF CF2F3CO CF3OFC CF3F3COCF3OF CF3OF2C CF3F3COFC CHF2F3COCF3OOCF3HHOCF3HHCF3OFOCF3HHCF3O F-OCF3CF3O HFCF3OCF3O CF3OOCF3134 139 136136134140140 141136142 143143 134 144 136 145 136136 136 146 31 inexpensive an readily accessible substrates or reagents, potential to selectively produce reactive species under mild conditions, release of CO2 and simplified purification.103 There are few methods for the direct fluorodecarboxylation; the first radical fluorodecarboxylation was reported in 1983, in which aryloxyacetic acids were fluorinated using XeF2.61 The recent discoveries include xenon difluoride mediated fluorodecarboxylations44 and Li’s silver-catalyzed Hunsdiecker-type decarboxylative fluorination.104 Hence, this strategy shows an interesting and attractive approach to access fluorinated compounds.  A radical fluorodecarboxylation method was also reported by Sammis, Paquin, Kennepohl and coworkers, and it represented a renaissance in radical fluorination.9 This new approach was based on DFT calculations, which revealed that the N-F bond in some electrophilic fluorinating reagents have relatively low bond dissociation energies. Fluorination of alkyl radicals via the decomposition of tert-butyl peresters of carboxylic acids (147) with NFSI afforded the target fluorinated products (148).9 The first examples of fluorine transfer from an organic reagent to a variety of alkyl radicals, in particular tertiary, benzylic and heteroatom-stabilized substrates were reported. A broad range of tert-butyl alkylperoxoates, upon treatment with NFSI under photolysis or thermolysis conditions, generated the corresponding alkyl fluorides in 24-98% yield (Scheme 2.19).9   Scheme 2.19. Decarboxylative radical fluorination of alkylperoxoates9 FF FFO FPhthN FO H OHOHF24%98% 98%54% (68% NMR yield)45% 57% 57%R OOO tBu5.0 equiv. NFSIPhH, 4 min - 16 h, 110 ˚C RF147 148149 150 151 152153 154155 32 Sammis, Paquin and coworkers reported the first transition-metal-free photo-fluorodecarboxylation strategy to form C-F bond from α-aryloxyacetic acids and α-aryloxy-α-fluoroacetic using Selectfluor® as a fluorine source.64 The reaction conditions were very mild and afforded aryl monofluoromethyl ethers, aryl difluoromethyl ethers in 25-83% yield. Halide-substituted aryl derivatives successfully provided fluorinated products (158, 163, 164) in good yields, whereas an unsubstituted aryloxy substrate 0d was fluorinated cleanly to give 46% yield. Aromatics containing alkyl group, the tert-butyl group substituted substrate (159), also afforded 83% of the isolated product (Scheme 2.20).64    Scheme 2.20. Photodecarboxylative radical fluorination of aryloxycarboxylic acids64  The reaction mechanism of photodecarboxylation is proposed to go through a single-electron transfer (SET) (Scheme 2.21).64 The B band of the benzenoid nucleus of 165 is excited from the π to π∗ state (166), which makes it a better electron donor than the ground state molecule. Upon treatment with Selectfluor®, the ground state intermediate then undergoes a single-electron transfer (SET) to afford the oxidized species 167. These species immediately undergo decarboxylation, and the resulting intermediate can be represented as three different resonance contributers (168-170). Fluorination with Selectfluor® proceeds either in a radical54b or an ionic manner54c to provide product 171. HOOOArR11.5 equiv. NaOH,3.5 equiv. F-TEDA-BF4H2O or MeCN/H2O (2:1)1h, 300 nm hνOArFR1R1 = H, F 25-83%FOFH tBuOFHHOFFOMeOFH HOFHFOFF BrOFF60% 83% 78% 46%25% 44% 64%156 157158 159 160 161162 163 164 33  Scheme 2.21. Mechanistic model of photodecarboxylative fluorination64  Recently, the same group, Sammis, Paquin and Wolf, reported the first example of photocatalyzed C(sp3)-F bond formation, based on fluorodecarboxylation approach, which relied on using the Ru(bpy)3Cl2 photocatalyst and Selectfluor®.105 Aryloxyacetic acid derivatives were subjected to photofluorodecarboxylation  reaction conditions to afford the desired products in 51-92% yield (Scheme 2.22).105 Moreover, the mechanistic investigations were performed using transient absorption spectroscopy, and the reaction is thought to proceed via a  photoredox pathway involving SET from the MLCT (triplet metal-to-ligand charge transfer) state of the ruthenium catalyst to Selectfluor®. This SET enables the formation of a key oxidant, which leads to a subsequent decarboxylative fluorination.    Scheme 2.22. Photodecarboxylation of aryloxyacetic acid derivatives and photoredox catalyzed system105   This photocatalyst assisted decarboxylative fluorination allowed to access a broader range of substrates than the previous UV light-promoted methodology developed by the same group.64 p-Phenylaryloxy and o-phenylaryloxy derivatives (174 and 175) resulted in 92% RO OOhνRO OOF-TEDA-BF4RO OO-CO2RORORORO F165 166 167168169170171F-TEDA-BF4NaOH, H2Ohν (300 nm)F-TEDA-BF4photocatalysthν (450 nm)Ar O OHOAr O F 34 and 89% yields, respectively. Alkyl substituted aryloxy rings and pyridyl derivatives afforded the fluorinated products from in the 63% to 79% yield range (176, 177, 180). Yields for aromatics with electron-withdrawing substituents, such as fluorine (178) and bromine (179) were 67% and 56%, respectively. Double decarboxylation-fluorination was also observed, yielding 80% fluorinated product (182) (Scheme 2.23).105    Scheme 2.23. Catalytic photoredox decarboxylative fluorination105  Li and coworkers reported a silver-catalyzed fluorodecarboxylation of aliphatic carboxylic acids.104 The reactions were performed using Selectfluor® as a fluorine source and a catalytic amount of silver nitrate (AgNO3) (Scheme 2.24).104 This new fluorination method afforded the synthesis of a broad range of alkyl fluorides in 47-95% yields under mild conditions.  O OHOO F2.1-3.5 equiv F-TEDA-BF41-1.5 equiv NaOHRu catalystH2O or H2O/MeCN (1:1)500W lamp 84%OPhF O F OtBuFPhOtBuFtBuOFF OBrF O F92% 89% 79% 74%65%67% 56%NO F63%O FOF80%172 173174 175 176 177178 179 180 181182 35  Scheme 2.24. Decarboxylative radical fluorination of aliphatic carboxylic acids104  Likewise, Gouverneur and coworkers reported silver-catalyzed fluorodecarboxylation of α,α-difluoroaryl acetic acids in the presence of Selectfluor®.106 This strategy provides access to trifluoromethoxyarenes and difluoromethylated arenes through late-stage fluorination. In addition, the method was found to be useful for [18F]-labeling using [18F] Selectfluor® bis(triflate). The protocol tolerated different functional groups, and yields ranged from 17% to 91% (Scheme 2.25).106   R OHO 10 mol% AgNO32.0 equiv. F-TEDA-BF4acetone/H2O (1:1) or H2O10h, 23-55 ˚CR FOOCO2HFHO2C FHHOH HHF71% 95%NOOF73%ClO F87%FOPh84%PhOF86%80%47-95%F67%n-C16H33 F56%183 184185 186 187 188189 190 191 192193 36  Scheme 2.25. Decarboxylative fluorination for the synthesis of tri- and difluoromethyl ethers106  Similarly, silver-assisted decarboxylative fluorination of paraconic acids was reported.107 Analogous to the earlier methods, this strategy also uses Selectfluor® as a fluorine source to prepare β-fluorinated γ-butyrolactones in 28-88% yield (Scheme 2.26). A class of γ-butyrolactones, bearing a carboxylic acid group at the β position as their characteristic functionality, were precursors for the direct and site-selective fluorodecarboxylative method. This method has an interesting potential application, since butyrolactones are an important class of compounds in organic synthesis and pharmaceutical science.   RX FOHOX = H, FR = alkyl, EWG, EDG20 mol% AgNO32.0 equiv. F-TEDA-BF4acetone/H2O (1:1) or H2O10h, 23-55 ˚CR FX F17-91%CF3Ph85%OMeCF388%CF377%CF351%CF3NHO86%CF3HO2C49%CHF272%MeO CHF283%CHF2Ph91%BrCHF282%CF3Br33%CF356%194 195196 197 198 199200 201 202 203204 205 206 207 37  Scheme 2.26. Decarboxylative fluorination of γ-butyrolactones107  MacMillan and coworkers recently reported a photoredox-assisted decarboxylative fluorination strategy to transform aliphatic carboxylic acids into the corresponding alkyl fluorides.108 In this protocol, a catalytic amount of iridium and ruthenium catalysts, along with a fluorine source Selectfluor® were employed. Due to mild reaction conditions, this strategy significantly expands the scope of carboxylic acids that undergo photodecarboxylative fluorination.  Primary, secondary, tertiary, and benzylic fluorides were obtained in 70-99% yields (Scheme 2.27).108   OOR1R3R2HO2C1.0 equiv. AgNO32.0 equiv. F-TEDA-BF4benzene/H2O (1:1)reflux, 10 hOOR1R3R2FOFO73%OOF83%OOFEtEt83%OOF75%OOF40%OFO25%208 209210 211 212 213214 215 38  Scheme 2.27. Decarboxylative fluorination aliphatic carboxylic acids108  These strategies show that the radical fluorination processes are effective, complementary methods to traditional ionic techniques. Considering the lack of synthetically available methods to access trifluoromethoxyarenes, our group started a project toward a development of a novel, easy-to-perform trifluoromethoxylation methodology. The next section presents the radical trifluoromethoxylation methodology that has been developed in our laboratory.   2.4 Results and discussion  Due to limitations of the present trifluoromethoxylation methods, such as poor substrate scope and application of highly toxic, thermally labile reagents, there is still a need for a reliable method. Given our long-standing interest in radical fluorination of organic molecules, we began investigating a new approach to the synthesis of trifluoromethoxyarenes using bench-stable, easily handled fluorinating reagents (Scheme 2.28).   RCO2HRF1 mol% catalyst3.0 equiv. F-TEDA-BF42.0 equiv. Na2HPO4H2O/MeCN (1:1)34W blue LEDsPhFtBuFPhOF87% 70%F71% 99%PhFPh FMe85%NHBocF82%81%216 217218 219 220 221222 223 224 39  Scheme 2.28. Synthetic methods to access trifluoromethoxy arenes and decarboxylative-fluorination    2.4.1 Initial studies toward the synthesis of trifluoromethoxy arenes  While most of the known trifluoromethoxylation strategies are accomplished via ionic intermediates, few radical fluorodecarboxylation methods for the synthesis of mono- and difluoromethoxy arenes have been reported previously. Initial studies in radical fluorodecarboxylation were performed by Claire Chatalova, a senior member of the Sammis group. Claire optimized the reaction conditions, including variations of solvents, additives, temperature, concentrations and molar ratio of reactants. During her investigations, Selectfluor® and XeF2 were screened as fluorinating reagents with XeF2 providing superior results. Claire established the following protocol as the optimal reaction conditions for trifluoromethoxylation of α,α-difluoroaryloxyacetic acids: application of 1.0 equivalent of XeF2 as a fluorine source and CDCl3 as a solvent, in a plastic vessel. Regardless of the substitution pattern, the reaction is completed at room temperature in 3-5 min. Thus, Claire demonstrated that XeF2 can be successfully used as a fluorine source to synthesize the target products.  2.4.2 The synthesis of trifluoromethoxy arenes through fluorodecarboxylatons of difluoroaryloxyacetic acids   With the optimized conditions in hand, another member of the Sammis group, M. Epifanov and I worked towards expanding the substrate scope of this reaction. I initially performed trifluoromethoxylation reactions using the substrates that previously have been synthesized by Claire (Scheme 2.28). This allowed me to familiarize with the methodology and reconfirm the yields that earlier have been isolated. The α, α- difluoroaryloxyacetic acids were    FOF FAr"F-" source"CF3+" source"-OCF3" sourceAr O CX3 Ar XAr OH "F " Ar OF FOHOour approach 40 subjected to the XeF2 reaction conditions, and all the isolated yields were similar to the previous observations.      [a] Isolated yield Scheme 2.29. Fluorodecarboxylation reaction scope for α, α- difluoroaryloxyacetic acid derivatives  Next, I synthesized various α,α-difluoroaryloxy acetic acids, such as napthol derivatives, bearing electron-donating and electron-withdrawing substituents, from the corresponding phenols in two steps. The observed yields are presented in Scheme 2.30. The best yield of 64% obtained for 1,2-difluoro-4-(trifluoromethoxy)-benzene (234). The next highest yields were observed for mono- and di-trifluoromethyl substituted substrates: 60% (237) and 51% (236) respectively. Dimethyl and trimethyl substituted difluoroaryloxyacetic acid derivatives gave lower results, 25% (238) and 4% (235) respectively. The conversion showed poorer results for naphthol derivatives; both bromo- and dichloro-substituted naphthol products afforded 3% (240) and 15% (239) yields, while unsusbtituted naphthol substrate was obtained in 4% (241) yield.   To determine the isolated yields of trilfuoromethoxylated products, I ran the reactions on a 1 mmol scale (Scheme 2.30). The synthesis of the trifluoromethoxylated product was easy to perform and the reaction time was under 5 min. The isolation of the target product 1.2 equiv. XeF2CDCl342% yielda45% yielda69% yielda 70% yielda17% yielda77% yielda 42% yieldaBrO FF FO FF FClO FF FBrtBuO FF FtBuO FF FClO FF FPhO FF FCltBuRO225 226227 228 229 230231 232 233F FFROF FOHO 41 was achieved through filtration using a short plug of silica gel. Generally, the isolated yields of the products were lower than the yields measured by 19F NMR using an internal standard. For instance, 1,2-difluoro-4-(trifluoromethoxy)-benzene was isolated in 60% yield (234), which is lower by 4% than the NMR yield. Similarly, the yields of dimethyl and trimethyl substituted aromatic rings were also lower by approximately 4% (235 and 238); benzene rings containing mono- and di-trifluoromethyl groups gave significantly lower isolated yields: 16% (237) and 18% (236), respectively. Bromo- and dichloro-substituted naphthol derivatives yielded 2% (240) and 7% (239) of the target product, respectively. Difluoroacetic acids with electron-withdrawing substituents produced relatively higher yields compared to substrates with electron-donating groups, whereas all naphthol derivatives afforded poor results. Moreover, due to the volatility of some products, the isolated yields were lower than those measured with internal standard.   [a] Yields were measured by 19F NMR using ethyl trifluoroacetate as an internal standard.  [b] Isolated yield. Scheme 2.30. Fluorodecarboxylation reaction scope for α, α- difluoroaryloxyacetic acid derivatives  ClClO FFFBrO FFF O FF FO FFF O FFFO FFF O FFFO FFFFFF3CCF3F3C64%a (60%)b 4%a (>1%)b 51%a (18%)b 60%a (16%)b25%a (21%)b 15% yielda (7%)b 4% yielda3%a (2%)b1.2 equiv. XeF2CDCl3 RO225 226F FFROF FOHO234 235 236 237238 239 240 241 42 As outlined in Scheme 2.31, the proposed mechanism of fluorodecarboxylation initially begins with the formation of a xenon-ester (244), which is generated after adding XeF2 to the substrate. The xenon-ester intermediate (244) then rapidly undergoes decarboxylation to provide carbon radical 245. Conversion of radical 245 into the trifluoromethoxy arene (243) might proceed through two mechanisms: either the radical 245 may directly undergo a radical atom transfer reaction, or a xenon species could first oxidize radical 245 to the cation, which then reacts with fluoride. In fact, direct radical fluorine transfer mechanism is consistent with Ramsden’s protocol, who showed that reactions of acids with XeF2 run in plastic vials disfavor ionic mechanistic pathway.110 Further analysis showed that the addition of excess fluoride does not affect the reaction yield. Although the latter mechanism is not excluded, we suggest that mechanism of fluorodecarboxylation of difluoroacetic acids is most consistent with a radical mechanism (Scheme 2.31).     Scheme 2.31. Proposed mechanism of fluorodecarboxylation of difluoroaryloxyacetic acids  2.5 Conclusion  To conclude, our group has developed a new method for the synthesis of molecules containing OCF3 fragment. This fluorodecarboxylation strategy has a potential to access a wide variety of synthetically useful organic molecules, and it can be a complementary methodology to the traditional transformations. Substrate scope for a novel radical methodology for the synthesis of trifluoromethoxy arenes from the corresponding difluoroaryloxy acetic acids was enhanced. The strategy is efficient for a range of aryloxy Ar O OHOF F1 equiv XeF2CDCl3242Ar O OOF F244XeFAr OF F245fluorine transferAr O FF F243 43 substituents, affording the target products in very fast reaction. In general trend, the yields of products bearing electron-withdrawing substituents were significantly higher than those with electron-donating groups, while all naphthol derivatives showed poor results. Furthermore, the isolated yields were lower than those measured with internal standard, it could attribute to high volatility of compounds. The future directions of this methodology are further expansion of substrate scope, including natural products and synthesis of 18FXeF to incorporate 18F-labelled moiety into organic molecules. This radical fluorodecarboxylation can be attractive for the late-stage incorporation of 18F for PET imaging applications, due to its very fast reaction time (5 min) and ease of purification. Both electrophilic and radical fluorination methods are not ideally suited for PET imaging: fluorine source required for the synthesis of 18F-labelled compounds is difficult to prepare in high specific activities. Moreover, XeF2 can be enriched with 18F employing high-specific activity fluoride sources.44 Hence, this new methodology represents great potential application for the synthesis of 18F-labelled PET tracers.  2.6 Experimentals  2.6.1 General experimental  Anhydrous dimethylformamide was used. All other solvents were used without further purification. Preparatory TLC was performed on Analtech GF UV254 pre-coated silica gel plates (20 × 20 cm, 2000 µm). All chemicals were purchased from commercial sources and used as received. Infrared (IR) spectra were obtained using a Thermo Nicolet 4700 FT-IR spectrometer. Proton nuclear magnetic resonance (1H NMR) spectra were recorded using a Bruker AV-300 or AV-400 spectrometer. Fluorine nuclear magnetic resonance (19F NMR) spectra were recorded using a Bruker AV-300. Carbon nuclear magnetic resonance (13C NMR) spectra were recorded using a Bruker AV-300 or AV-400 spectrometer. Chemical shifts are reported in parts per million (ppm) and are referenced to the centerline of deuterochloroform (7.27 ppm 1H NMR; 77.0 ppm 13C NMR), dimethyl sulfoxide-d6 (2.50 ppm 1H NMR; 39.5 ppm 13C NMR). Fluorine NMR (19F NMR) spectra were calibrated relative to ethyl  44 trifluoroacetate. High resolution mass spectra (HRMS) were recorded on either a Waters or Micromass LCT spectrometer.   2.6.2 Synthesis of ethyl difluorophenoxyacetates   2.6.2.1 General ethyl difluorophenoxyacetate synthesis procedure    To a stirring solution of 0.17 M phenol derivative in dry N,N-dimethylformamide (DMF) under nitrogen, was added 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (2.5 equiv.) over 5 min. The resulting solution was heated to 70 °C and ethyl bromodifluoroacetate (2.5 equiv.) was added dropwise using a syringe pump over 15 min. and stirred for 24 h, upon which it turned black. The completion of the reaction was monitored by TLC. The reaction mixture was allowed to cool to room temperature and quenched with water (one volume equivalent to the amount of dry DMF initially used). The product was extracted with diethyl ether (3 × half the volume of dry DMF initially used). The combined organic layers were washed with brine (15 ml) and dried over Na2SO4. The resulting solution was filtered and concentrated under reduced pressure by rotary evaporation. The title compound was purified by flash column chromatography (using hexanes/EtOAc mixture, gradient: 10% to 50% EtOAc) to give a colorless oil.   Ethyl 2,2-difluoro-2-[3,4-difluoro-phenoxy] acetate (246). 3,4-difluoro-phenol (3.229 g, 24.8 mmol) was subjected to the general ethyl difluorophenoxy acetate synthesis procedure to yield 1.78 g of ester as bright yellow oil in 28% yield. 1H NMR (400 MHz; CDCl3): δ 7.21 to 7.08 (m, 2H), 7.01 to 6.97 (m, 1H), 4.41 (q, J = 7.17 Hz, 2H), 1.39 (t, J = 7.17 Hz, 3H). OHR2.5 equiv. DBU2.5 equiv. BrCF2CO2EtDMF, 70 ˚ C, 12-24 hOR OFFOOF FOOFF246 45 13C NMR (100.63 MHz; CDCl3): δ 158.9 (t, J = 41.41 Hz), 149.7 (dd, J = 13.80, 237.70 Hz), 148.4 (dd, J = 12.27, 234.63 Hz), 144.5 to 144.2 (m), 117.6 to 117.5 (m), 117.1 (d, J = 18.40 Hz), 113.3 (t, J = 274.50 Hz), 111.6 (d, J = 19.94 Hz), 63.5, 13.5. 19F NMR (282.40 MHz): δ -77.4, -134.0 to -134.2 (m), -140.0 to -140.1 (m). IR (neat): 3094, 2990, 1776, 1620, 1514, 1342, 1148, 1101, 1011, 960, 856, 775. HRMS-EI (m/z) calcd for C10H8O3F4: 252.04096. Found: 252.04100.     Ethyl 2,2-difluoro-2-[2,4,6-trimethyl-phenoxy] acetate (247). 2,4,6-Trimethyl-phenol (3.448 g, 25.3 mmol) was subjected to the general ethyl difluorophenoxy acetate synthesis procedure to yield 3.00 g of ester as colorless oil in 46% yield. 1H NMR (400 MHz; CDCl3): δ 6.87 (s, 2H), 4.41 (q, J = 7.17 Hz, 2H), 2.28 (s, 6H), 2.27 (s, 3H), 1.40 (t, J = 7.17 Hz, 3H). 13C NMR (100.63 MHz; CDCl3): δ 160.5 (t, J = 41.41 Hz), 144.8, 136.2, 132.5, 129.8, 115.1 (t, J = 272.97 Hz), 63.7, 20.9, 17.2, 14.1. 19F NMR (282.40 MHz): δ -74.9. IR (neat): 3480, 3034, 2985, 2929, 1775, 1607, 1481, 1337, 1142, 1120, 1013, 854, 720. HRMS-EI (m/z) calcd for C13H16O3F2: 258.10675. Found: 258.10653.    Ethyl 2,2-difluoro-2-[3,5-bis(trifluoromethyl)phenoxy] acetate (248). 3,5-bis(trifluoromethyl)-phenol (5.75 g, 25 mmol) was subjected to the general ethyl difluorophenoxy acetate synthesis procedure to yield 6.93 g of ester as a colorless oil in 79% yield. 1H NMR (400 MHz; CDCl3): δ 7.81 (s, 1H), 7.70 (s, 2H), 4.44 (q, J = 7.17 Hz, 2H), 1.41 (t, J = 7.17 Hz, 3H). 13C NMR (100.63 MHz; CDCl3): δ 158.8 (t, J = 39.87 Hz), 150.0, OF FOO247OF FOOF3CCF3 248 46 132.2 (q, J =33.74 Hz), 122.5 (q, 272.97 Hz), 122.2, 120.2 (sept., J = 3.07 Hz), 113.7 (t, J = 276.04 Hz), 64.2, 13.8. 19F NMR (282.40 MHz): δ -63.4, -77.3. IR (neat): 3086, 2992, 1780, 1617, 1463, 1369, 1276, 1172, 1126, 958. HRMS-EI (m/z) calcd for C12H8O3F8: 352.03457. Found: 352.03438.    Ethyl 2,2-difluoro-2-[4-(trifluoromethyl)phenoxy] acetate (249). 4-(trifluoromethyl)-phenol (4.439 g, 27.4 mmol) was subjected to the general ethyl difluorophenoxy acetate synthesis procedure to yield 4.97 g of ester as a colorless oil in 64% yield. 1H NMR (400 MHz; CDCl3): δ 7.65 (d, J = 8.53 Hz, 2H), 7.34 (d, J = 8.53 Hz, 2H), 4.41 (q, J = 7.17 Hz, 2H), 1.38 (t, J = 7.17 Hz, 3H). 13C NMR (100.63 MHz; CDCl3): δ 159.6 (t, J = 41.41 Hz), 152.3, 128.6 (t, J = 33.74), 127.3 (m), 125.3 (t, J = 271.44 Hz), 121.9, 114.1 (t, J = 274.50 Hz), 64.2, 14.07. 19F NMR (282.40 MHz): δ -62.2, -77.0. IR (neat): 3030, 2991, 1777, 1616, 1514, 1323, 1210, 1166, 1122, 1101, 1063, 1016, 911, 855. HRMS-EI (m/z) calcd for C11H9O3F5: 284.04719. Found: 284.04733.    Ethyl 2,2-difluoro-2-[2,5-dimethyl-phenoxy] acetate (250). 2,5-Dimethyl-phenol  (1.22 g, 10 mmol) was subjected to the general ethyl difluorophenoxy acetate synthesis procedure to yield 1.36 g of ester as straw coloured oil in 56% yield. 1H NMR (400 MHz; CDCl3): δ 7.11 (d, J = 7.85 Hz, 1H), 7.05 (s, 1H), 6.97 (d, J = 7.85 Hz, 1H), 4.40 (q, J = 7.17 Hz, 2H), 2.33 (s, 3H), 2.27 (s, 3H), 1.37 (t, J = 7.17 Hz, 3H). 13C NMR (100.63 MHz; CDCl3): δ 160.3 (t, J = 41.40 Hz), 148.1, 137.1, 131.2, 128.3, 127.2, 122.5, 114.4 (t, J = 271.44 Hz), 63.8, 21.2, OF FOOF3C249OFFOO250 47 16.1, 14.1. 19F NMR (282.40 MHz): δ -75.5. IR (neat): 3030, 2930, 1777, 1511, 1377, 1339, 1244, 1155, 1138, 1013, 856. HRMS-EI (m/z) calcd for C12H14O3F2: 244.09110. Found: 244.09107.    Ethyl 2,2-difluoro-2-[2,4-dichloro-1-naphthalenoxy] acetate (251). 2,4-dichloro-1-naphthalenol (5.272 g, 24.8 mmol) was subjected to the general ethyl difluorophenoxy acetate synthesis procedure to yield 3.620 g of ester as a yellow-white oil in 44% yield. 1H NMR (400 MHz; CDCl3): δ 8.27 to 8.23 (m, 1H), 8.19 to 8.17 (m, 1H), 7.70 to 7.65 (m, 3H), 4.49 (q, J = 7.17 Hz, 2H), 1.44 (t, J = 7.17 Hz, 3H). 13C NMR (100.63 MHz; CDCl3): δ 159.49 (t, J = 39.87 Hz), 140.5, 131.1, 130.2, 130.1, 128.3, 127.8, 127.0, 125.3, 124.6, 122.9 to 122.8 (m), 114.4 (t, J = 279.11 Hz), 63.9, 13.8. 19F NMR (282.40 MHz): δ -74.9. IR (neat): 3079, 2995, 1956, 1772, 1499, 1375, 1339, 1205, 1189, 1139, 1098, 1054, 851, 748. HRMS-EI (m/z) calcd for C14H10O3F235Cl2: 333.99751. Found: 333.99724.    Ethyl 2,2-difluoro-2-[6-bromo-2-naphthalenoxy] acetate (252). 6-Bromo-2-naphthalenol (5.517 g, 24.7 mmol) was subjected to the general ethyl difluorophenoxy acetate synthesis procedure to yield 1.568 g of ester as a yellow-white oil in 18% yield. 1H NMR (400 MHz; CDCl3): δ 8.01 (d, J = 1.71 Hz, 1H), 7.72 (dd, J = 8.88 Hz, 20.14 Hz, 2H), 7.65 (d, J = 1.37 Hz, 1H), 7.59 (dd, J = 2.05 Hz, 6.83 Hz, 1H), 7.39 (dd, J = 2.05 Hz, 6.83 Hz, 1H), 4.41 (q, J = 7.17 Hz, 2H), 1.37 (t, J = 7.17 Hz, 3H). 13C NMR (100.63 MHz; CDCl3): δ 159.3 (t, J = O FFOOClCl251OF FOOBr252 48 41.41 Hz), 147.0 to 140.0 (m), 132.1, 131.7, 129.9, 129.4, 128.9, 128.5, 121.7, 119.6, 118.2, 113.7 (t, J = 272.97 Hz), 63.4, 13.5. 19F NMR (282.40 MHz): δ -76.1 IR (neat): 3030, 2986, 1773, 1629, 1589, 1501, 1470, 1447, 1377, 1265, 1191, 1146, 1111, 1011, 909, 879, 856. HRMS-EI (m/z) calcd for C14H11O3F279Br: 343.98596. Found: 343.98571.    Ethyl 2,2-difluoro-2-[1-naphthalenyloxy)] acetate (253). 1-Naphthalenol (3.749 g, 26.0 mmol) was subjected to the general ethyl difluorophenoxy acetate synthesis procedure to yield 3.89 g of ester as bright yellow oil in 56% yield. 1H NMR (400 MHz; CDCl3): δ 7.87 to 7.82 (m, 3H), 7.69 (s, 1H), 7.55 to 7.48 (m, 2H), 7.37 (dd, J = 2.39 Hz, 6.49 Hz, 1H), 4.41 (q, J = 7.17 Hz, 2H), 1.38 (t, J = 7.17 Hz, 3H). 13C NMR (100.63 MHz; CDCl3): δ 160.1 (t, J = 41.41 Hz), 147.3, 133.8, 131.8, 130.0, 129.5, 128.0, 127.1, 126.3, 121.3, 118.8, 114.4 (t, J = 272.97 Hz), 64.0, 14.1. 19F NMR (282.40 MHz): δ -76.0. IR (neat): 3062, 2986, 2910, 1773, 1635, 1511, 1465, 1356, 1209, 1157, 1140, 1129, 1109, 960, 814, 784. HRMS-EI (m/z) calcd for C14H12O3F2: 266.07545. Found: 266.07527.  2.6.3 Synthesis of α,α-difluorocarboxylic acids  2.6.3.1 General α,α-difluorocarboxylic acid synthesis procedure     The 2 M solvent mixture of THF, methanol and water (1:2:1 ratio) were used. To a solution ethyl difluorophenoxy acetate in THF and methanol (1:2 ratio) mixture, was slowly added an O F FOO253OR OFFO3.0 equiv. NaOHTHF:H2O:MeOH (1:2:1)r.t., 18hOR OHFFO 49 aqueous NaOH (3.0 equiv.) solution. The resulting reaction mixture was stirred for 18h at room temperature. The completion of the reaction was monitored by TLC. The reaction was then concentrated under reduced pressure by rotary evaporation. The resulting solution was then acidified with a 10% HCl (aq) until the pH ≤ 2, then extracted with dichloromethane (3×10 ml). The solvent was removed from combined organic extracts via rotary evaporation. The title compound, α,α-difluorocarboxylic acid, was obtained as bright brown crystals.     2-[3,4-difluoro-phenoxy]-2,2-difluoro-acetic acid (254). Ethyl 2,2-difluoro-2-[3,4-difluoro-phenoxy] acetate (1.779 g, 7.05 mmol) was subjected to the general synthesis of α,α-difluorocarboxylic acids to give 1.34 g title compound as dark brown liquid in 85% yield. 1H NMR (400 MHz; C2D6OS): δ 7.57 to 7.44 (m, 2H), 7.15 to 7.13 (m, 1H). 13C NMR (100.63 MHz; C2D6OS): δ 160.6 (t, J = 38.34 Hz), 149.7 (dd, J = 13.80, 234.63 Hz), 143.7 (dd, J = 12.27, 233.10 Hz), 145.3 to 145.2 (m), 118.8 to 118.7 (m), 118.6 (d, J = 18.40 Hz), 114.4 (t, J = 272.97 Hz), 112.3 (d, J = 19.94 Hz). 19F NMR (282.40 MHz): δ -77.3, -135.0 to -135.2 (m), -140.9 to -141.1 (m). IR (neat): 3098, 2733, 1767, 1619, 1514, 1438, 1155, 1129, 1102, 959, 873, 813, 705. HRMS-EI (m/z) calcd for C8H4O3F4: 224.00966. Found: 224.00970.    2-[2,4,6-trimethyl-phenoxy]-2,2-difluoro-acetic acid (255). Ethyl 2,2-difluoro-2-[2,4,6-trimethyl-phenoxy] acetate (1.289 g, 4.9 mmol) was subjected to the general synthesis of α,α-difluorocarboxylic acids to give 1.10 g title compound as white crystals in 96% yield. 1H NMR (400 MHz; C2D6OS): δ 6.92 (s, 2H), 2.22 (s, 3H), 2.19 (s, 6H). 13C NMR (100.63 MHz; C2D6OS): δ 161.3 (t, J = 39.87 Hz), 144.5, 136.0, 131.9, 129.9, 115.3 (t, J = 272.97 Hz), 20.6, 16.9. 19F NMR (282.40 MHz): δ -75.5. IR (neat): 3480, 3034, 2929, 2744, 2592, OF FOOHFF254OF FOOH255 50 1760, 1606, 1478, 1301, 1157, 1094, 1036, 954, 900, 857. HRMS-EI (m/z) calcd for C11H12O3F2: 230.07545. Found: 230.07548.    2-[3,5-bis(trifluoromethyl)phenoxy]-2,2-difluoro- acetic acid (256). Ethyl 2,2-difluoro-2-[3,5-bis(trifluoromethyl)phenoxy] acetate (1.456 g, 4.1 mmol) was subjected to the general synthesis of α,α-difluorocarboxylic acids to give 0.82 g title compound as brown crystals in 61% yield. 1H NMR (400 MHz; C2D6OS): δ 8.13 (s, 1H), 7.97 (s, 2H). 13C NMR (100.63 MHz; C2D6OS): δ 160.0 (t, J = 38.34 Hz), 150.3, 132.3 (q, J =33.74 Hz), 122.7, 122.7 (q, 272.97 Hz), 120.6 (sept., J = 3.07 Hz), 114.4 (t, J = 276.04 Hz). 19F NMR (282.40 MHz): δ -63.3, -77.5. IR (neat): 3076, 2990, 1769, 1617, 1464, 1366, 1276, 1172, 1107, 936, 886. HRMS-EI (m/z) calcd for C10H4O3F8: 324.00343. Found: 324.00356.    2-[4-(trifluoromethyl)phenoxy]-2,2-difluoro-acetic acid (257). Ethyl 2,2-difluoro-2-[4-(trifluoromethyl)phenoxy] acetate (1.301 g, 4.6 mmol) was subjected to the general synthesis of α,α-difluorocarboxylic acids to give 0.76 g title compound as bright brown crystals in 65% yield. 1H NMR (400 MHz; C2D6OS): δ 7.85 (d, J = 8.88 Hz, 2H), 7.46 (d, J = 8.19 Hz, 2H). 13C NMR (100.63 MHz; C2D6OS): δ 160.1 (t, J = 38.34 Hz), 152.2, 127.5 (m), 126.8 (t, J = 32.20 Hz), 125.1 (t, J = 271.44 Hz), 121.4, 114.1 (t, J = 272.97 Hz). 19F NMR (282.40 MHz): δ -61.1, -76.8. IR (neat): 2969, 2737, 2575, 1764, 1603, 1512, 1321, 1200, 1164, 1149, 1062, 1120, 1017, 9578, 848, 712. HRMS-EI (m/z) calcd for C9H5O3F5: 256.01589. Found: 256.01571. OF FOOHF3CCF3 256OF FOOHF3C257 51   2-[2,5-dimethyl-phenoxy]-2,2-difluoro-acetic acid (258). Ethyl 2,2-difluoro-2-[2,5-dimethyl-phenoxy] acetate (1.039 g, 4.6 mmol) was subjected to the general synthesis of α,α-difluorocarboxylic acids to give 0.57 g title compound as dark brown crystals in 62% yield. 1H NMR (400 MHz; C2D6OS): δ 7.19 (d, J = 7.51 Hz, 1H), 7.02 (d, J = 8.19 Hz, 2H), 2.28 (s, 3H), 2.18 (s, 3H). 13C NMR (100.63 MHz; C2D6OS): δ 160.3 (t, J = 39.87 Hz), 147.0, 136.2, 130.7, 126.9, 126.6, 121.3, 113.9 (t, J = 271.44 Hz), 20.0, 14.9. 19F NMR (282.40 MHz): δ -75.9. IR (neat): 2928, 2595, 1761, 1623, 1509, 1467, 1300, 1181, 1156, 1115, 1093, 893, 813. HRMS-EI (m/z) calcd for C10H10O3F2: 216.05980. Found: 216.05969.    2-[2,4-dichloro-1-naphthalenoxy]-2,2-difluoro- acetic acid (259). Ethyl 2,2-difluoro-2-[2,4-dichloro-1-naphthalenoxy] acetate (1.67 g, 5 mmol) was subjected to the general synthesis of α,α-difluorocarboxylic acids to give 0.87 g title compound as light brown crystals in 57% yield. 1H NMR (400 MHz; CDCl3): δ 8.28 to 8.24 (m, 1H), 8.19 to 8.17 (m, 1H), 7.72 to 7.65 (m, 3H), 6.97 (broad, 1H). 13C NMR (100.63 MHz; CDCl3): δ 162.1 (t, J = 41.41 Hz), 140.2, 131.4, 130.2, 129.9, 128.5, 127.9, 127.0, 125.3, 124.6, 122.7 to 122.7 (m), 114.1 (t, J = 279.11 Hz). 19F NMR (282.40 MHz): δ -75.4. IR (neat): 2884, 2585, 1757, 1581, 1499, 1373, 1357, 1191, 1163, 1118, 1051, 857, 744. HRMS-EI (m/z) calcd for C12H6O3F235Cl2: 305.96621. Found: 305.96602.  OFFOHO258O FFOHOClCl259 52   2-[6-bromo-2-naphthalenoxy]-2,2-difluoro- acetic acid (260). Ethyl 2,2-difluoro-2-[6-bromo-2-naphthalenoxy] acetate (1.568 g, 4.5 mmol) was subjected to the general synthesis of α,α-difluorocarboxylic acids to give 1.06 g title compound as white crystals in 74% yield. 1H NMR (400 MHz; C2D6OS): δ 8.27 (d, J = 1.71 Hz, 1H), 7.98 (dd, J = 9.22 Hz, 10.24 Hz, 2H), 7.84 (d, J = 1.37 Hz, 1H), 7.69 (dd, J = 2.05 Hz, 6.83 Hz, 1H), 7.46 (dd, J = 2.05 Hz, 6.83 Hz, 1H). 13C NMR (100.63 MHz; CDCl3): δ 160.6 (t, J = 38.34 Hz), 147.4 to 147.3 (m), 132.4, 132.0, 130.2, 130.1, 129.8, 129.5, 122.1, 119.5, 118.1, 114.5 (t, J = 272.97 Hz). 19F NMR (282.40 MHz): δ -76.4. IR (neat): 3030, 2760, 2855, 1756, 1625, 1588, 1503, 1473, 1459, 1316, 1221, 1189, 1170, 1132, 1073, 905, 874, 845. HRMS-EI (m/z) calcd for C12H7O3F279Br: 315.95466.  Found: 315.95457.    2,2-difluoro-2-(1-naphthalenyloxy)-acetic acid (261). Ethyl 2,2-difluoro-2-[1-naphthalenyloxy)] acetate (3.885 g, 14.6 mmol) was subjected to the general synthesis of α,α-difluorocarboxylic acids to give 1.87 g title compound as bright brown crystals in 54% yield. 1H NMR (400 MHz; CDCl3): δ 7.89 to 7.82 (m, 3H), 7.70 (s, 1H), 7.56 to 7.48 (m, 2H), 7.38 (dd, J = 2.31 Hz, 6.67 Hz, 1H), 6.47 (s, 1H). 13C NMR (100.63 MHz; C2D6OS): δ 160.1 (t, J = 39.87 Hz), 146.4, 132.8, 130.6, 129.6, 127.2, 126.6, 125.7, 120.3, 117.4, 114.0 (t, J = 271.44 Hz). 19F NMR (282.40 MHz): δ -76.5. IR (neat): 3062, 2930, 2583, 1755, 1633, 1510, 1464, 1357, 1208, 1161, 1132, 1083, 959, 865, 735. HRMS-EI (m/z) calcd for C12H8O3F2: 238.04415. Found: 238.04405. OF FOOHBr260O F FOHO261 53  2.6.4 Synthesis of trifluoromethoxyarenes  2.6.4.1 General trifluoromethoxyarene synthesis procedure     To a stirring 2 M solution of α,α-difluorocarboxylic acid derivative in CDCl3, was slowly added xenon difluoride (XeF2) (1.0 equiv.). The resulting solution was stirred for 3-5 min, upon which the solution turned black. The reaction mixture was then filtered through a short plug of silica using pentane. The solvent was then removed by rotary evaporator at 0 ºC. The trifluoromethoxyarene was obtained as transparent, colorless oil.      1-bromo-4-(trifluoromethoxy)-benzene (227). 2-(4-bromophenoxy)-2,2-difluoro-acetic acid (0.178 g, 0.67 mmol) was subjected to the general synthesis of trifluoromethoxyarenes to afford 0.11 g title compound as colorless oil in 69% yield. 1H NMR (300 MHz; CDCl3): δ 7.53 (dd, J = 2.31 Hz, 4.36 Hz, 2H), 7.11 (dd, J = 0.77 Hz, 8.21 Hz, 2H). 13C NMR (100.63 MHz; CDCl3): δ 147.9, 132.5, 122.4, 119.7, 118.7 (t, J = 257.64 Hz). 19F NMR (282.40 MHz): δ -58.4. HRMS-EI (m/z) calcd for C7H4OF379Br: 239.93976. Found: 239.93993.    1.0 equiv. XeF2CDCl3, r.t., 3-5 min. ROF FFROF FOHOBrO FF F227O FF FBr228 54 1-bromo-3-(trifluoromethoxy)-benzene (228). 2-(3-bromophenoxy)-2,2-difluoro-acetic acid (0.235 g, 0.88 mmol) was subjected to the general synthesis of trifluoromethoxyarenes to afford 0.16 g title compound as colorless oil in 77% yield. 1H NMR (400 MHz; CDCl3): δ 7.46 to 7.40 (m, 2H), 7.29 to 7.25 (m, 1H), 7.19 to 7.16 (m, 1H). 13C NMR (100.63 MHz; CDCl3): δ 149.5, 130.8, 130.0, 124.4, 122.7, 121.6 (t, J = 257.64 Hz ), 119.6. 19F NMR (282.40 MHz): δ -58.2. IR (neat): 3074, 1584, 1472, 1427, 1251, 1204, 1164, 1087, 937, 871, 780. HRMS-EI (m/z) calcd for C7H4OF379Br: 239.93976. Found: 239.93997.    2,4-bis(1,1-dimethylethyl)-1-(trifluoromethoxy)-benzene (229). 2-(2,4-bis(1,1-dimethylethyl)-phenoxy)-2,2-difluoro-acetic acid  (0.292 g, 0.97 mmol) was subjected to the general synthesis of trifluoromethoxyarenes to afford 0.11 g title compound as colorless oil in 42% yield. 1H NMR (400 MHz; CDCl3): δ 7.42 (d, J = 2.39 Hz, 1H), 7.24-7.14 (m, 2H), 1.40 (s, 9H), 1.33 (s, 9H). 13C NMR (100.63 MHz; CDCl3): δ 148.0, 146.1, 139.4, 124.3, 123.6, 117.9, 117.8 (q, J = 257.64 Hz). 19F NMR (282.40 MHz): δ -54.8. IR (neat): 2964, 2874, 1594, 1484, 1244, 1218, 1164, 1152, 1123, 1088, 887. HRMS-EI (m/z) calcd for C15H21OF3: 274.15445. Found: 274.15431.    1-(1,1-dimethylethyl)-4-(trifluoromethoxy)-benzene (230). 2-[4-(1,1-dimethylethyl)phenoxy]-2,2-difluoro-acetic acid (0.183 g, 0.75 mmol) was subjected to the general synthesis of trifluoromethoxyarenes to afford 0.12 g title compound as colorless oil in 70% yield. 1H NMR (400 MHz; CDCl3): δ 7.42 (dd, J = 2.05 Hz, 4.78 Hz, 2H), 7.11 (dd, J = 1.02 Hz, 7.85 Hz, 2H), 1.35 (s, 9H). 13C NMR (100.63 MHz; CDCl3): δ 150.1, 147.3, 126.9, tBuO FF FtBu229tBuO FF F230 55 120.7, 119.6 (t, J = 256.10 Hz), 34.8, 31.6. 19F NMR (282.40 MHz): δ -58.2. HRMS-EI (m/z) calcd for C11H13OF3: 218.09185. Found: 218.09162.    1-chloro-4-(trifluoromethoxy)-benzene (231). 2-(4-chlorophenoxy)-2,2-difluoro-acetic acid  (0.193 g, 0.98 mmol) was subjected to the general synthesis of trifluoromethoxyarenes to afford 0.08 g title compound as colorless oil in 45% yield. 1H NMR (400 MHz; CDCl3): δ 7.37 (d, J = 8.88 Hz, 2H), 7.17 (d, J = 8.53 Hz, 2H). 13C NMR (100.63 MHz; CDCl3): δ 148.0, 132.7, 130.2, 122.7, 120.6 (q, J = 257.64 Hz). 19F NMR (282.40 MHz): δ -58.4. IR (neat): 3109, 1488, 1252, 1204, 1223, 1158, 1089, 1016, 920, 845, 805. HRMS-EI (m/z) calcd for C7H4OF335Cl: 195.99028. Found: 195.99016.    2,4-dichloro-1-(trifluoromethoxy)-benzene (232). 2-(2,4-dichlorophenoxy)-2,2-difluoro-acetic acid  (0.258 g, 1 mmol) was subjected to the general synthesis of trifluoromethoxyarenes to afford 0.09 g title compound as colorless oil in 42% yield. 1H NMR (400 MHz; CDCl3): δ 7.50 (dd, J = 0.68 Hz, 2.05 Hz, 1H), 7.31-7.26 (m, 2H). 13C NMR (100.63 MHz; CDCl3): δ 143.6, 132.7, 130.4, 128.7, 127.7, 123.1, 120.0 (q, J = 260.70 Hz). 19F NMR (282.40 MHz): δ -58.3. IR (neat): 3102, 1475, 1384, 1254, 1206, 1168, 1142, 1100, 1061, 870, 714. HRMS-EI (m/z) calcd for C7H3OF335Cl2: 229.95130. Found: 229.95122.  ClO FF F231ClO FF FCl232 56   4-(trifluoromethoxy)-1,1'-biphenyl (233). 2-([1,1'-biphenyl]-4-yloxy)-2,2-difluoro-acetic acid (0.258 g, 0.98 mmol) was subjected to the general synthesis of trifluoromethoxyarenes to afford 0.04 g title compound as colorless oil in 17% yield. 1H NMR (400 MHz; CDCl3): δ 7.62 to 7.56 (m, 4H), 7.46 (t, J = 7.51 Hz, 2H), 7.38 (t, J = 7.17 Hz, 1H), 7.30 (d, J = 8.19 Hz, 2H). 13C NMR (100.63 MHz; CDCl3): δ 148.3, 139.6, 139.5, 128.5, 128.1, 127.3, 126.7, 122.6 (t, J = 257.64 Hz ),  120.8. 19F NMR (282.40 MHz): δ -58.1. IR (neat): 3076, 3040, 1606, 1591, 1519, 1486, 1405, 1280, 1239, 1206, 1151, 1113, 1005, 851, 764. HRMS-EI (m/z) calcd for C13H9OF3: 238.06055. Found: 238.06057.    1,2-difluoro-4-(trifluoromethoxy)-benzene (234). 2-[3,4-difluoro-phenoxy]-2,2-difluoro-acetic acid (0.119 g, 0.53 mmol) was subjected to the general synthesis of trifluoromethoxyarenes to afford 0.06 g title compound as colorless oil in 60% yield. 1H NMR (400 MHz; CDCl3): δ 7.24 to 7.08 (m, 2H), 7.01 to 6.99 (m, 1H). 13C NMR (100.63 MHz; CDCl3): δ 150.1 (dd, J = 13.80, 237.70 Hz), 149.0 (dd, J = 12.27, 236.17 Hz), 144.6 to 144.5 (m), 119.0 (t, J = 259.17 Hz), 117.7 (d, J = 19.94 Hz), 117.3 to 117.2 (m), 111.4 (d, J = 19.94 Hz). 19F NMR (282.40 MHz): δ -58.4, -133.0 to -133.1 (m), -138.7 to -138.8 (m). HRMS-EI (m/z) calcd for C7H3OF5: 198.01041. Found: 198.00999.     PhO FF F233O FFFFF234O FFF235 57 1,3,5-trimethyl-2-(trifluoromethoxy)-benzene (235). 2-[2,4,6-trimethyl-phenoxy]-2,2-difluoro-acetic acid (0.109 g, 0.51 mmol) was subjected to the general synthesis of trifluoromethoxyarenes to afford 0.001 g title compound as colorless oil in 2% yield. 1H NMR (400 MHz; CDCl3): δ 6.88 (s, 2H), 2.28 (s, 9H). 13C NMR (100.63 MHz; CDCl3): δ 144.9, 136.4, 131.6, 129.7, 115.7 (t, J = 256.10 Hz), 20.6, 16.5. 19F NMR (282.40 MHz): δ -56.1. HRMS-EI (m/z) calcd for C10H11OF3: 204.07620. Found: 204.07645.    1-(trifluoromethoxy)-3,5-bis(trifluoromethyl)-benzene (236). 2-[3,5-bis(trifluoromethyl)phenoxy]-2,2-difluoro- acetic acid (1.464 g, 4.5 mmol) was subjected to the general synthesis of trifluoromethoxyarenes. Kugelrohr distillation afforded 0.13 g title compound as colorless oil in 18% yield. 1H NMR (400 MHz; CDCl3): δ 7.87 (s, 1H), 7.70 (s, 2H). 13C NMR (100.63 MHz; CDCl3): δ 149.6, 133.7 (q, J =33.74 Hz), 121.4, 122.4 (q, 272.97 Hz), 120.4 (sept., J = 3.07 Hz), 115.0 (q, J = 265.30 Hz). 19F NMR (282.40 MHz): δ -58.4, -63.47. IR (neat): 3076, 1619, 1464, 1373, 1276, 1172, 1131, 978, 901. HRMS-EI (m/z) calcd for C9H3OF9: 298.00402. Found: 298.00375.    1-(trifluoromethoxy)-4-(trifluoromethyl)-benzene (237). 2-[4-(trifluoromethyl)phenoxy]-2,2-difluoro-acetic acid acid (0.129 g, 0.51 mmol) was subjected to the general synthesis of trifluoromethoxyarenes to give 0.02 g title compound as colorless oil in 16% yield. 1H NMR (400 MHz; CDCl3): δ 7.70 (d, J = 8.53 Hz, 2H), 7.34 (d, J = 8.53 Hz, 2H). 13C NMR (100.63 MHz; C2D6OS): δ 151.9, 129.2 (t, J = 33.74 Hz), 120.6 (m), 125.3 (t, J = 271.44 Hz), 125.2, O FFFF3CCF3236O FFFF3C237 58 121.8 (t, J = 259.17 Hz). 19F NMR (282.40 MHz): δ -57.8, -62.4. IR (neat): 3096, 1457, 1408, 1282, 1212, 1172, 1104, 999, 812. HRMS-EI (m/z) calcd for C8H4OF6: 230.01663. Found: 230.01673.    1,4-dimethyl-2-(trifluoromethoxy)-benzene (238). 2-[2,5-dimethyl-phenoxy]-2,2-difluoro-acetic acid (0.125 g, 0.58 mmol) was subjected to the general synthesis of trifluoromethoxyarenes to afford 0.02 g title compound as colorless oil in 21% yield. 1H NMR (400 MHz; CDCl3): δ 7.13 (d, J = 7.85 Hz, 1H), 7.01 (d, J = 8.19 Hz, 2H), 2.34 (s, 3H), 2.28 (s, 3H). 13C NMR (100.63 MHz; CDCl3): δ 147.7, 137.1, 131.1, 127.6, 127.4, 121.5, 113.9 (t, J = 256.10 Hz), 20.8, 15.6. 19F NMR (282.40 MHz): δ -57.2. HRMS-EI (m/z) calcd for C9H9OF3: 190.06055. Found: 190.06044.    2,4-dichloro-1-naphthalenoxy-1-(trifluoromethoxy)-benzene (239). 2-[2,4-dichloro-1-naphthalenoxy]-2,2-difluoro- acetic acid (0.299 g, 0.98 mmol) was subjected to the general synthesis of trifluoromethoxyarenes to afford 0.02 g title compound as colorless oil in 7% yield. 1H NMR (400 MHz; CDCl3): δ 8.29 to 8.25 (m, 1H), 8.13 to 8.11 (m, 1H), 7.73 to 7.66 (m, 3H). 13C NMR (100.63 MHz; CDCl3): δ 140.3, 131.8, 130.4, 129.5, 128.8, 128.1, 127.1, 125.3, 125.0, 122.4 to 122.2 (m), 119.8 (t, J = 260.70 Hz). 19F NMR (282.40 MHz): δ -56.2. O FFF238ClClO FFF239 59 IR (neat): 2884, 1556, 1475, 1466, 1452, 1343, 1252, 1215, 1177, 1131, 1096, 987, 959, 919, 838. HRMS-EI (m/z) calcd for C11H5OF335Cl2: 279.96696. Found: 279.96676.     [6-bromo-2-naphthalenoxy]-1-(trifluoromethoxy)-benzene (240). 2-[6-bromo-2-naphthalenoxy]-2,2-difluoro- acetic acid (0.185 g, 0.58 mmol) was subjected to the general synthesis of trifluoromethoxyarenes to afford 0.003 g title compound as colorless oil in 2% yield. 1H NMR (400 MHz; CDCl3): δ 8.04 (d, J = 1.54 Hz, 1H), 7.75 (dd, J = 8.98 Hz, 15.39 Hz, 2H), 7.62 (dd, J = 2.05 Hz, 6.92 Hz, 2H), 7.37 (dd, J = 1.80 Hz, 7.18 Hz, 1H). 13C NMR (100.63 MHz; CDCl3): δ 146.7, 132.3, 131.6, 130.2, 129.5, 129.0, 128.8, 120.8, 119.9, 117.7, 118.9 (t, J = 257.64 Hz). 19F NMR (282.40 MHz): δ -58.0. IR (neat): 3030, 1630, 1592, 1504, 1365, 1253, 1212, 1195, 1159, 1063, 927, 866, 799. HRMS-EI (m/z) calcd for C11H6OF379Br: 289.95541. Found: 289.95553.              BrO FFF240 60 Chapter 3. Fluorination of boronic acid derivatives  The number of fluorine and fluorine-containing functional groups in organic molecules has been escalating due to the important properties of fluorine in agrochemicals and pharmaceuticals.111 The continuous improvement and development of new fluorinated molecules requires the design of more efficient, selective fluorine-installing methodologies.    In this chapter, our investigation on the safer radical fluorination of boronic acid and boronic acid derivatives utilizing N-F reagents is presented. Our main goal was to develop a new, metal-free method for the synthesis of aryl fluorides from aryl boronic acid derivatives.  3.1 Generation of aryl radicals from deborylation of arylboronic acids  There are number of ways to access aryl fluorides, such as nucleophilic aromatic substitution reactions, including the halogen exchange process (Halex process) and the Balz-Schiemann reaction (Scheme 3.1).112-114 Transition metal-mediated and/or catalyzed aryl fluorides coupling reactions are also known: several different palladium and silver-based strategies via cross-coupling with aryl C-H bonds,115 aryl triflates,116 aryl stannanes,117 aryl boronic acids118 and aryl silanes.119 For instance, Sanford and coworkers disclosed a copper-mediated fluorination of aryl stannanes and aryl trifluoroborates with N-fluoro-2,4,6-trimethylpyridinium triflate.120      Scheme 3.1. Synthesis of simple fluoroarenes  ArN2 +BF4- Ar F N2 BF3ΔEWGXΔF-EWGFX-Balz-Schiemann reaction:Halex process:(1)(2)262 263264 265 61 Given extremely importance of structural motifs like aryl fluoride, and our interest in radical fluorination methodology, we sought to develop a mild, transition metal-free fluorination from aryl boronic acids. The generation of aryl radicals can be accomplished via the oxidation of aryl boronic acids, using manganese (III) acetate121,122 or oxyl radicals generated by catalytic amounts of iron.123 The manuscript by Demir revealed a method of biaryl synthesis employing arylboronic acids and manganese triacetate (Scheme 3.2, eq.1).121 In addition, further reactions of this type initiated by microwave heating were reported.122 Studer and coworkers used this strategy of aryl radical generation in addition reactions of aryl radicals to alkenes (Scheme 3.2, eq.2).124    Scheme 3.2. Aryl radical reactions utilizing boronic acids and Mn(III)  Arylboronic acids and their derivatives are extensively used as coupling reagents in the catalytic formation of C-C bonds, including the Suzuki-Miyaura coupling.125 Arylboronic acids are stable under atmospheric and aqueous conditions such that Suzuki coupling can be carried out with aqueous organic solvents. It was found that arylboronic acids decompose to aryl radicals in the presence of some oxidants.126  For these reasons, we decided to study the introduction of fluorine on boronic acid and boronic acid derivatives via a boron-fluorine exchange. This method of aryl radical generation was a promising alternative, in which the aryl radical precursor is an arylboronic acid that acts as a SET reducing agent. The addition of an oxidant such as manganese (III) acetate (Mn(OAc)3) should not affect the electrophilic fluorine sources, which are also BrB OHOHMn(OAc)3BrClB OHOHPOMeOMeOMn(OAc)32PO(OMe)2ClPOOMeMeO(1)(2)266 267 268269 270 271 62 oxidants. The next section presents the work performed by our group toward the transition metal-free synthesis of fluorobenzenes from aryl boronic acids.   3.2 Results and discussion: metal free fluorination of aryl boronic acids   J. Leung, a previous member of the Sammis group, tested reaction parameters, including time, equivalents of Selectfluor® (sequential and single addition), additives to force borate formation (including fluoride ion sources and carbonate bases), and solvents. He established the following protocol: phenylboronic acid (272) with 1.5 equivalents of Selectfluor® (added in one portion) was heated for 2 hours at 110 °C in deuterated water in a sealed tube, affording the fluorobenzene (273) 34% yield by 19F NMR analysis (Scheme 3.3).127 J. Leung also showed that manganese was unnecessary for deborylative fluorination of phenylboronic acids.    Scheme 3.3. Conversion of aryl boronic acid into fluorobenzene using Selectfluor®  In previous work performed by our partner Paquin group at the University of Laval, Québec focused on fluorination experiments of different boronate esters. The Paquin group screened a number of reaction conditions using electrophilic N-F reagents, such as NFSI, N-fluoropyridinium salts and Selectfluor®, additives NaF, CsF, KF and copper catalysts, as well as trying different reaction conditions.  Overall, the highest yields of 33% and 35% were observed when 3.0 equivalents of Selectfluor® in the presence of NaF or Et3N·3HF additives in MeCN/H2O (ratio 9:1) solvent (Scheme 3.4).    Scheme 3.4. Fluorination reaction with Selectfluor® BD2O, 110 ˚C(in a sealed tube)F1.5 equiv F-TEDA-BF434%OHOH272 273R RPh"B"F-TEDA-BF4, additivesolvent (0.38 M), T ˚ C, time PhF274 275 63 However, given the low yields throughout all the screening of the reactions and application of 3 equivalents of Selectfluor® to access the target product, Paquin’s protocol did not give the promising results. Thus, in order to optimize the reactions of J. Leung and the Paquin’s group, we began examining a number of transition metal-free reaction conditions using Selectfluor® as a fluorine atom source and additives (Scheme 3.5).    Scheme 3.5. Conversion of aryl boronic acid into fluorobenzene  As mentioned earlier, the previous work performed in the Sammis group has demonstrated that Selectfluor® can effectively fluorinate alkyl radicals.9,64,105 Therefore, I studied fluorination of (4-methylphenyl)-boronic acid (Figure 3.1, 276), pinacol phenylboronate (277), (3-pyridinyl) boronic acid (278), 4-methylphenylboronic acid pinacol ester (279) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-o-xylene (280), employing J. Leung’s optimized conditions: a variety of additives and solvents were screened with 2 hours of reaction time at 110 °C in a “sealed” microwave vial.    Figure 3.1. Boronic acid substrates for fluorination reactions    B OHOHRFR F-TEDA-BF4B(OH)2 B OONB OHOHB OOB OO276 277 278279 280 64 The first substrate that I investigated was (4-methylphenyl)-boronic acid (276), and the best result of 22% yield was obtained, when 1.5 equivalents of Selectfluor®-PF6 was used in deuterated water/acetonitrile solvent system (Table 3.1, entry 7). The second best yield was 17%, when N-methylmorpholine-N-oxide (NMO) was added as an additive (entry 13). Both Selectfluor®-BF4 and Selectfluor®-PF6 showed highest results of 12% and 22%, respectively, in D2O/CD3CN solvent system. No reaction was detected in a number of organic solvents, such as C6D6, CD2Cl2, THF-d8 and toluene-d8.     Table 3.1. Fluorination of 4-methylbenzene boronic acid  Entry Source of fluorine Additive Solvent Yield∗  1 Selectfluor®-BF4 (1.5 eq.) - D2O/CD3CN 12% 2 Selectfluor®-BF4 (1.5 eq.) - CD3OD 10% 3 Selectfluor®-BF4 (1.5 eq.) - C6D6 No reaction 4 Selectfluor®-BF4 (1.5 eq.) - CD2Cl2 No reaction 5 Selectfluor®-BF4 (1.5 eq.) - THF-d8 No reaction 6 Selectfluor®-BF4 (1.5 eq.) - Toluene-d8 No reaction 7 Selectfluor®-BF4 (1.5 eq.) - D2O/CD3CN 22% 8 Selectfluor®-BF4 (1.5 eq.) - C6D6 No reaction 9 Selectfluor®-BF4 (1.5 eq.) - CD2Cl2 No reaction 10 Selectfluor®-BF4 (1.5 eq.) - THF-d8 No reaction 11 Selectfluor®-BF4 (1.5 eq.) - Toluene-d8 No reaction 12 Selectfluor®-BF4 (1.5 eq.) - CD2Cl2/D2O No reaction 13 Selectfluor®-BF4 (1.5 eq.) NMO (1.0 eq.) CD3OD 17% 14 Selectfluor®-BF4 (1.5 eq.) NMO (1.0 eq.) D2O/CD3CN 1%        ∗All reaction yields were determined using ethyl trifluoroacetate as an internal standard  It is possible that (4-methylphenyl)-boronic acid was not a good substrate for fluorodeborylation and better optimization results could have been obtained with another boronic acid derivative. Hence, the fluorination of pinacol phenylboronate (277) was examined (Table 3.2). Interestingly, the reaction proceeded to afford fluorobenzene (282) in higher yields than boronic acid. The transformation of pinacol phenylboronate into B(OH)2 Fluorine source,solvent, additive110 ˚C, 2 hF276 281 65 fluorobenzene worked well with Selectfluor®-PF6 in CD3OD, and fluorinated product was obtained in 53% yield (entry 4). Likewise, Selectfluor®-PF6 in a range of solvents (entries 5-8) led to successful conversions in 15-36% yield. To the reaction mixture of pinacol phenylboronate and Selectfluor®-PF6, was added di-tert-butyl peroxide (DTBP) as an additive, and it provided the corresponding product in 36% yield. The yield was lower, 30%, when no additive was used (entry 6). When Selectfluor®-PF6 was used in D2O/CD3CN solvent in the presence of additives 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) or manganese (III) triacetate dihydrate (Mn(OAc)3•H2O), no product was observed (entry 1-3). Overall, the best result of 53% yield was obtained for pinacol phenylboronate using Selectfluor®-PF6 in CD3OD solvent.   Table 3.2. Fluorination of pinacol phenylboronate  Entry Source of fluorine Additive Solvent Yield∗  1 Selectfluor®-PF6 (1.5 eq.) DDQ (1.0 eq.) D2O/CD3CN No reaction 2 Selectfluor®-PF6 (1.5 eq.) DDQ (1.0 eq.) D2O/CD3CN No reaction 3 Selectfluor®-PF6 (1.5 eq.) Mn(OAc)3 dihydrate (1.0 eq.) D2O/CD3CN No reaction 4 Selectfluor®-PF6 (1.5 eq.) - CD3OD 53% 5 Selectfluor®-PF6 (1.5 eq.) DTBP (1.0 eq.) D2O/CD3CN 36% 6 Selectfluor®-PF6 (1.5 eq.) - D2O/CD3CN 30% 7 Selectfluor®-PF6 (1.5 eq.) - CD3CN 20% 8 Selectfluor®-PF6 (1.5 eq.) - 1-propanol 15% 9 Selectfluor®-PF6 (1.5 eq.) - C6D6 No reaction 10 Selectfluor®-PF6 (1.5 eq.) - 2-propanol 6% 11 Selectfluor®-PF6 (1.5 eq.) DDQ (1.0 eq.) 2-propanol No reaction 12 Selectfluor®-PF6 (1.5 eq.) - hexafluoroisopropanol No reaction 13 Selectfluor®-PF6 (1.5 eq.) - 2,2,2-trifluoroethanol No reaction ∗All reaction yields were determined using ethyl trifluoroacetate as an internal standard  B OOFluorine source,solvent, additiveF277 282110 ˚C, 2 h 66 A working model for the mechanism of fluorination reaction is outlined in Scheme 3.6. The biphenyl boronic acid (283) is excited to 284, a better electron donor than the ground state molecule. A SET step occurs between 284 and Selectfluor®, resulting in the oxidized species 285, which then undergoes a fluorodecarboxylation to afford 287. However, we do not have any experimental evidence to support this mechanism.               Scheme 3.6. Proposed SET mechanism of fluorodeborylation  It was next decided to investigate fluorination of the pyridine ring, given the fact that it is one of the most common heterocycles in drug discovery.128 More than 100 pharmaceutical drugs contain a pyridine ring unit: esomeprazole (Nexium), loratadine (Claritin) and recently approved cancer therapeutic crizotinib (Xalkori).128 As a result, methods to functionalize derivatives of pyridines have been highly sought.128 The testing studies were performed using Selectfluor®-PF6, Selectfluor®-BF4 and XeF2 as atomic fluorine sources. Treatment of (3-pyridinyl) boronic acid (262) with fluorine sources and additives in different solvents was studied, as outlined in Table 00. Different additives were screened to examine the product yield, including N-methylmorpholine-N-oxide (NMO), DDQ, Mn(OAc)3•H2O and DTBP. Since the previous reactions run with pinacol phenylboronate revealed that Selectfluor®-PF6 in CD3OD to be the best condition, we started by applying this reaction condition to (3-pyridinyl) boronic acid. However, the corresponding product, 3-fluoropyridine (272), was never observed.  PhB(OH)2283hvPhB(OH)2284O HHF-TEDA-BF4PhB(OH)2285O HHF-TEDA-BF4PhB(OH)2286O HHFB(OH)3PhF287 67 Table 3.3. Fluorination of (3-pyridinyl) boronic acid  Entry Source of fluorine Additive Solvent Yield∗  1 Selectfluor®-BF4 (1.5 eq.) NMO (1.0 eq.) CD3OD No reaction 2 Selectfluor®-BF4 (1.5 eq.) NMO (1.0 eq.) D2O/CD3CN No reaction 3 Selectfluor®-BF4 (1.5 eq.) NMO (1.0 eq.) C6D6 No reaction 4 Selectfluor®-BF4 (1.5 eq.) NMO (1.0 eq.) CD2Cl2 No reaction 5 Selectfluor®-BF4 (1.5 eq.) NMO (1.0 eq.) THF-d8 No reaction 6 Selectfluor®-BF4 (1.5 eq.) NMO (1.0 eq.) Toluene-d8 No reaction 7 Selectfluor®-BF4 (1.5 eq.) NMO (1.0 eq.) CD2Cl2/D2O No reaction 8 Selectfluor®-PF6 (1.5 eq.) DDQ (1.0 eq.) CD3OD No reaction 9 Selectfluor®-PF6 (1.5 eq.) DDQ (1.0 eq.) D2O/CD3CN No reaction 10 Selectfluor®-PF6 (1.5 eq.) DDQ (1.0 eq.) CD2Cl2 No reaction 11 Selectfluor®-PF6 (1.5 eq.) DDQ (1.0 eq.) THF-d8 No reaction 12 Selectfluor®-PF6 (1.5 eq.) DDQ (1.0 eq.) CD2Cl2/D2O No reaction 13 Selectfluor®-PF6 (1.5 eq.) Mn(OAc)3 dihydrate (1.0 eq.) CD3OD No reaction 14 Selectfluor®-PF6 (1.5 eq.) Mn(OAc)3 dihydrate (1.0 eq.) D2O/CD3CN No reaction 15 Selectfluor®-PF6 (1.5 eq.) Mn(OAc)3 dihydrate (1.0 eq.) CD2Cl2 No reaction 16 Selectfluor®-PF6 (1.5 eq.) Mn(OAc)3 dihydrate (1.0 eq.) THF-d8 No reaction 17 Selectfluor®-PF6 (1.5 eq.) Mn(OAc)3 dihydrate (1.0 eq.) Toluene-d8 No reaction 18 Selectfluor®-PF6 (1.5 eq.) Mn(OAc)3 dihydrate (1.0 eq.) D2O/ CD3OD No reaction 19 Selectfluor®-PF6 (1.5 eq.) DTBP (1.0 eq.) CD3OD No reaction 20 Selectfluor®-PF6 (1.5 eq.) DTBP (1.0 eq.) D2O/CD3CN No reaction 21 Selectfluor®-PF6 (1.5 eq.) DTBP (1.0 eq.) CD2Cl2 No reaction 22 Selectfluor®-PF6 (1.5 eq.) DTBP (1.0 eq.) THF-d8 No reaction 23 Selectfluor®-PF6 (1.5 eq.) DTBP (1.0 eq.) D2O/ CD3OD No reaction ∗All reaction yields were determined using ethyl trifluoroacetate as an internal standard  To gain further insight into the substrate scope, 4-methylphenylboronic acid pinacol ester (279) substrate was subjected to the same as previous reaction conditions (Table 3.4). Similar to (3-pyridinyl) boronic acid substrate, the corresponding fluorination product of boronic acid was never detected, when both Selectfluor®-PF6and XeF2 were used. NB OHOHNFFluorine source,solvent, additive110 ˚C, 2 h278 288 68 Fluoromethylbenzene (289) was never observed and the main product was C6D5F when XeF2 was employed.  Table 3.4. Fluorination of 4-methylphenylboronic acid pinacol ester  Entry Source of fluorine Additive Solvent Yield∗  1 XeF2 (2.0 eq.) - C6D6 mainly C6D5F 2 XeF2 (1.0 eq.) Selectfluor®-BF4 (1.5 eq.) C6D6 mainly C6D5F 3 XeF2 (1.0 eq.) Selectfluor®-PF6 (1.5 eq.) C6D6 mainly C6D5F 4 Selectfluor®-PF6 (1.5 eq.) - 2,2,2-trifluoroethanol No reaction ∗All reaction yields were determined using ethyl trifluoroacetate as an internal standard  Analogous to the previous pinacol ester substrate, the fluorination of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-o-xylene (280) was studied (Table 3.5); however, the optimized reaction conditions failed to affect xylene derivative. The conversion of the boronate ester derivative into 4-fluoro-1,2-o-xylene in various solvents (D2O/CD3CN, CD3OD, CD3CN and hexafluoroisopropanol) did not provide the target product (290). Table 3.5. Fluorination of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-o-xylene   Entry Source of fluorine Additive Solvent Yield∗  1 Selectfluor®-PF6 (1.5 eq.) - D2O/CD3CN No reaction 2 Selectfluor®-PF6 (1.5 eq.) - CD3OD No reaction 3 Selectfluor®-PF6 (1.5 eq.) - CD3CN No reaction 4 Selectfluor®-PF6 (1.5 eq.) DDQ (1.0 eq.) CD3OD No reaction 5 Selectfluor®-PF6 (1.5 eq.) - hexafluoroisopropanol No reaction ∗All reaction yields were determined using ethyl trifluoroacetate as an internal standard B OO FFluorine source,solvent, additive110 ˚C, 2 h279 289B OOFFluorine source,solvent, additive110 ˚C, 2 h280 290 69 There is more to investigate in the fluorodeboryaltion of aryl boronic acids with Selectfluor® as atomic fluorine source. To optimize the yields of the target products, various substrates that have greater electron density (Figure 3.2, 275 and 276) can be tested. The increased electron density on the aromatic ring can facilitate the fluorodeborylation process via formation of “ate” complexes.    Figure 3.2. Electron dense boronic acid derivatives   3.3 Conclusion  Overall, a route to functionalize the boronic acid derivatives through metal catalyst free method was further investigated. Fluorine sources, such as Selectfluor®-BF4 and Selectfluor®-PF6 in different solvent systems and in the presence of a range of additives were screened. The proposed mechanism of the new method of fluorination involves radical intermediates. We were not able to obtain promising results in order to further develop experimental conditions: the general product yields are low and substrate scope is narrow. While 4-methylphenylboronic acid (260) (10-22% yield) and pinacol phenylboronate (261) (6-53%) gave corresponding products (265 and 266), substrates 3-pyridinyl boronic acid (262) and phenyl-boronic acid pinacol esters (263 and 264) did not give any target products. The best yield that was obtained during the screening was for pinacol phenylboronate (261) (53%). Although the reaction conditions are milder compared to the present available methods, this strategy still needs significant improvements, as such current strategies that utilize transition metal catalysts are favoured.111     PhBONOOOBrBONOOO291 292 70 Chapter 4. Conclusions and future work  Two different research projects have been presented in this thesis. They involve new radical methodologies to introduce fluorine in structurally important molecules utilizing XeF2 (Chapter 2) and Selectfluor® (Chapter 3). Chapter 1 of this written work described concepts from fluorine chemistry. The chapter summarized fluorine chemistry history and the effect of the presence of this atom on the bioactivity of some molecules. In addition, a description of traditional nucleophilic, electrophilic as well as radical sources of fluorine was also included.    Scheme 4.1. Studies performed in thesis work  In Chapter 2, the synthesis of aryl trifluoromethyl ethers focused on developing operationally simple, functional group tolerant method using benign aryl substrates such as difluoroaryloxyacetic acids with bench-top stable XeF2. The chapter also summarizes synthetic strategies to access trifluoromethoxylated molecules that have been developed previously. The method was examined for a number of substrates, producing the trifluoromethoxy ethers in very fast reaction (3-5 min). The substrates with electron-withdrawing substituents gave relatively higher yields (51-64%) than substrates with electron-donating groups (4-25%), whereas naphthol derivatives produced (3-15%).  My colleague Max Epifanov in the Sammis group is exploring the possibility of trifluoromethoxylation of the natural products (Figure 4.1). A number of complex organic molecules are being investigated under several reaction conditions.  OR OHFFO1.0 equiv. XeF2CDCl3, r.t., 3 - 5 min.ORFFFradical fluorodecarboxylation (Chapter 2)"B"R F-TEDA-BF4, additivesolvent, 110 ˚C, 2 hFRfluorination of boronic acids (Chapter 3) 71   Figure 4.1. Difluoroacetic acid substrates for trifluoromethoxylation  Furthermore, my colleagues will then explore fluorodecarboxylation reaction of monofluoroacetic acids to synthesize difluoromethyl ethers, which are also important biological moieties. Substrate scope of this methodology will be investigated, along with mechanistic studies of this process.       Scheme 4.2. Proposed synthesis of difluoromethyl ethers through fluorodecarboxylative fluorination.  Future endeavors for the synthesis of trifluoromethoxyarenes can be two different routes: extension of substrate scope to natural products and preparation of 18FXeF with the possibility to introduce 18F-labelled fluorine into organic molecules. Due to the very fast fluorodecarboxylation time, this method could be used in the late-stage incorporation of 18F-labelled fluorine for PET tracers. The aryl fluorides were prepared from arylboronic acid and arylboronate derivatives using Selectfluor® in a transition metal-free fluorination methodology. I investigated a number of different substrates in numerous solvents and in the presence of additives; however, the general product yields were low and substrate scope was narrow. Whereas 4-methylphenylboronic acid and pinacol boronate gave corresponding products, substrates 3-NHO FFOHOOHHHOFFHO OOOH OOFFHOOO OOF FHOO293 294295 296OR OHFOORFFXeF2 72 pyridinyl boronic acid and phenyl-boronic acid pinacol esters did not give any target products.                73 Bibliography  1. Phelps, M. E. Proc. Natl. Acad. Sci. 2000, 97, 9226-9233.  2. Müller, K.; Faeh, C.; Diederich, F. Science 2007, 317, 1881–1886. 3. Isanbor, C.; O’Hagan, D. Journal of Fluorine Chemistry 2006, 127, 303–319. 4. 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Nature Chemistry 2013, 5, 54–60.                     80 Appendix Selected spectra for Chapter 2                      81 Ethyl 2,2-difluoro-2-[3,4-difluoro-phenoxy] acetate (246):    82 Ethyl 2,2-difluoro-2-[2,4,6-trimethyl-phenoxy] acetate (247):   83    84 Ethyl 2,2-difluoro-2-[3,5-bis(trifluoromethyl)phenoxy] acetate (248):   85  Ethyl 2,2-difluoro-2-[4-(trifluoromethyl)phenoxy] acetate (249):  86    87  Ethyl 2,2-difluoro-2-[2,5-dimethyl-phenoxy] acetate (250):   88  Ethyl 2,2-difluoro-2-[2,4-dichloro-1-naphthalenoxy] acetate (251):  89    90    91 Ethyl 2,2-difluoro-2-[6-bromo-2-naphthalenoxy] acetate (252):   92  Ethyl 2,2-difluoro-2-[1-naphthalenyloxy)] acetate (253):  93    94   2-[3,4-difluoro-phenoxy]-2,2-difluoro-acetic acid (254):  95    96 2-[2,4,6-trimethyl-phenoxy]-2,2-difluoro-acetic acid (255):   97    98 2-[3,5-bis(trifluoromethyl)phenoxy]-2,2-difluoro- acetic acid (256):   99  2-[4-(trifluoromethyl)phenoxy]-2,2-difluoro-acetic acid (257):  100    101  2-[2,5-dimethyl-phenoxy]-2,2-difluoro-acetic acid (258):  102    103 2-[2,4-dichloro-1-naphthalenoxy]-2,2-difluoro- acetic acid (259):   104    105 2-[6-bromo-2-naphthalenoxy]-2,2-difluoro- acetic acid (260):   106  2,2-difluoro-2-(1-naphthalenyloxy)-acetic acid (261):  107    108  1-bromo-4-(trifluoromethoxy)-benzene (227):  109    110 1-bromo-3-(trifluoromethoxy)-benzene (228):   111    112 2,4-bis(1,1-dimethylethyl)-1-(trifluoromethoxy)-benzene (229):   113  1-(1,1-dimethylethyl)-4-(trifluoromethoxy)-benzene (230):  114    115  1-chloro-4-(trifluoromethoxy)-benzene (231):  116    117  2,4-dichloro-1-(trifluoromethoxy)-benzene (232):  118    119  4-(trifluoromethoxy)-1,1'-biphenyl (233):  120    121 1,2-difluoro-4-(trifluoromethoxy)-benzene (234):   122    123 1,3,5-trimethyl-2-(trifluoromethoxy)-benzene (235):   124  1-(trifluoromethoxy)-3,5-bis(trifluoromethyl)-benzene (236):  125    126   1-(trifluoromethoxy)-4-(trifluoromethyl)-benzene (237):  127    128 1,4-dimethyl-2-(trifluoromethoxy)-benzene (238):   129    130 2,4-dichloro-1-naphthalenoxy-1-(trifluoromethoxy)-benzene (239):   131  [6-bromo-2-naphthalenoxy]-1-(trifluoromethoxy)-benzene (240):  132    133  

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