Dr David M Perrin

Samson Lai

The B-F bond has an expansive and rich history in chemical transformations and the versatility of the B-F bond has also shown immense utility in fields as far reaching as PET and NIRF imaging. The application of B-F bonds for nucleophilic C-F bond formation and the development of novel fluorophores with potential applications in PET/NIRF bi-modal imaging are investigated in this work.

Organotrifluoroborates are well known as indispensable synthetic tools for the elaboration of organic molecules. However, the trifluoroborate functionality is generally regarded as an auxiliary group, and its potential as a nucleophilic F -source has remained untested. In this context, the ability of organotrifluoroborates to serve as competent sources of F -was investigated. In an update to the historic Balz-Schiemann reaction, that traditionally uses BF4 -as a source of F -, organotrifluoroborates were shown to mediate the fluorodediazoniation of in situ generated aryl diazonium salts under mild reaction conditions (chapter 2). In reactions with an analogous substrate class, unsymmetrical diaryliodonium salts could also be fluorinated using phenyltrifluoroborate via thermal decomposition of the ion pair (chapter 3). Finally, the ability of the trifluoroborate moiety to mediate intramolecular fluorination reactions was investigated through the synthesis of various trifluoroborate-containing molecular scaffolds (chapter 4).

We also investigated novel fluoroborate (B-Fn) complexes of the 2-aryl-benzothiazole scaffold, known for its interaction with Aβ aggregates, as fluorophores. Three complexes were isolated, characterised and their photophysical properties are reported. A 2,4-diarylbenzothiazole monofluoroborate complex displaying the most promising photophysical iii properties, was shown to be stable to aqueous conditions. Fluoride abstraction from this complex was also demonstrated, providing promising preliminary results towards the viability of radiolabelling via 19 F-18 F isotope exchange. The monofluoroborate complex also showed interesting structural properties given the asymmetric boron centre.

Enantiomers of the complex were successfully chirally resolved from the racemic mixture, characterised by Circular Dichroism and their stability to racemization via inversion investigated (chapter 5).

iv

Lay Summary

This work focuses on new uses and applications of the Boron-Fluorine chemical bond; organic compounds containing this bond are called 'organofluoroborates'. Our work has focused on investigating the use of organofluoroborates as a source of fluorine for chemical reactions in which a substrate is fluorinated, which is a departure from the classical use of organofluoroborates. We have also investigated the synthesis and characterisation of new organofluoroborates as potential tools in medical imaging.

List of Tables

 Table 1.1 Bond Dissociation Energies of O-F or N-F bond from selected electrophilic fluorine reagents 14,15 5.11, 5.12, 5.15 and 5.17 H3PO4 aq. (0,5 éq.), Phényltrifluoroborate de potassium (0,38 mmol), t-BuOH (1,3 ml) dans un flacon de pression avec capuchon doublé de téflon, purge Ar, puis t-BuONO (0,38 mmol), t.a. pendant 20 min, puis chauffé à 45-50 °C pendant 2h. Rendement déterminé par RMN 19 (2-methylphenyl)(phenyl)iodonium fluoride (3.28). 209 Noël et al., Chem. Soc. Rev., 2013, 42, 7747-7762, copyright Royal Society of Chemistry) ......... 190 xxiii Figure 5.2 [ 11 C]-PiB standardized uptake value (SUV) in healthy (left) and AD (right) patients (adapted with permission from Klunk et al., Ann. Neurol., 2004, 55, 306-319, copyright John Wiley and Sons) 5.5 CD spectra of 5.19rac, 5.19a and 5.19b 19 F and 11 B NMR spectra evolution for 5.17 This thesis is built around one central theme, the Boron-Fluorine (B-F) bond. The B-F bond has an expansive and rich history in chemical transformations as well as materials and fundamental bonding studies, while finding valuable applications in organic structure elaboration by contributing to the domains of cross-coupling reactions, 1 fluoride ion capture and sensing, 2 and fluorination in both chemical and radiochemical contexts 3 among countless others. The versatility of the B-F bond has also shown immense utility in fields as far reaching as Positron Emission Tomography (PET) 4 and fluorescence imaging 5 . We are especially interested in the use of the B-F for nucleophilic Carbon-Fluorine (C-F) bond formation and the development of novel fluorophores with potential applications as bi-modal PET/fluorescence imaging agents. A general bibliographic presentation of the B-F bond in C-F bond formation and its use in PET and fluorescence imaging probes will be detailed in this chapter.

Sources of fluorine in organic synthesis

The fluorine atom is a versatile tool in the chemist's tool box. Its incorporation in a molecule can have dramatic effects on pKa, conformation, lipophilicity, bioavailability and metabolic stability. [6][7][8][9][10][11] The remarkable ability of fluorine to induce such favourable properties has underscored the need for and driven the development of practical and efficient fluorination methodologies. To this end, various nucleophilic, electrophilic and radical fluorination strategies have been reported. 12 Chapter 1 Introduction 2

Electrophilic and radical sources of fluorine

Generally, the sources of fluorine described below can function as sources of both electrophilic (F + ) and radical (F . ) fluorine, expression of either form of reactivity is highly dependent on reaction conditions. The main source of F + and F . is F2, this gas is highly reactive and as such reactions can often be unselective; diluting F2 in inert gases (N2)

has been used as a strategy to control reactivity. 13 Xenon difluoride (XeF2) has been found as an easier to handle alternative. F + itself does not exist as an independent species, however several strategies have been developed to allow nucleophilic attack at fluorine effectively allowing F + transfer. The use of electron-withdrawing or good leaving groups adjacent to fluorine have been successful in the generation of numerous F + reagents (Scheme 1.1). Fluoroxy reagents, such as trifluoro and acetyl hypofluorite, can serve as both F + and F .

sources, however their toxicity and latent explosivity has limited their use. 13 Through the stronger N-F bond (see Table 1.1), N-F reagents are more stable and have the added advantage of usually being solid and crystalline facilitating their handling. 13 Given these favourable properties a vast number of N-F reagents have been developed the most Table 1.1 Bond Dissociation Energies of O-F or N-F bond from selected electrophilic fluorine reagents 14,15 Reagent Bond Dissociation Energy (kcal/mol)

trifluoromethyl hypofluorite (O-F)

Nucleophilic sources of fluorine

Typical sources of nucleophilic "naked" fluoride (F -) are inorganic alkali metal fluoride (MF) salts such as NaF, KF, CsF and KHF2. However, these salts are generally insoluble in organic solvents due to tight ion-pair formation. While soluble in water, F -displays low nucleophilicity due to its high hydration energy (-104 kcal/mol). 16 Common strategies for improving the solubility and reactivity of MF salts include increasing reaction temperatures and the use of chelating agents (crown ethers or cryptands) or solvents (glymes and glycols). 13 Efforts to overcome inherent drawbacks of MF salts led to development of various nucleophilic fluorinating agents (Scheme 1.2). Tetra-n-butylammonium (TBAF) has become a widely used fluorinating agent, and further advancements by DiMagno et al. in the production of anhydrous TBAF demonstrate the effectiveness of this reagent in the fluorination of various substrates. 17,18 Polypyridinium hydrogen fluoride, more commonly known as "Olah's reagent", and other alkyl amine hydrogen fluorides were developed to "tame" the corrosive nature of anhydrous hydrogen fluoride, and have found widespread applications in the fluorination of alkene and epoxide functionalities. 13,19,20 Sulphur-based reagents such as diethylaminosulphur trifluoride (DAST) and Deoxo-Fluor ® have been successfully used in deoxofluorination reactions.

Scheme 1.2 Selected nucleophilic fluorinating agents.

Ritter et al. have also developed a suite of deoxyfluorination reagents that use simple MF salts (CsF and KF) as sources of F -(Scheme 1.3). These reagents activate the alcohol or phenol into a leaving group which then allows facile fluorination by F -. Using these reagents, a wide substrate scope of phenols and alcohols can be fluorinated with good functional group tolerance. 21 PhenoFluor TM will be discussed in further detail in chapter 4. andc) oxidation of the substrate to form a carbon-centred radical or radical cation species followed by radical fluorination (Scheme 1.4). 22 Examples of these pathways will be discussed in the next section.

The B-F bond as a F-source

The use of the B-F bond as a F -source for various organic transformations is well documented. Historical applications and new paradigms using B-F bonds for fluorination will be outlined in the following sections.

BF4-and BF3•OEt2 as F-sources

The use of the tetrafluoroborate ion (BF4 -) and boron trifluoride diethyl etherate (BF3•OEt2) as sources of F -remain attractive as they are inexpensive, easy to use, soluble in organic solvents and are of low molecular weight and high F -content. 3 BF4 -and BF3•OEt2 have been employed in a multitude of reactions including the ring-opening fluorination of strained ring systems, and addition to unsaturated systems such as alkenes and alkynes (examples of these reactions will be detailed in chapter 4). The following section will

present selected examples of the application of BF4 -and BF3•OEt2 as F -sources in C-F bond formation.

The earliest and most representative example of BF4 -as a F -source is the Balz-Schiemann reaction, first reported in 1927 (Scheme 1.5). 23 While this reaction will be the focus of chapter 2, it is an important milestone to mention in the use of the B-F bond for fluorination.

Chapter 1 Introduction An alternative approach to the synthesis of aryl fluorides, reported by Pinhey et al., is the fluorodeplumbation of aryllead(IV) acetates by excess BF3•OEt2 (Scheme 1.6). This methodology allowed the synthesis of a range of electron-rich and electron-poor aryl fluorides in low to good yields. 24,25 Fluorination was proposed to occur via BF3-assisted The authors also reported that simple arenes could be fluorinated in good yields in the presence of catalytic amounts of Hg(OAc)2 and stoichiometric amounts of Pb(OAc)4 in Chapter 1 Introduction 8 BF3•OEt2 (Scheme 1.7). 24 The transformation is proposed to occur via initial electrophilic aromatic mercuration, followed by transmetalation from mercury to lead, after which fluorination occurs through similar intermediates proposed in scheme 1.6.

heterolytic
Scheme 1.7 Fluorination of simple arenes BF3•OEt2.

Miyamoto et al., reported access to aryl fluorides via selective para-fluorination of 3phenylpropyl ethers in low to good yields (Scheme 1.8). 26 The hypervalent phenyl-λ 3iodane mediated reaction is proposed to occur via initial electrophilic iodination of 1.3 at the para position, followed by intramolecular ether oxygen attack to furnish intermediate Bloodworth and Mitchell et al. demonstrated the fluorination of halocarbenium ions in the presence of BF4 -that afforded convenient access to gem-difluorides under mild conditions (Scheme 1.9). 27 Silver-induced dehalogenation of gem-dichlorides and iodides 1.7, generates halocarbenium ion 1.8, which is consequently fluorinated by BF4 -to provide a series of gem-difluorides 1.9 in moderate yields. Under these same conditions, α,α,αtrifluorotoluene could be obtained from α,α,α-trichlorotoluene in 48% yield. An important reaction class in which BF4 -and BF3•OEt2 have found notable applications is the Prins cyclization-fluorination (Scheme 1.11). One-, two-and three-component oxa-Prins cyclization-fluorination reactions allow access to a variety of substituted 4fluorotetrahydropyrans. [29][30][31] Similarly, substituted 4-fluoropiperidenes can be synthesized through one and two component aza-Prins cyclization-fluorination. 30,32 When BF3•OEt2 is used as the F -source, diastereoselectivities of oxa-and aza-Prins cyclization-fluorination products were generally found to be low as reported by O'Hagan et al. 30 Interestingly, Yadav et al. showed that switching to HBF4•OEt2 improved yields and allowed the formation of 4-fluorotetrahydropyran and 4-fluoropiperidene products as single diastereomers. 33,34 Chapter 1 Introduction

Organofluoroborates as F-sources

In contrast to the abundant use of BF4 -and BF3•OEt2, there are few reports describing the use of organofluoroborates as nucleophilic F -sources. Building on their expertise in the design and synthesis of cationic borane systems for F -sensing, 2,35,36 Gabbaï and Zhao reported the application of sulfonium boranes in the capture of F -from aqueous solutions, followed by nucleophilic fluorination of organic substrates via a triggered release of F -in organic solutions (Scheme 1.12). 37 Sulfonium borane 1.15, obtained from the methylation of 1.14, could be efficiently converted to the corresponding zwitterionic sulfonium fluoroborate 1.16 using KF in wet MeOH, highlighting the fluorophilicity of boron and the ability of cationic borane species to sequester F -from aqueous solutions.

Characterization of zwitterion 1.16 led the authors to conclude that the ability of 1.15 to sequester F -from aqueous solutions was due to favourable Coulombic effects and additional stabilization provided by donor-acceptor interaction between a lone pair on F and the Sulphur-Carbon (S-C) σ* orbital. They further rationalized that if these stabilizing factors could be removed, then the lability of the B-F bond would greatly increase and F - release could be triggered.

Scheme 1.12 Synthesis of zwitterionic sulfonium fluoroborate 1.16.

Using tetra-n-butylammonium phenylthiolate (TBASPh), sulfonium fluoroborate 1. 16 could be demethylated to furnish fluoroborate 1.17. Addition of various organic substrates to solutions of 1.17 resulted in rapid and efficient fluorination of most substrates (Table 1.2, entries 1, 2 and 3), whereas fluorination of benzylchloride and 1-bromooctane required heating of reaction mixtures (entries 4 and 5). The authors concluded that at ambient temperatures F -transfer occurs directly from 1.17, however at elevated reaction temperatures 1.17 dissociates to produces anhydrous TBAF.

Chapter 1 Introduction 14 capture/release by cationic boranes to radiofluorination (Scheme 1.13). 38 Using phosphonium borane 1.18, known to sequester F -from aqueous solutions, the authors demonstrated the successful and quantitative trapping of 18 the zwitterionic phosphonium fluoroborate 1.19. Zwitterion 1. 19 was dried under a flow of N2 and heating to remove all traces of water. 18 F -release was triggered by anion exchange with tetra-n-butylammonium cyanide (TBACN), to produce anhydrous [ 18 F]-TBAF and phosphonium cyanoborate 1.20. The authors then demonstrated that the anhydrous [ 18 F]-TBAF could be used in the nucleophilic aromatic fluorination of 1,4dinitrobenzene to produce 4-[ 18 F]-fluoronitrobenzene in 48-55% radiochemical yield.

Scheme 1.13 18 F -capture/release using phosphonium boranes for radiofluorination.

The authors further demonstrated that the capture and release of 18 F -could be adapted to a solid-supported adsorption strategy (Scheme 1.14). A reverse-phase C18 cartridge was pre-loaded with 1.18 into which 18 F -in water/MeCN was eluted to quantitively produce 1.19 in the cartridge. Quantitative elution of 18 F -was achieved using a

MeCN/TBACN solution. The efficiency of this cartridge-based method was showcased by the synthesis of [ 18 F]-Setoperone, a 5-HT2A antagonist.

Scheme 1.14 Cartridge-based 18 F -capture/release in the production of [ 18 F]-Setoperone (adapted with permission from Perrio et al. Chem. Commun. 2017, 53, 340-333, copyright Royal Society of Chemistry).

Frohn et al. reported the only example of employing organotrifluoroborates as F -sources, describing the neat fluorodediazoniation of aryl diazonium perfluoroorganotrifluoroborates (Scheme 1.15). 39 This will be further detailed in chapter 2.

Scheme 1. 15 Fluorodediazoniation of aryl diazonium perfluoroorganotrifluoroborates.

Fluorination of organotrifluoroborates

At this point it is important to note that organotrifluoroborates have been previously used in fluorination reactions, not as sources of F -but as substrates. Petasis, Olah and Prakash et al. were the first to describe the electrophilic fluorination of alkenyl trifluoroborates using

Selectfluor ® to the corresponding alkenyl fluorides or difluoromethylated alcohols or amides (Scheme 1.16, a). 40 Over a decade later, Lemaire et al. extended this methodology towards the fluorination of aryl and benzylic trifluoroborates (Scheme 1.16, b). 41 The substrate scope of these transformations was expanded through metalmediated processes (Scheme 1.16, c). Sanford et al. reported a Cu I -mediated electrophilic fluorination of aryl trifluoroborates using N-fluoro-2,4,6-trimethylpyridinium triflate as an electrophilic fluorine (F + ) source. 42 The same authors then reported the Cu IImediated nucleophilic fluorination of aryl trifluoroborates using KF. 43 In the same year Ritter et al. described the Pd III -catalysed fluorination of aryl trifluoroborates with Selectfluor ® . 44 Finally, Dubakka et al. described the Ag I or Fe III -mediated electrophilic fluorination of aryl trifluoroborates using Selectfluor ® . 45,46 Scheme 1. 16 Metal-free fluorination of alkenyl (a) and aryl or benzylic (b) trifluoroborates. c, metalmediated/catalysed fluorination of aryl trifluoroborates.

The works discussed above are the only examples of the use of organofluoroborates as sources of F -for fluorination. Additionally, with only one report using organotrifluoroborates as a F -source, the application of organotrifluoroborates in this context has been overlooked and merits further investigation.

Molecular Imaging

Molecular imaging is a rapidly evolving and expanding field that plays increasingly important roles in drug development, early disease diagnosis and therapeutic evaluation. 47,48 Generally, molecular imaging is defined as the non-invasive "ability to visualize and quantitatively measure the function of biological and cellular processes in vivo". 47 Molecular imaging requires two important aspects: 1) the probe/ligand used to detect a specific biological process must display a change in concentration or spectral properties and 2) an appropriate method is available to monitor these probes. 48 Typically, in vivo molecular imaging probes are Near-Infrared (NIR) emitting molecules or compounds that have been labelled with radioisotopes. 47,48 Currently there are various molecular imaging modalities available, the choice of which is dependent on the desired application, these include: Computed Tomography (CT), PET, Single Photon-Emission CT (SPECT), Magnetic Resonance Imaging (MRI), Ultrasound (US) and Optical (nearinfrared fluorescence (NIRF)) imaging. The following sections will focus on the use of B-F bonds in probes designed for use in PET and NIRF imaging.

PET imaging

PET imaging is based on the emission of a positron (β + ) resulting from the decay of a radionuclide. The emitted β + travels a mean free path, dependent on its kinetic energy

(determined by the nature of the radionuclide), before colliding with an electron (e -) in the surrounding tissue and undergoing an annihilation event. The annihilation event results

in the simultaneous emission of two γ-rays of equal energy (511 keV) and opposite direction. The γ-rays are detected on opposite sides of a circular array of detectors, from which the position of the annihilation event can be determined. Reconstruction of the location of these annihilation events produces a 3D image of regions in which the positron-emitting probe has accumulated (Figure 1.1). A range of β + radionuclides are commonly used in PET imaging including 11 C, 15 O, 18 F, 64 Cu, 68 Ga and 89 Zr. Among these 18 F has emerged as a radionuclide of particular utility in the radiolabelling of small molecules due to its small size, sufficient half-life (t1/2 = 110 min), weak β + energy (shorter mean free path) and clean decay (97% β + decay).

Chapter 1 Introduction

20

Most 18 F-labelled radiopharmaceuticals are synthesized using nucleophilic 18 F -for C- 18 F bond formation, which is produced by the nuclear reaction of 18 O(p,n) 18 F through the proton bombardment of [ 18 O]-H2O in a cyclotron. 49,50 A consequence of the high hydration energy of the fluoride anion, radiotracer syntheses typically require the stringent "drying" of generated 18 F -. In most cases 18 F -is trapped on an anion exchange column, then eluted in a mixture of water and acetonitrile with a base and a cryptand (usually K.2.2.2). Water is ultimately removed by repeated cycles of azeotropic drying under heating, reduced pressure and inert gas flow. Finally, radiofluorination can occur in anhydrous solvent (routinely MeCN, DMSO or DMF) at elevated temperatures. 49 This process has been extensively used for the production of many 18 F-PET imaging probes, 49,50 most notably 2- ]-FDG) which has found extensive diagnostic applications in oncology among other domains (Scheme 1.17). 51,52 Scheme 1.17 Synthesis of [ ]-FDG.

[ 18 F]-fluoro-2-deoxy-D-glucose ([

B-F in PET Imaging

To circumvent some of the limitations associated with traditional C- 18 F bond formation, other groups have looked towards harnessing the fluorophilicity of main group elements as a way to introduce 18 F into molecules of interest. To this end, 18 F-labelling has been reported with the formation of P- 18 F, 53,54 Si- 18 F, 55-58 B- 18 F bonds, and Al- 18 F 59-61 and Ga-

The use of the B-F bond in this context is particularly interesting given boron's high affinity for fluoride, demonstrated by the plethora of organotrifluoroborates used in synthesis 1 and the application of triarylboranes as fluoride sensors. 2 The first example of B- 18 F formation was reported by Perrin et al. in 2005, where the authors showed that a biotinylated aryl boronic ester 1.21 could be easily converted into the corresponding radiolabelled [ 18 F]-trifluoroborate 1.22 (Scheme 1.18). 64 They also observed that the specific activity (SA) of 1.22 was three times that of the source 18 F, highlighting that boron can be used to effectively concentrate radioactivity and triple SA. be observed (free 18 F -is deposited in bone due to the presence of high concentrations of calcium). 66 Further validation was provided by the conjugation of the same phenylboronic ester to marimastat, a noncovalent matrix metalloproteinase inhibitor, for tumour targeting. Conjugate 1.24 was radiolabelled under aqueous conditions in one-step to [ Building on the seminal work reported by Shirrmacher et al. on the 18 F radiolabelling of organosilyl fluorides by isotope exchange (IEX) 69 ,Perrin et al. reported that this procedure could be extended to a kit-like approach using trifluoroborate-labelled precursors (Scheme 1.20). 70,71 IEX is an attractive radiolabelling method as the stable precursor can Chapter 1 Introduction

23

be synthesized and stored beforehand, also the precursor is the product so time consuming purification methods can be avoided. 72 This one-pot two-step method, using radiosynthon 1.27, could also be applied to the radiolabelling of biological molecules of interest and used in in vivo animal models. [72][73][74] Chapter 1 Introduction With the demonstrated fluorophilicity and hydrolytic stability of cationic boranes, as demonstrated by Gabbaï et al., 35,36,[75][76][77][78] Ammoniomethyltrifluoroborate (AMBF3 -), reported by Perrin et al., 79 is facilely prepared from the preceding tertiary amine followed by treatment with KHF2 (Scheme 1.22).

AMBF3

-was demonstrated to be hydrolytically stable and could be "clicked", via the alkyne moiety, to a variety of tumour targeting peptides including octreotate, bombesin and bradykinin and successfully employed in in vivo animal models. . NHC-BF3 could be "click" conjugated to a series of tumour peptides (cyclic RGD and neurotensin) using thiol-Michael addition to the maleimide group. 83,84 Gabbaï et al. also showed that phosphonium trifluoroborate 1.29

was suitably stable and easily radiolabelled. Zwitterionic 1.29 was conjugated to indomethacine and successfully radiolabelled via IEX and shown to be stable in vivo (Scheme 1.22). 85 The radiolabelling of boron-dipyrromethene (BODIPY) dyes also represents an emerging application due to their popularity as fluorescent tags in biology and their potential as bimodal imaging agents (PET and NIRF). 86 However, given the stability of B-F bonds in these compounds, radiolabelling via IEX usually requires Brønsted or Lewis acid activation; these conditions will be further detailed in chapter 5. Radiolabelled BODIPY dyes have been successfully conjugated to the Trastuzumab antibody, 87 cyclic RGD peptide 88,89 and a biologically relevant PARP inhibitor small molecule. 90

NIRF Imaging

In vivo NIRF is of particular interest, as the absorption coefficient of biological tissue and its constituents is minimal in the NIR window, from 600-900 nm (Figure 1.2). [91][92][93][START_REF] Fischer | [END_REF][95] Additionally, both light scattering and autofluorescence from endogenous fluorophores (e.g. elastin, collagen, mitochondria, lysosomes) are decreased in the NIR. These two factors allow deeper penetration of NIR, compared to visible, light into tissue which enables the investigation and assessment of biological processes from deeper structures. 93 Low endogenous absorption and emission are conducive to high signal-tobackground ratios, which contribute to improved determination of specific or unspecific binding of a probe to its designated target. The low cost of equipment (light sources and detectors) and non-radiative nature of NIRF imaging make this modality an attractive and

promising technology for research and potential clinical applications. relies on the accumulation of probes in regions of interest. [91][92][93] Generally, other than endogenous NIR peptides, NIRF imaging probes are divided into two groups: 1) nanoparticle probes and 2) organic small molecule fluorophores.

B-F in NIRF Imaging

While fluorescent probes have been routinely employed in biology as selective stains, translation of these probes to in vivo applications has required the development of NIR emitting probes. 93 Emission wavelengths can be shifted towards the NIR by increasing the degree of π-conjugation within the molecular structure of the probe. Another successful strategy involves the rigidification of molecular scaffolds by B-F2 complexation, this renders the entire structure increasingly planar and increases the extent of πconjugation. Increased structural stiffness and π-conjugation usually induce sharp absorption and emission profiles, high quantum yields and increase fluorescence lifetimes. 96 Additionally, the B-F2 ring complex can function as an acceptor in Donor-π-Acceptor electronic architectures (see chapter 5). was stable for several hours post-injection and that the mice displayed no adverse effects several days after administration of the dye (Scheme 1.23, a). 97 As previously mentioned the BODIPY family of dyes has been extensively used as a biological fluorescent tag and therefore it is not surprising to find that several NIRF probes Chapter 1 Introduction 30 incorporate a BODIPY motif as the fluorophore. 99 The BODIPY core is attractive due to its facile synthesis and further functionalization as well as its stability towards physiological conditions. 100,101 Kikuchi et al. reported the synthesis of a BODIPY analogue sensitive to the pH of its environment that could be used for the in vivo imaging of boneresorbing osteoclasts (Scheme 1.24). 102 They designed the probe to incorporate a N,Nalkyl aniline at the meso position of the BODIPY core which functions as a pH probe to detect acidified bone regions due to osteoclast activity (pH ~4.5); fluorescence is quenched when the aniline is deprotonated and turned on when protonated in acidic environments. The BODIPY core was also functionalized with bisphosphonate for bone targeting. Both Bap-M and Bap-E were demonstrated to bind to hydroxyapatite (a main constituent of bone) in vitro, additionally their pH responsiveness was validated by increasingly high fluorescence intensities observed with decreasing pH. These findings were further validated in vivo in mice, where osteoclasts were detected and real-time imaged using two-photon microscopy.

Scheme 1.24 pH activated in vivo probe for osteoclasts.

BODIPY dyes could also be used to investigate the biodistribution of an antiparasitic (Trypanosoma cruzi, Chagas disease) drug candidate as described by González and Cerecetto et al. 103 The BODIPY-drug conjugate 1-BODIPY was synthesized using a conjugatable form of a known antiparasitic agent with a piperidinyl handle and 1,3,5,7tetramethyl-BODIPY (Scheme 1.25). While possessing appropriate photophysical properties, 1-BODIPY was also determined to display similar in vitro bioactivity to the unmodified antiparasitic agent. 1-BODIPY was then administered to mice and the biodistribution imaged in vivo over 24 hours. Accumulation of the probe was observed in the bladder, liver, lungs and Chagas disease relevant organs such as the heart and intestines; this was confirmed by ex vivo organ fluorescence studies. two-step methodology for the fluorination of anilines using organotrifluoroborates will be described.

Introduction

There is an ever-increasing demand for fluorinated aromatic compounds given their importance in pharmaceuticals, agrochemicals and materials. 7,[108][109][110][111][112] Particularly for drugs, the incorporation of fluorine into a molecular scaffold can have advantageous effects on neighbouring proton acidities (pKa), conformation, lipophilicity, bioavailability and, perhaps most importantly, metabolic stability. 6,[8][9][10][11]113 The inherent difficulty of forming C-F bonds has historically presented a considerable obstacle in the synthesis of fluorinated building blocks and advanced intermediates. To this end, significant advances have been made in the formation of aryl C-F bonds. 114 These include improvements to traditional fluorination methods such as the Balz-Schiemann reaction 23 and Halex (halogen exchange) process. 115 Important contributions include various transition metal Chapter 2 mediated processes starting from aryl(pseudo)halides, di-aryl iodonium salts and aryl boron(ate) species. [40][41][42][43][44][45][46][116][117][118][119] While these methods have expanded the repertoire of fluorination processes, the Balz-Schiemann reaction continues to be a favourable method for the synthesis of aryl fluorides. 120-127

The Balz-Schiemann Reaction

This venerable reaction, first reported in 1927, represents one of the earliest and hence most frequently used methodologies for the synthesis of fluoroaromatic compounds. 23 The procedure is operationally simple; it requires diazotization of an aniline substrate, isolation and drying of the consequent aryl diazonium tetrafluoroborate salt after which, fluorodediazoniation is thermally induced (typically > 100 °C) to produce the desired aryl fluoride along with extrusion of molecular nitrogen and boron trifluoride (Scheme 2.1).

Scheme 2.1 Balz-Schiemann reaction.

Mechanism

The mechanism of the Balz-Schiemann reaction has been an area of intense study over the past 30 years. While a definite mechanism is yet to be described, 128 the weight of excellent experimental work, at present, implicates the formation of an aryl cation (I) as the first and rate-limiting step of the transformation (Figure 2.1, a). [128][129][130][131][132][133][134][135][136][137] The dediazoniation process was determined to be first-order with respect to the aryl diazonium, providing evidence for an SN1 process rather than a bimolecular reaction (SNAr, II). 131,132,136 Further evidence of an aryl cation intermediate is the observed isotopic Chapter 2

37

Nα-Nβ rearrangement, up to 37%, of β- 15 N labelled aryl diazonium salts; in reactions conducted under an atmosphere of unlabelled nitrogen incorporation of "external" nitrogen, up to 17%, into the aryl diazonium salt was observed (Figure 2.1, b). 133,134,137 Importantly, the ability of these intermediates to react with nitrogen highlights the highly reactive nature of aryl cations. A homolytic pathway, which has been invoked, has been regarded as non-productive, as it leads to the formation of unwanted side products and tars. Indeed, the radical pathway has been shown to be dependent on the solvent and reaction additives. 131,132,135,136,138 disadvantages. Firstly, (hetero)aryl diazonium salts with polar substituents become increasingly difficult to precipitate 140 leading to an overall decrease in reaction efficiency and severely limiting the substrate scope. Secondly, and more importantly, the isolation of aryl diazonium salts poses a serious safety concern as they can be explosive even at low temperatures. [139][140][141] Since 1927, intense research has been dedicated towards improving on harsh reaction conditions and limited substrate scope. Fluorodediazoniation traditionally occurs by thermal decomposition, at high temperatures (> 100 °C), in the solid state. Usually, initial heating is required until decomposition begins which can spontaneously continue due to the highly exothermic nature of the transformation. Decompositions of this kind can quickly become uncontrollable leading to both product degradation and additional safety concerns. 140 Several conditions have been investigated to mitigate this issue including dilution of diazonium salts in inert solids (sand, kieselguhr or Na2CO3) thereby allowing for safer conditions. 140 While decomposition in inert solids is safer than that run with pure diazonium salts, heat exchange through large quantities of these solids becomes difficult limiting applications on larger scales.

Decomposition in inert solvents

The suspension and decomposition of diazonium salts in inert solvents was sought as an alternative. Aryl diazonium tetrafluoroborates could be efficiently decomposed in high boiling solvents such as toluene, xylenes and dichlorobenzenes. By contrast, the use of nucleophilic (alcohols and MeCN) or hygroscopic solvents resulted in low aryl fluoride yields due to increased by-products. 136,138,140 Perfluorinated solvents have also proved efficient in Balz-Schiemann reactions where they have been observed to increase product procedures as well as continuous flow processes. 120,140,[144][145][146] One-pot procedures have largely focused on the use of hydrogen fluoride (HF), whether in its anhydrous form or as an adduct with ammonium salts or pyridine (Olah's reagent). 121,124,127,147 The use of "HF" allows for decreased decomposition temperatures and increased yields, 140 however the requirement of handling "HF" limits its general applicability due to added safety concerns.

Flow processes have been developed that are able, through careful selection of (co)solvents, to allow the continuous generation and decomposition of aryl diazonium tetrafluoroborates but require high decomposition temperatures (> 125 °C). 120,144,145 Chapter 2

Importance of the fluoro-ate anion

The effect of various "fluoro-ate" anions were investigated including hexafluorosilicates (SiF6 2-), hexafluorophosphates (PF6 -), hexafluorantimonates (SbF6 -) and hexafluoroarsenates (AsF6 -). 148-151 PF6 -and SiF6 2-, were of initial interest due to their high insolubility in aqueous solutions, facilitating the aryl diazonium salt isolation process.

These anions (X) afford a potentially higher effective fluoride concentration over BF4 -by simply increasing the number of fluorine atoms around the aryl diazonium cation. An additional advantage is the weaker X-F bond when compared to B-F. Yet this has not always translated into higher yields and more efficient transformations as strong Lewis acids can be formed during the reaction (AsF5 or SbF5) which go on to catalyse the formation of by-products. Generally, reaction efficiencies with alternative fluoro-ate salts were highly dependent on substrate; no single anion proved more advantageous than the rest (Table 2.1). Despite the rich history of organofluoroborates, 1 in particular their application in metal mediated cross-coupling reactions with aryl diazonium salts, their use for fluorodediazoniation has not been extensively studied. To the best of our knowledge their application in Balz-Schiemann transformations is limited to but one report; Frohn et al.

described the synthesis and subsequent thermolysis of a series 4fluorobenzenediazonium perfluoroorganofluoroborates to produce 1,4-difluorobenzene (Table 2.2). 39 While this seminal report indeed proves the feasibility of using organotrifluoroborates as anions in the Balz-Schiemann reaction the investigation was quite limited. Only one aryl diazonium substrate was investigated, the authors did not explore other non-perfluorinated organofluoroborates and perhaps the biggest limitation was the necessity of isolating and drying the salts prior to decomposition. Nevertheless, inspired by this work, we sought to further investigate the potential of organotrifluoroborates to serve as F -sources in the Balz-Schiemann reaction.

Chapter 2 a Yield determined by 19 F NMR spectroscopy using C6F6 as internal standard

In contrast to the aforementioned fluoro-ate salts, organotrifluoroborates do not present the hypothetical advantage in terms of an increased number of fluorine atoms compared to BF4 -(in fact the contrary would be the case). Nevertheless, the presence of an organic moiety was hypothesised to present two interesting advantages. Firstly, given the access to a diverse array of organotrifluoroborates the organic fragment can be used to tune solubility of the organotrifluoroborate into solvents compatible with fluorodediazoniation;

allowing the development of one-pot two-step procedures and obviating the need for aryl Chapter 2 diazonium organotrifluoroborate salt isolation. Secondly, the organic moiety of organotrifluoroborates has been demonstrated, by Perrin et al., to affect the rate at which aryl trifluoroborates undergo solvolysis. 65 Electron withdrawing-groups were found to retard solvolysis while electron-donating groups were found to accelerate the process.

The ability to modulate, through stereoelectronic considerations of the organic fragment,

Results and Discussion

Initial optimization

We began the investigation by determining the viability of employing organotrifluoroborates as F -sources for the fluorodediazoniation of preformed aryl diazonium salts in solution. We started by reacting potassium aryl trifluoroborates (2. 19 F NMR spectroscopy using 2,4-dinitrofluorobenzene as internal standard. b 1 eq. (0.25 mmol) of potassium phenyltrifluoroborate used. c 2 eq. (0.5 mmol) of potassium phenyltrifluoroborate used.

Extension to one-pot Balz-Schiemann reaction

Having proven organotrifluoroborates to in fact be capable of mediating fluorodediazoniations in solution with preformed aryl diazonium salts, we focused our attention on extending our methodology towards a one-pot two-step reaction, avoiding the need to isolate the aryl diazonium salt. We argued that the reaction would benefit from a one-pot process due the diazotization step occurring in the presence of the Having determined t-BuOH to be the most suitable solvent, we focused on optimizing remaining reaction parameters. We first examined the effect of other diazotizing agents on the reaction, t-Butyl and n-Butyl nitrite provided similar yields (Table 2.5, entries 1 and

2), while yields with iso-Amyl nitrite were significantly reduced (Table 2.5, entry 3).

Continuing with t-Butyl nitrite as the [NO] + source, we explored the effect of varying concentrations of 2.5 on reaction outcomes. As expected decreasing equivalents of 2.5

in the reaction mixture reduced yields significantly (Table 2.5, entries 4 and 5). A significant increase in yields was achieved when 3 equivalents of 2.5 were used however, moving to 5 equivalents did not result in further improvements in yield (Table 2.5, entry 8). Some groups have reported that Brønsted or Lewis acids are not required for the diazotization step. 143,145,146,154,155 It was clear that the transformation required the presence of an acid to facilitate the diazotization step, as in its absence poor yields were obtained (Table 2.6, entry 1). Surprisingly, efficient transformations were observed when aqueous acids, namely HCl and HNO3, were used (Table 2.6, entries 4, 5 and 7). The presence of water is usually detrimental to fluorodediazoniation as it can act as a nucleophile attacking the intermediate aryl cation and producing phenol by-products. 140 The use of p-toluenesulfonic (Table 2.6, entry 6) acid lowered yields to 40%, identical to the reactivity observed using 2.1, the preformed salt, previously described (Table 2 Equivalents of acid could be decreased to 0.5 before reaction yields diminished (Table 2.6, entries 14 and 15). 19 F NMR spectroscopy using 2,4-dinitrofluorobenzene as an internal standard.

To support the specific value of organotrifluoroborates for this transformation, traditional sources of fluorine were explored to determine whether they could mediate fluorodediazoniation under established reaction conditions. Of all fluorine salts tested, Chapter 2 54 only KBF4 gave trace amounts of the aryl fluoride, while no product formation was observed for others (Table 2.9). These results clearly support our hypothesis that organotrifluoroborates are better fluoride donors than the tetrafluoroborate anion.

Moreover, these results demonstrate that under these mild conditions, a standard Balz-Schiemann reaction is not feasible. Finally, this result serves to exclude the possibility that BF4 -, which may form adventitiously following C-B bond fission, is not functioning as a source of F -under reaction conditions.

Mechanism

The reactivity trend observed, especially the requirement for steric bulk at ortho positions, is not easy to rationalize. Balz-Schiemann reactions are known to tolerate both the presence and lack of steric hindrance. 139,140 However, it has been reported that difficulties arise when diazonium salts are substituted with polar or p-electron-containing moieties, especially at the ortho position; ortho-fluoro and nitro phenyl diazonium tetrafluoroborates are known to undergo poor fluorodediazoniation. 139,140 For example, 1-fluoro-2,4dimethoxybenzene can only be obtained in 10% yield from decomposition of the parent diazonium tetrafluoroborate. 157 These reports corroborate our experimental observations for 2.20. On the other hand ortho-halogenated, except fluorine substitution, aryl diazonium salts undergo efficient fluorodediazoniation. 140 The substituent-dependent reactivity has been suggested to relate to the stabilization of the aryl cation. 140 The enhanced reactivity and higher yields for certain di-ortho-substituted diazonium ions is consistent with the well-known effects of alkyl substituents that stabilize the intermediate aryl cation complex IV (Scheme 2.3). 128,129,[131][132][133][134][135][136][137]158,159 Indeed, a single ortho methyl substitution on the benzenediazonium cation has been shown to be rate enhancing, with regards to trapping the aryl cation with a nucleophile, a second ortho methyl further enhances rates and yields due to further stabilization of intermediate IV. 160

Conclusion and Perspectives

The Balz-Schiemann continues to be a relevant method for the synthesis of aryl fluorides due to its operational simplicity. However, the transformation remains limited by harsh reaction conditions, low yields and requirement for the isolation of potentially explosive intermediates. While several improvements have been made over the years and multiple sources of fluorine investigated, the use of organotrifluoroborates to mediate this reaction has been limited to but one report. To unveil the full potential of organotrifluoroborates to serve as F -sources, we demonstrated that they could mediate fluorodediazoniation in solution with preformed aryl diazonium salts. This could be successfully extended to a one-pot two-step process avoiding the isolation of diazonium salts. The reaction conditions allowed the fluorination of various aniline substrates in moderate to good yield, and allows access to 2,6-disubstitued fluorobenzenes whose corresponding diazonium salts are known to be unstable. 141,154 In stark contrast to typical Balz-Schiemann reactions that usually demand stringently dry decomposition; the described conditions employ an

Analysis

NMR spectroscopy experiments were performed in deuterated solvents. 1 H NMR, 13 C NMR, 11 B NMR and 19 F spectra were recorded on 300 and 400 MHz Bruker spectrometers. Chemical shifts are reported in parts per million (ppm) relative to the residual protium in the solvents ( 1 H) or the solvent carbon ( 13 C) as internal standards. 19 F spectra of aryl fluorides were referenced to 2,4-dinitrofluorobenzene or 2,2,2trifluoroethanol as internal standards (0.5 equivalents). A significant background signal was observed, depending on the concentration of the sample, in the 11 B NMR spectra of some products as the utilized NMR tubes were constructed from borosilicate glass. Because of their low intensity (resulting from quadruple coupling), 13 C signals arising from the quaternary carbon bearing the trifluoroborate group were not always observed and therefore were not always listed. We note that there are discrepancies between 1 JB-F in the 19 F and 11 B NMR spectra; possibly arising from asymmetry in the 19 F multiplets. On this basis, the 11 B value is probably the most reliable, and therefore only this value is reported. In addition, 19 F and 11 B chemical shifts were sometimes observed to be slightly different (0.1-2.0 ppm) from those reported in the literature.

Detection was accomplished by irradiation with a UV lamp (λ= 254 nm) or staining reagents (KMnO4, HBQ) followed by heating. HBQ was particularly used to detect boron compounds on plates. Chromatographic separations were achieved on silica gel columns ( Kieselgel 60, 40-63 µm).

IR spectra were recorded on a PerkinElmer Frontier FT-IR spectrometer with frequencies expressed in cm -1 .

Low resolution mass spectra were obtained on Waters LC-MS and Agilent GC-MS. Highresolution mass spectra (HRMS) were recorded using either electron impact (EI) and desorption chemical ionization (DCI) using Kratos MS-50/Kratos Concept IIHQ spectrometers or electrospray ionization (ESI +/--TOF) using Waters/Micromass LCT spectrometer. Agilent GC-MS (7890B GC and 5977A MAD) was used to detect the formation of volatile by-products and confirm some NMR spectroscopy yields via the ALS-Split method.

Molecular sieves (pellets or powder) and magnesium sulphate were flame dried under high vacuum (<1 mbar) for 30 minutes. Degassing (sparging) of t-BuOH was performed by bubbling argon gas for 1 hour.

2,4,6-trimethylphenyldiazonium tosylate (2.1)

In a 100 mL round-bottom flask, 2,4,6-trimethylaniline (1.0 eq., 5.0 mmol, 0.702 mL) was dissolved in a 1:1 mixture of THF and glacial acetic acid (50 mL), followed by the addition of para-toluene sulfonic acid (1.1 eq., 5.5 mmol, 1.046 g). The solution was then cooled to -10 °C in an ice-brine bath and t-BuONO (2.0 eq., 10.0 mmol, 1.19 mL) was added dropwise. The reaction mixture was stirred for 30 min at -10 °C and further allowed to warm to room temperature for another 30 min. The resulting clear solution was poured into diethyl ether (add until precipitation) and the diazonium tosylate salt immediately precipitated. After careful filtration, the product was collected, washed three times with cold THF to remove the undesired organic compounds and then dried under high vacuum overnight. The title compound was isolated as a colourless powder (1.500 g, 95%). IR νmax/cm -1 (neat film): 3032, 2261, 1589, 1406, 1311, 1193, 1120, 1032, 1010, 813, 678.

General Procedure B for the Synthesis of Potassium Aryltrifluoroborates

To a 25 mL round-bottom flask was added the aryl boronic acid (1.0 eq.), KHF2 (3.3 eq.) and a 20:1 mixture of MeOH/distilled water (for every 2.0 mmol of the starting boronic acid, 4 mL of methanol and 0.2 mL of H2O were required). The colourless reaction mixture was stirred for 30 min at room temperature where the solution became turbid (white).

After complete conversion, solvents were removed by rotary evaporation and the remaining traces of water were dried under high vacuum overnight. Next, acetone was added to the point where most of the precipitate was dissolved and the solution was further dried using anhydrous magnesium sulphate. Following Buchner filtration, the filtrate was concentrated by rotary evaporation to a saturation point where Et2O was added until the product precipitated out. The desired product was then collected by filtration, washed with cold Et2O (3 times) and dried overnight on a high vacuum pump.

Characterization Data of the Synthesized Aryltrifluoroborates

Potassium phenyltrifluoroborate (2a)

The title compound was prepared from phenylboronic acid (10.0 mmol) according to the general procedure B and isolated as a crystalline white solid (1.740 g, 95%). 1 H and 13 C NMR data are in accordance with those previously reported in literature. 1 H NMR (300 MHz, DMSO-d6) δ 7.32 (d, J = 7.3 Hz, 2H), 7.10 -6.98 (m, 3H). 13 C NMR (75 MHz, DMSO-d6) δ 131.3 (CH), 126.2 (CH), 124.9 (CH). 11 B NMR (77 MHz, DMSO-d6) δ 3.6 (bs). 19 F NMR (282 MHz,. Spectroscopic data matches those previously reported. 161

Potassium 4-methoxyphenyltrifluoroborate (2b)

The title compound was prepared from 4-methoxyphenylboronic acid (2.0 mmol) according to the general procedure B and isolated as a crystalline white solid (0.419 g, 98%). 1 H and 13 C NMR data are in accordance with those previously reported in literature. 1 H NMR (300 MHz, DMSO-d6) δ 7.67 (d, J = 8.4 Hz, 2H), 7.67 (d, J = 8.4 Hz, 2H), 3.67 (s, 3H). 13 C NMR (75 MHz, DMSO-d6) δ 157.2 (Cq), 132.3 (CH), 111.9 (CH), 54.5 (CH3). 11 B NMR (77 MHz, DMSO-d6) δ 3.4 (bs). 19 F NMR (282 MHz,.

Spectroscopic data matches those previously reported. 162

Potassium 4-fluorophenyltrifluoroborate (2c)

The title compound was prepared from 4-fluorophenylboronic acid (2.0 mmol) according to the general procedure B and isolated as a colourless solid (0.402 g, 84%). 1 H and 13 C NMR data are in accordance with those previously reported in literature. 1 H NMR (300 MHz, DMSO-d6) δ 7.33 (t, J = 7.3 Hz, 2H), 6.88 (t, J = 6.9 Hz, 2H). 13 C NMR (75 MHz, DMSO-d6) δ 160.9 (d, 1 JC-F = 237.1 Hz, Cq), 131.3 (d, 3 JC-F = 6.6 Hz, CH), 112.7 (d, 2 JC-F = 18.3 Hz, CH). 11 B NMR (77 MHz, DMSO-d6) δ 4.4 (bs). 19 F NMR (282 MHz,1F),3F). Spectroscopic data matches those previously reported. 163 Chapter 2 Experimental Section Potassium 4-trifluoromethylphenyltrifluoroborate (2d)

The title compound was prepared from 4-trifluoromethylphenylboronic acid (6.0 mmol) according to the general procedure B and isolated as a white crystalline solid (1.480 g, 98%). 1 H and 13 C NMR data are in accordance with those previously reported in literature. 1 H NMR (300 MHz, DMSO-d6) δ 7.54 (d, J = 7.5 Hz, 2H), 7.53 (d, J = 7.5 Hz, 2H). 13 C NMR (75 MHz, DMSO-d6) δ 131.7 (q, 3 JC-F = 18.0 Hz, CH), 126.4 (q, 2 JC-F = 30.7 Hz, Cq), 125.4 (q, 1 JC-F = 271.4 Hz, Cq), 122.8 (q, 4 JC-F = 3.8 Hz, CH). 11 B NMR (77 MHz, DMSO-d6) δ 2.9 (bs). 19 F NMR (282 MHz,3F),3F). Spectroscopic data matches those previously reported. 163

Potassium 4-formylphenyltrifluoroborate (2e)

The title compound was prepared from 4-formylphenylboronic acid (2.0 mmol) according to the general procedure B and isolated as a white crystalline solid (0.331 g, 78%). 1 H and 13 C NMR data are in accordance with those previously reported in literature. 1 H NMR (300 MHz, DMSO-d6) δ 9.91 (s, 1H), 7.66 (d, J = 7.6 Hz, 2H), 7.56 (d, J = 7.8 Hz, 2H). 13 C NMR (75 MHz, DMSO-d6) δ 193.4 (Cq), 134.1 (Cq), 131.8 (CH), 127.9 (CH). 11 B NMR ( 77MHz, DMSO-d6) δ 2.9 (bs). 19 F NMR (282 MHz,. Spectroscopic data matches those previously reported. 164

Potassium 4-carboxyphenyltrifluoroborate (2f)

The title compound was prepared from 4-carboxyphenylboronic acid (6.0 mmol) according to the general procedure B and isolated as an off-white solid (1.310 g, 96%).

IR νmax/cm -1 (neat film): 3034, 2659, 2536, 1713, 1685, 1561, 1514, 1425, 1368, 1318, 1289, 1220, 1188, 1125, 959, 851, 801, 708. 1 H NMR (300 MHz, DMSO-d6) δ 12.40 (bs, 1H, OH), 7.71 (d, J = 8.1 Hz, 2H), 6.87 (d, J = 8.1 Hz, 2H). 13 C NMR (75 MHz, DMSO-d6) δ 168. 3 (Cq), 131.3 (CH), 127.5 (Cq), 127.4 (CH). 11 B NMR (77 MHz, DMSO-d6) δ 3.7 (bs). 19 F NMR (282 MHz,. HRMS-ESI-TOF (m/z): found [M-K] - 188.0379, calc'd C7H5 10 BF3O2 requires 188.0371.

Potassium 4-nitrophenyltrifluoroborate (2g)

The title compound was prepared from 4-nitrophenylboronic acid (2.0 mmol) according to the general procedure B and isolated as a pale brown solid (0.332 g, 73%). 1 H and 13 C NMR data are in accordance with those previously reported in literature. 1 H NMR (300 MHz, Acetone-d6) δ 7.98 (dd, J = 8.4, 1.0 Hz, 2H), 7.59 (dd, J = 8.4, 1.0 Hz, 2H). 13 C NMR (75 MHz, Acetone-d6) δ 147.2 (Cq), 133.2 (CH), 121.8 (CH). 11 B NMR (77 MHz, Acetone-d6) δ 2.7 (q, JB-F = 40.1 Hz). 19 F NMR (282 MHz,. Spectroscopic data matches those previously reported. 163

Potassium 3-nitrophenyltrifluoroborate (2h)

The title compound was prepared from 3-nitrophenylboronic acid (2.0 mmol) according to the general procedure B and isolated as a cream solid (0.350 mg, 80%). 1 H and 13 19 F NMR (282 MHz,. Spectroscopic data matches those previously reported. 165

Potassium 2-nitrophenyltrifluoroborate (2i)

The title compound was prepared from 2-nitrophenylboronic acid (2.0 mmol) according to the general procedure B and isolated as a light beige solid (0.404 g, 88%). IR νmax/cm -1 (neat film): 3672, 3067, 2863, 1610, 1569, 1520, 470, 1433, 1344, 1300, 1167, 1141, 1051, 999, 979, 965, 861, 880, 701. 1 H NMR (300 MHz, DMSO-d6) 7.54 (d, JH-H = 7.1 Hz, 1HAr), 7.37 (appt, JH-H = 6.4 Hz, 2HAr), 7.30 -7.19 (m, 1HAr). 13 C NMR (75 MHz, DMSO-d6) δ 155.0 (Cq), 134. 1 (CH), 129.8 (CH), 126.3 (CH), 125.5 (Cq), 120.8 (CH). 11 B NMR (77 MHz, DMSO-d6) δ 2.1 (q, JB-F = 47.7). 19 F NMR (282 MHz,. HRMS (ESI-TOF) (m/z): found [M-K] -189.0320, calc'd C6H4 10 BF3NO2 requires 189.0324.

Potassium 2-hydroxyphenyltrifluoroborate (2j)

The title compound was prepared from 2-hydroxyphenylboronic acid (2.0 mmol) according to the general procedure B and isolated as a colourless solid (0.380 g, 95%). 1 H and 13 C NMR data are in accordance with those previously reported in literature. 1 H NMR (300 MHz, DMSO-d6) δ 7. 40 -7.29 (bm, 1H, OH), 7.13 (d, J = 6.8 Hz, 1H), 6.92 (td, J = 7.6, 1.9 Hz, 1H), 6.61 (t, J = 7.2 Hz, 1H), 6.50 (d, J = 8.0 Hz, 1H). 13 77MHz, DMSO-d6) δ 4.0 (q, JB-F = 45.7 Hz). 19 F NMR (282 MHz,. Spectroscopic data matches those previously reported. 166

Potassium 3,5-bis(trifluoromethyl)phenyltrifluoroborate (2k)

The title compound was prepared from 3, 5-bis(trifluoromethyl)phenylboronic acid (4.0 mmol) according to the general procedure B and isolated as an off-white solid (1.280 g, 99%). 1 H and 13 C NMR data are in accordance with those previously reported in literature. 1 H NMR (300 MHz, DMSO-d6) δ 7.86 (s, 2H), 7.72 (s, 1H). 13 C NMR (75 MHz, DMSO-d6) δ 131.8 (s, CH), 129.0 (q, 2 JC-F = 31.5 Hz, Cq), 124.7 (q, 1 JC-F = 270.7 Hz, Cq), 119.6-119.4 (m, CH). 11 B NMR (77 MHz, DMSO-d6) δ 2.0 (bs). 19 F NMR (282 MHz,6F),3F). Spectroscopic data matches those previously reported. 167 Potassium 2,3,4,5,6-pentafluorophenyltrifluoroborate (2l)

The title compound was prepared from 2, 3, 4, 5, 6-pentafluorophenylboronic acid (2.0 mmol) according to the general procedure B and isolated as a colourless solid (0.218 g, 40%). 1 H and 13 C NMR data are in accordance with those previously reported in literature. 13 C NMR (75 MHz, DMSO-d6) δ 147.5 (d,Cq),138.3 (d, Hz, Cq), 136.1 (d, 1 JC-F = 244.1 Hz, Cq). 11 B NMR (77 MHz, ) δ 1.4 (q, J = 33.7 Hz). 19 F NMR (282 MHz, ) δ -132.9 (qB, 3F), -134.9 (bs, 2F), -161.3 (t, JF-F = 21.4 Hz, 1F), -165.7 (bs, 2F). Spectroscopic data matches those previously reported. 166

Potassium 3-nitrophenyltrifluoroborate (2m)

The title compound was prepared from 3-nitrophenylboronic acid (2.0 mmol) according to the general procedure B and isolated as a colourless solid (0.383 g, 80%). IR νmax/cm -1 (neat film): 3389, 3252, 1684, 1648, 1613, 1582, 1548, 1485, 1414, 1317, 1299, 1248, 1173, 995, 977, 944, 886, 872, 783. 1 H NMR (300 MHz, DMSO-d6) δ 9.54 (bs, 1H), 7.49 -7.45 (m, 1H), 7.28 (d, J = 2.4 Hz, 1H), 6.97 (m, 2H), 1.98 (s, 3H). 13 C NMR (75 MHz, DMSO-d6) δ 167. 5 (Cq), 137.6 (Cq), 126.6 (CH), 126.0 (CH), 122.6 (CH), 116.3 (CH), 23.7 (CH3). 11 B NMR (77 MHz, DMSO-d6) δ 3.5 (bs). 19 The title compound was prepared from 2, 4, 6-trimethylphenylboronic acid (2.0 mmol) according to the general procedure B and isolated as an off-white solid (0.384 g, 85%).

IR νmax/cm -1 (neat film): 3025, 2977, 2941, 2867, 1605, 1547, 1446, 1420, 1382, 1239, 1212, 1152, 1145, 1200, 1056, 1037, 938, 915, 886. 1 H NMR (300 MHz, DMSO-d6) δ 6.74 (s, 2H), 2.20 (s, 3H), 2.16 (s, 6H). 13 C NMR (75 MHz, DMSO-d6: δ 140.2 (Cq), 137.2 (Cq), 127.8 (CH). 11 B NMR (77 MHz, DMSO-d6) δ 3.9 (bs). 19 Procedure for the synthesis of zwitterionic trifluoroborates 2.6 and 2.7

5,5-dimethyl-2-(o-tolyl)-1,3,2-dioxaborinane

A 250 mL round-bottom flask was charged with a stir bar then flame dried, and purged with an Ar balloon. Under Ar, the flask was then charged with 2-bromtoluene (2.41 mL, 20 mmol) and THF (100 mL); the flask was then cooled to -78 °C in an acetone-dry ice bath. n-BuLi (23.1 mL, 30 mmol) was added dropwise, via syringe, to the stirring reaction mixture over 2 minutes; the reaction mixture was stirred at -78 °C for 1 h. B(OMe)3 (4.46 mL, 40 mmol) was then added via syringe and the mixture stirred for an additional 30 min at -78 °C then allowed to stir for 3 h at rt. The crude reaction mixture was then concentrated to dryness onto Celite and the residue purified by flash column chromatography on silica gel using an eluent of 100% hexane to 1:9 hexane/EtOAc. Identity of boronic acid was confirmed by crude NMR and mass spectrometry, boronic acid was used for next step without further purification. A 100 mL round-bottom flask was charged with a stir bar, condenser, Dean-Stark adapter, crude boronic acid (1.5996 g, 11.77 mmol), 2,2-dimethyl-1,3-propanediol (1.2414 g, 11.77 mmol) andtoluene (75 mL).

The reaction mixture was heated at reflux for 1 h then allowed to cool to rt. The reaction mixture was then concentrated under reduced pressure to an approximate volume of 50 mL after which it was filtered, and the filtrate concentrated to dryness under reduced pressure, and further dried under high vacuum overnight, to provide the desired boronic ester as a clear yellow oil (2.1421 g, 52% over two steps, GCMS purity: >97%). IR νmax/cm -1 (neat film): 2961, 2932, 2888, 1599, 1476, 1302, 1275, 1135, 1106. 1 H NMR (300 MHz, Chloroform-d) δ 7.96 -7.73 (m, 1H), 7.55 -7.28 (m, 1H), 7.27 -7.20 (m, 2H), 3.84 (s, 4H), 2.62 (s, 3H), 1.10 (s, 6H). 13 allowing to cool to rt the reaction mixture is filtered and the precipitate washed with CCl4, the filtrate is concentrated under reduced pressure, and further dried under high vacuum overnight, to furnish the desired product as a clear dark brown oil (2.8049 g, 94%, GCMS purity: >90%). IR νmax/cm -1 (neat film): 3065, 2962, 2935, 2891, 1719, 1476, 1286, 1245, 1127, 765. 1 H NMR (300 MHz, Chloroform-d) 1H),7.37 (dt,J = 4.4,2.1 Hz,2H),1H),4.95 (s,2H),3.81 (s,4H),1.06 (s,6H). 13

1-(2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)phenyl)-N,N-dimethylmethanamine

A 100 mL round-bottom flask was charged with a stir bar, dimethylamine (6.0 mL, 40% aq. Solution) and Et2O (50 mL). The flask was placed in an ice-bath and NaOH (10 g) was added; the solution was stirred for 30 min. The reaction mixture was then transferred to a separatory funnel and the organic layer collected in a 50 mL round-bottom flask charged with a stir bar. To this flask 2-bromomethylphenylboronic acid neopentyl ester (2.2 g, 7.8 mmol) followed by Et2O (20 mL). This mixture was stirred at rt for 30 min and the developed precipitate filtered off, the filtrate was concentrated to ~10 mL and transferred to a 50 mL round-bottom flask charged with a stir bar. To this flask hexanes (15 mL) were added and the reaction mixture heated at reflux, in an oil bath, for 1 h. The reaction mixture was then cooled to rt and all solvent removed under reduced pressure, then further dried under high vacuum overnight, to yield the desired product as a clear dark brown oil (2.0988 g, 99%, GCMS purity: >91%). IR νmax/cm -1 (neat film): 2952, 2891, 2869, 1717 1473, 1448, 1221, 1119, 747. 1 H NMR (300 MHz, Chloroform-d) δ 7.52 (dd, Chapter 2 Experimental Section 75 J = 6.5, 1.8 Hz, 1H), 7.17 (pd, J = 7.4, 1.5 Hz, 2H), 6.98 (d, J = 7.0 Hz, 1H), 3.78 (s, 2H), 3.63 (s, 4H), 2.55 (s, 6H), 1.03 (s, 6H). 13 C NMR (75 MHz, Chloroform-d) δ 139.9 (Cq), 130.7 (CH), 127.44 (CH), 127.39 (CH), 123.2 (CH), 72.3 (CH2), 64.6 (CH2), 45.9 (CH3), 32.2 (Cq), 22.3 (CH3). 11 B NMR (96 MHz, Chloroform-d) δ 11.95 (bs). GCMS-EI (m/z): 246 [M-H] + , 247 [M] + . Spectroscopic data matches those previously reported. 170

(2-((dimethylammonio)methyl)phenyl)trifluoroborate (2.6) The title compound was prepared from 1- (2-(5,5-

dimethyl-1,3,2-dioxaborinan-2- yl)phenyl)-N,N-dimethylmethanamine (2.0 mmol) according to the general procedure B
and isolated as a beige powder (250.5 mg, 61%). IR νmax/cm -1 (neat film): 3201, 3178, 2950, 1464, 1181, 1024, 973, 937 765. 1 H NMR (300 MHz, Acetonitrile-d3) δ 7.63 (d, J = 7.2 Hz, 1H), 7.35 -7.27 (m, 1H), 7.27 -7.18 (m, 2H), 4.27 (s, 2H), 2.75 (s, 6H). 13 C NMR (75 MHz, Acetonitrile-d3) δ 133.88 (q, 3 JC-F = 2.9 Hz) (CH), 133.86 (Cq), 131.8 (CH), 129.5 (CH), 127.6 (CH), 64.5 (CH2), 43.5 (CH3). 19 F NMR (282 MHz, Acetonitrile-d3) δ -139.17.

1-(2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)phenyl)-N,N,N-trimethylmethanaminium iodide

A 10 mL flask, stir bar and attached condenser were flame dried then purged with Ar. The flask was then charged with 1-(2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)phenyl)-N,Ndimethylmethanamine (250.4 mg, 1 mmol) and dry CH2Cl2 (5 mL). To this stirring reaction at rt, MeI (623 µL, 10 mmol) was added and left stirring at rt for 6 h; the reaction mixture was then heated at reflux overnight. After allowing to cool to rt the reaction mixture was dropped onto Et2O to precipitate the product. The precipitate was collected by filtration and washed with Et2O; the product, a yellow powder, was collected and dried under high vacuum overnight (293.4 mg, 74%). IR νmax/cm -1 (neat film): 3060, 3001, 2955, 2900, 2871, 1477, 1414, 1298, 1253, 881, 657. 1 H NMR (300 MHz, Acetonitrile-d3) δ 8. 02 -7.95 (m, 1H), 7.62 -7.46 (m, 3H), 4.89 (s, 2H), 3.85 (s, 4H), 3.05 (s, 9H), 1.00 (s, 6H). 13

trifluoro(2-((trimethylammonio)methyl)phenyl)borate (2.7)

The title compound was prepared from 1- (2-(5,5- N-dimethylmethanamine (0.72 mmol) according to the general procedure B and isolated as a very hygroscopic resin (270.5 mg, >99%). Residual 2,2-dimethyl-1,3propanediol could not be separated from the product, the crude was used as is. 1 H NMR (300 MHz, Acetonitrile-d3) δ 7.68 (d, J = 7.4 Hz, 1H), 7.46 -7.13 (m, 3H), 4.70 (s, 2H), 3.01 (s, 9H). 13 C NMR (75 MHz, Acetonitrile-d3) δ 134. 84, 132.87, 131.09, 129.74, 127.01, 70.16, 53.75. 19 F NMR (282 MHz,. 11 B NMR ( 96MHz, Acetonitrile-d3) δ 3.00 (q, J = 53.2 Hz). LRMS-ESI (m/z): [M+K] + 256.

dimethyl-1,3,2-dioxaborinan-2- yl)phenyl)-N,

Synthesis of Anilines 2,6-dihydroxyaniline

A glass reaction vessel is charged with a stir bar, 2-nitroresorcinol (7.7599 g, 50 mmol), palladium on carbon (10% loading, 532.1 mg, 0.5 mmol, 1 mol%) and 125 mL of EtOH. The glass vessel was loaded into a metal pressure reactor and the system evacuated and purged with Argon three times, then evacuated and charged with 5 atm. of H2. The reactor was sealed, and the reaction mixture stirred at room temperature for 24 h. After which the reaction mixture was filtered over Celite and the residue washed (2x10 mL EtOH). The filtrate was concentrated by rotary evaporation furnishing a white powder (6.0431 g, 97%). 1 H NMR (400 MHz, DMSO-d6) δ 8.82 (bs, 2H), 6.33-6.23 (m, 4H). 13 Chapter 2 Experimental Section 78

2,6-bis(methoxy)aniline

A 250 mL round bottom flask was charged with a stir bar, 2-nitroresorcinol (15.5124 g, 100 mmol), K2CO3 (41 g, 300 mmol), Me2SO4 (28.39 mL, 300 mmol) and 100 mL acetone.

The mixture was heated at reflux for 2 h then allowed to cool to room temperature. The solvent was then removed by rotary evaporation and further dried under high vacuum.

The remaining residue was washed with H2O and triethylamine to remove unreacted starting material, after which the remaining white powder was dried under high vacuum (14.7301 g, 80%) and used for the next step without further purification.

A glass reaction vessel is charged with a stir bar, 1,3-dimethoxy-2-nitrobenzene (3.66 g, 19.65 mmol), palladium on carbon (10% loading, 212.84 mg, 0.2 mmol, 1 mol%) and 50 mL of EtOH. The glass vessel was loaded into a metal pressure reactor and the system evacuated and purged with Argon three times, then evacuated and charged with 5 atm. of H2. The reactor was sealed, and the reaction mixture stirred at rt for 24 h. After which the reaction mixture was filtered over Celite and the residue washed (2x10 mL EtOH).

The filtrate was concentrated by rotary evaporation furnishing a white powder (2.8221 g, 92%). 1 H NMR (400 MHz,J = 8.8,7.7 Hz,1H),6.55 (d,J = 8.2 Hz, 2H), 3.86 (s, 7H). 13 Chapter 2 Experimental Section 79

2,6-bis(benzyloxy)aniline

A 50 mL round bottom flask was charged with a stir bar, phthalic anhydride (1.4446 g, 9.75 mmol) and 2-aminoresorcinol (1.2521 g, 10 mmol). The flask was placed in a heat bath at 160 °C and stirred, as the anhydride began to melt the evolution of water vapour was observed along with a fluffy powder; stirring and temperature were maintained for 40 min. After allowing to cool to room temperature the residue was extracted with CHCl3, CH2Cl2 and acetone. The CH2Cl2 and acetone fractions were combined and concentrated to furnish a black solid which was further triturated with Et2O, the black solid was then dried over high vacuum (2.0979 g, 82%) and used for the next step without further purification.

A 100 mL round-bottom flask was charged with a stir bar, condenser, 2-(2,6dihydroxyphenyl)isoindoline-1,3-dione (1.5 g, 5.9 mmol), benzyl bromide (1.75 mL, 14.7 mmol), K2CO3 (2.0458 g, 14.7 mmol) and acetone (30 mL). The flask was then placed in an oil bath and heated to reflux for 18 h, the reaction mixture was then allowed to cool to rt, then filtered to remove undissolved solids. The filtrate was concentrated to dryness then the residue dissolved in 100 mL EtOAc which was transferred into a separatory funnel. The organic phase was washed with aq. saturated NaHCO3 (2 x 50 mL), then aq.

NH4OH (1 x 50 mL, pH ~10). The organic phase was then dried over Na2SO4 then filtered and concentrated to dryness, this residue was used for the next step without further purification. The dibenzylated product (1.555 g, 3.6 mmol) was loaded into a 120 mL pressure vial with EtOH (40 mL) and hydrazine monohydrate (535 µL, 7.2 mmol). The vial was sealed and placed in an oil bath at 95 °C for 11h, after which it was allowed to cool to rt then filtered to remove undissolved solids. The filtrate was concentrated to dryness to furnish a purple viscous oil which was purified on silica gel using an eluent of 100% hexane to 9:1 hexane/EtOAc. Desired fractions were collected and concentrated to furnish the desired aniline as a light pink crystalline powder (849.7 mg, 47%). IR νmax/cm - 1 (neat film): 3474, 3378, 3063, 3032, 2867, 1602, 1501, 1477, 1466, 1453, 1135, 732. 1 H NMR (400 MHz, Chloroform-d) δ 7.48 (d,J = 7.2 Hz,4H),7.41 (t,J = 7.3 Hz,4H),7.35 (t,J = 7.2 Hz,2H),6.70 (dd,J = 9.4,6.8 Hz,1H),2H),5.12 (s,4H),4.20 (bs, 2H). 13 C NMR (75 MHz, DMSO-d6) δ 146.9 (Cq),137.4 (Cq),128.7 (

General Procedure C for the Synthesis of 2,6 Disubstituted Anilines

A 20 mL round bottom flask was charged with 2,6-dibromoaniline (1.0 eq, 1.0 mmol, 0.251 g), arylboronic acid (3.0 eq, 3.0 mmol, 0.367 g), Pd(PPh3)4 (0.1 eq., 10 mol%, 0.1 mmol, 0.116 g mg), PPh3 (0.1 eq., 10 mol%, 0.1 mmol, 0.280 g), Na2CO3 (8.3 eq, 8.3 mmol, 0.881 mg), 10 mL toluene, 2 mL EtOH and 4 mL H2O. The reaction mixture was partially degassed by bubbling with argon over an hour at room temperature and further refluxed for 12 h. After cooling to room temperature, 10 mL of H2O were added and the aqueous phase was extracted with CH2Cl2 (3 x 10 mL). The combined organic phases were dried over anhydrous MgSO4, filtered and concentrated by rotary evaporation. The crude residue was loaded onto Celite ® and purified by silica gel flash column chromatography using 100% cyclohexane to an 80:20 mixture of cyclohexane/EtOAc. Desired fractions were collected, concentrated by rotary evaporation and further dried under high vacuum.

2,6-diphenylaniline

The title compound was prepared from 2, 6-dibromoaniline (1 mmol) and phenylboronic acid (3 mmol) according to the general procedure C and isolated as an off-white/yellow solid (0.209 g, 85%). IR νmax/cm -1 (neat film): 2923, 1600, 1424, 1259, 1072, 1016, 798, 754, 703. 1 H NMR (300 MHz, Chloroform-d) δ 7.55-7.51 (m, 4H), 7.50-7.43 (m, 4H), 7.41-7.33 (m, 2H), 7.15 (d, J = 7.5 Hz, 2H), 6.90 (dd, J = 7.9, 7.1 Hz, 1H), 3.86 (bs, 2H). 13 C NMR (75 MHz, Chloroform-d) δ 140.9 (Cq),139.9 (Cq), 129.9 (CH), 129.

2,6-di-(4-methoxyphenyl)aniline

The title compound was prepared from 2, 6-dibromoaniline (1 mmol) and 4-methoxyphenylboronic acid (3 mmol) according to the general procedure C and isolated as a pale brown solid (0.284 g, 92%). IR νmax/cm -1 (neat film): 3009, 2954, 2837, 1603, 1507, 1462, 1239, 1178, 1036, 838, 785, 732. 1 H NMR (300 MHz, Chloroform-d) δ 7.43(d, J = 8.8 Hz, 4H), 7.08 (d, J = 7.5 Hz, 2H), 7.01-6.97 (d, J = 8.8 Hz, 4H), 6.85 (dd, J = 7.8, 7.2 Hz, 1H), 3.85 (s, 6H). 13 C NMR (75 MHz, Chloroform-d)

2,6-di-(3,5-bis(trifluoromethyl)phenyl)aniline

The title compound was prepared from 2, 6-dibromoaniline (1 mmol) and 3,5-bis(trifluoromethyl)phenylboronic acid (3 mmol) according to the general procedure C but instead of refluxing, the vial was irradiated in a microwave reactor at maximum 200 W to maintain a temperature of 85°C for 1 h. It was isolated as a yellowish powder (0.505 g, 95%). IR νmax/cm -1 (neat film): 3496, 3407, 3089, 3064, 1619, 1459, 1373, 1275, 1170, 1125, 1107, 900, 682. 1 H NMR (400 MHz, Chloroform-d)

General Procedure D for the Synthesis of Aryl Fluorides

To a Pyrex tube charged with a stirring bar was added the aniline (1.0 eq., 0.25 mmol), phosphoric acid (0.5 eq., 0.125 mmol, 6.52 μL) and t-BuOH (1 mL). The mixture was stirred for few minutes to ensure the formation of the anilinium salt. Potassium phenyltrifluoroborate (1.5 eq., 0.375 mmol, 0.690 g) was added and the walls of the tube were washed using 0.3 mL of t-BuOH. The vial was purged with argon for 30 seconds prior to the dropwise addition of t-BuONO (1.5 eq., 0.375 mmol, 45.0 μL). The reaction mixture was allowed to diazotize for 20 min at room temperature before placing the tube in a silicon bath and heating to 50 °C for 2 h. After cooling to room temperature, 1-fluoro-2, 4-dinitrobenzene (0.5 eq.) was added to the crude mixture, followed by DMSO-d 6 . Reaction yield was determined by 19 F NMR. Many aryl fluorides

were not isolated due to their low boiling points and subsequent high volatility.

Regarding the isolated fluorinated compounds: 2,2,2-trifluoroethanol was used as the internal standard followed by Chloroform-d. For purification, the crude residue was loaded onto silica and purified by silica gel flash column chromatography using 100% pentane to a mixture of pentane/EtOAc as the eluent. Desired fractions were collected and concentrated to furnish a colourless solid which was further dried under high vacuum.

Characterization Data of the Synthesized Aryl Fluorides

1-fluoro-2,4,6-trimethylbenzene (2.
3)

The title compound was obtained following the general procedure D in 81% NMR yield.

1,3,5-tri-tert-butyl-2-fluorobenzene (2.8)

The title compound was obtained following general procedure D in 68% NMR yield, purified by silica gel flash column chromatography using 100% pentane and isolated as a colourless solid (0.410 g, 62%). IR νmax/cm -1 (neat film): 2960, 2906, 2871, 1607, 1574, 1512, 1455, 1436, 1363, 1284, 1247, 1236, 1220, 1204, 1160, 1115, 1039, 839.

1-fluoro-2,6-dimethylbenzene (2.9)

The title compound was obtained following general procedure D in 50% NMR yield. 19 F NMR (282 MHz, DMSO-d6) δ -122.9 (s), δ (lit) -122.5 (s). Spectroscopic data matches reports in the literature. 174

Chapter 2 Experimental Section

1-fluoro-2-methylbenzene (2.10)

The title compound was obtained following general procedure D in 26% NMR yield. 19 F NMR (282 MHz, DMSO-d6) δ -118.3 (s), δ (lit) -118.1 (s). Spectroscopic data matches reports in the literature. 175

1-fluorobenzene (2.11)

The title compound was obtained following general procedure D in 13% NMR yield. 19 F NMR (282 MHz, DMSO-d6) δ -113.6 (s), δ (lit) -113.1 (s). Spectroscopic data matches reports in the literature. 144

1-fluoro-2,6-diisopropylbenzene (2.12)

The title compound was obtained following general procedure D in 78% NMR yield (73% GC-MS yield). The product was dissolved in acetone and analysed by GC-MS using ALS-SPLIT-L.M. method. Two peaks were observed with retention times (τR) of 6.207 min and 8.030 min, respectively. The fist peak (τR1=6.207 min) had an m/z of 180.2 corresponding to the desired aryl fluoride which was obtained in 73% yield while the second peak (τR2=8.030 min) had an m/z of 178.2 consistent with the phenol by-product. 19 F NMR ( 282MHz, DMSO-d6) δ -127.6 (s), δ (lit) -126.7 (t). Spectroscopic data matches reports in the literature. 145

1-tert-butyl-2-fluorobenzene (2.13)

The title compound was obtained following general procedure D in 39% NMR yield. 19 F NMR (282 MHz, DMSO-d6) δ -110.6 (s). Spectroscopic data matches reports in the literature. 176

1-tert-butyl-3-fluorobenzene (2.14)

The title compound was obtained following general procedure D in 26% NMR yield. 19 The title compound was obtained following general procedure D in 14% NMR yield. 19 F NMR (282 MHz, DMSO-d6) δ -119.0 (s), δ (lit) -119.2 (s). Spectroscopic data matches reports in the literature. 174

1-Fluoro-2-isopropylbenzene (2.16)

The title compound was obtained following general procedure D in 31% NMR yield. 19 F NMR (282 MHz, DMSO-d6) δ -120.2 (s), δ (lit) -121.8 (s). Spectroscopic data matches reports in the literature. 46 1-fluoro-4-isopropylbenzene (2.17)

The title compound was obtained following general procedure D in 14% NMR yield. 19 F NMR (282 MHz, DMSO-d6) δ -118.3 (s), δ (lit) -119.1 (s). Spectroscopic data matches reports in the literature. 177 Chapter 2 Experimental Section

3-fluoro-2-methylpyridine (2.18)

The title compound was obtained following general procedure D in 35% NMR yield. 19 F NMR (282 MHz, DMSO-d6) δ -125.2 (s). Spectroscopic data matches reports in the literature. 178

1-fluoro-2,6-diphenylbenzene (2.24)

The title compound was obtained following general procedure D in 68% NMR yield, purified by silica gel flash column chromatography using 100% pentane and isolated as a colourless solid (0.403 g, 65%). IR νmax/cm -1 (neat film): 3038, 2923, 1597[START_REF]calc'd C6H5BF3requires 144.0473[END_REF], 1565, 1499, 1464, 1417, 1395, 1315, 1305, 1211, 1202, 1190, 1074, 1027, 977, 823. 1 H NMR (300 MHz, Chloroform-d) δ 7.62-7.58 (m, 4H), 7.50-7.39 (m, 8H), 7.31-7.28 (m, 1H). 13

1-fluoro-2,6-bis(4-methoxyphenyl)benzene (2.25)

The title compound was obtained following general procedure D in 68% NMR yield, purified via reverse phase column chromatography using an eluent gradient of 100% H2O

to 100% MeCN over 1 hour and isolated as an off-white powder which was further dried under (0.478 g, 62%). IR νmax/cm -1 (neat film): 2955, 2838, 1607, 1573, 1512, 1456, 1440, 1396, 1364, 1283, 1211, 1159, 1111, 1085, 1020, 1002, 889, 817. The title compound was obtained following modified general procedure D (conc. H2SO4

1 eq. and t-BuOH at 95 °C) and purified by silica gel flash column chromatography using an eluent gradient of 100% cyclohexane to 1:1 cyclohexane/EtOAc. Four fractions were collected during cyclohexane elution, two of which contained the desired product along with some undesired impurities. Further purification was achieved via reverse phase column chromatography using an eluent gradient of 100% H2O to 100% MeCN over 1 hour. The desired fractions were concentrated to afford the desired product as an off-

Organotrifluoroborates as nucleophilic fluorine sources in the fluorination of diaryliodonium salts

In chapter 2, the development of a methodology for a one-pot two-step Balz-Schiemann reaction with organotrifluoroborates was described. Given the interesting reactivity observed, we were motivated to expand the fluorination reaction profile of organotrifluoroborates. Diaryliodonium salts presented the next logical substrate class to investigate as aryl cation equivalents. This chapter will briefly introduce the current literature on fluorinating diaryliodonium salts and our brief investigation of applying organotrifluoroborates towards the fluorination of these systems will be described.

Introduction

Hypervalent iodine compounds have become reagents of immense utility in organic synthesis. This special class of reagent has been found to be selective, mild and environmentally benign and as such they are considered to be competent alternatives to heavy-metal-based oxidants and organometallic catalysts. 179 Iodine(III) reagents, with two aryl ligands (diaryl-λ 3 -iodanes, more commonly known as diaryliodonium salts), have received considerable attention for the similar characteristics they share with their organometallic analogues. Owing to their favourable properties, these reagents allow efficient metal-free or catalysed transfer of aryl groups to a variety carbon and heteroatom (including nitrogen, chalcogen and halide) nucleophiles (Figure 3.1, a). 180,181 Chapter 3 92

Diaryliodonium salt reactivity and selectivity

The reactivity of diaryliodonium salts has been rationalised through an λ 3 -iodane aryl cation equivalent (Figure 3 182,183 It is important to note that the "ortho" effect is nucleophile dependant where the "anti-ortho" effect has been observed for boron and carbon nucleophiles with the least sterically hindered aryl ring functionalized. 180 While potentially problematic, unsymmetrical salts are highly desired in cases where the synthesis of starting aryl Chapter 3

94 moieties is expensive and laborious as these starting materials present a more atom economical functionalization approach. 180,181,185 This has spurred the incorporation and development of "dummy ligands" that allow highly selective transfer of the desired aryl ring. While this transformation was anecdotally reported, interest in the potential of this methodology increased, and, a decade later Van der Puy described the first systematic study of the conversion of diaryliodonium salts into aryl fluorides (Table 3.1). 187 The decomposition of these salts in solution provided the corresponding aryl fluoride in moderate yields (Table 3.1, entries 1-4). For unsymmetrical salts complete selectivity was observed following the selectivity rules discussed above (Table 3.1, entries 2 and3). The presence of a nucleophilic anion, chlorine, competes with fluorine resulting in lower yields of the fluorinated product; instead chlorobenzene was the major product (65%) (Table 3.1, entry 4). Aryl fluoride yields were improved by conducting the reaction in the melt (Table 3.1, entries 5-10) and could be further increased in the presence of excess KF (Table 3.1, entry 7). Furthermore, reactions conducted in the absence of solvent also avoided the formation of the reduced arene.

Chapter 3

96 ]-fluoroarenes using both [ 18 F]-KF/K222 and [ 18 F]-CsF. 189,190 Moderate to good radiochemical yields (RCY) were obtained under mild reaction conditions (Table 3.2). For unsymmetrical salts, complete selectivity and high Chapter 3

97 yields of [ 18 F]-fluoroarenes were observed when electron-rich and sterically bulky aryl substituents were used (Table 3.2, entries 2, 3 and5). Selectivity decreased when steric bulk was present on both aryl substituents and when the electronic character of both aryl rings was similar (Table 3.2, entries 6 and4, respectively). Given the potential applications in the production of [ 18 zwitterions have been synthesized and characterised, these interesting substrates have been applied as bifunctional arene reagents (Scheme 3.5). 204 The authors report that these systems are not benzyne precursors, and no fluorinated by-products have been observed.

Scheme 3.5 Iodonium trifluoroborate zwitterion bifunctional reagents.

To the best of our knowledge the use of organotrifluoroborates for the fluorination of diaryliodonium salts is unprecedented. In addition to the facile modulation of solubility and reactivity of organotrifluoroborates (see Chapter 2, section 2.1.1.6), their use as an organic counter-ion to diaryliodonium salts is attractive. Diaryliodonium salt dissociation in solution is usually favoured (for all anions except BF4 -), as this facilitates anion exchange between the counter-ion and incoming F -. 191 It would therefore be of interest to investigate the effect of an organotrifluoroborate counter-ion, that acts as a F -source, on the fluorination of diaryliodonium salts.

Results and Discussion

Synthesis of Unsymmetrical Diaryliodonium Phenyltrifluoroborates

We decided to begin the investigation with the synthesis of a series of unsymmetrical diaryliodonium salts to study the influence of the organotrifluoroborate anion on the selectivity of the reaction. With the increasing interest and application of unsymmetrical diaryliodonium salts in organic synthesis, many one-pot synthetic methodologies, largely [205][206][207][208] These methods are attractive as they reduce reaction time and can increase the substrate scope especially when certain intermediates are not stable to isolation. 181 The one-pot syntheses involve the in situ oxidation (usually with mCPBA) of an aryl iodide to an iodine(III) intermediate which can then undergo ligand exchange with the second aryl fragment to form the desired unsymmetrical salt.

My first attempt involved exploiting a method developed by Stuart et al., where 4trifluoromethyliodobenzene is oxidized by mCPBA using p-TsOH as the activator in MeCN, ligand exchange with mesitylene is induced by its addition to the reaction mixture. 207 Unfortunately in our hands, after reaction work-up, 1 H NMR spectroscopy showed that the intended product was formed (Scheme 3.6, product 3.9), but in poor yield and as an inseparable mixture with numerous impurities. Prior to changing the synthetic method, we thought that the choice of counter-ion would be important in the anion exchange step following the synthesis of the diaryliodonium salt.

Deciding that BF4 -would be a suitable counter-ion for the subsequent exchange, due to its facile exchange with various anions, we tested a method described by Olofsson et al. This method still uses mCPBA as the oxidant, but it is activated by BF3•OEt2 as a Lewis Chapter 3 104 acid, ligand exchange is then promoted by the addition of the desired boronic acid into the reaction mixture (Scheme 3.7, a). 205 Unfortunately, these conditions as described, did not work in our hands; after reaction work-up, several unidentifiable products were observed by TLC and NMR spectroscopy. However, by applying harsher conditions using an electron-rich arylboronic acid the desired salt 3.11 could be isolated pure but in poor yield (Scheme 3.7, b). Scheme 3. 7 Olofsson et al. one-pot diaryliodonium salt synthesis conditions. Isolated yields.

We attributed poor yields to the inefficient initial oxidation of iodomesitylene to iodomesitylene diacetate (3.12), the latter was therefore synthesized by oxidation of the former with sodium perborate in AcOH (Scheme 3.8). We applied 3.12 directly, bypassing in situ oxidation, with BF3•OEt2 in CH2Cl2 at 0 °C for 10 min, after which the arylboronic acid was added (Scheme 3.9). Gratifyingly, this modified protocol allowed the synthesis, in moderate to excellent yields, of a series of aryl(mesityl)iodonium tetrafluoroborate salts (Scheme 3.9, products 3.11, 3.13, 3.14 and 3.15). We could also synthesize a series of aryl(phenyl)iodonium salts by substituting MesI(OAc)2 for phenyliodine(III) diacetate (PIDA) (Scheme 3.9, products 3.16, 3.17 and 3.18). Scheme 3.9 Scope of unsymmetrical diaryliodonium tetrafluoroborate salts synthesized. Isolated yields.

With the tetrafluoroborate salts in hand, we focused our attention on developing efficient anion exchange conditions for the introduction of the organotrifluoroborate component.

We argued that if we could initially displace BF4 -with Br -, anion exchange with potassium phenyltrifluoroborate (KPhBF3) could be driven by KBr precipitation. Therefore, the bromide salt was synthesized by stirring a biphasic mixture of 3.13 in CH2Cl2 and a saturated aqueous NaBr solution, after simple extraction and Et2O precipitation 3.19 was Chapter 3 106 afforded in good yield and purity (Scheme 3.10, a). We then tested anion exchange in acetone and MeCN however, poor solubility of 3.19 in both solvents resulted in poor exchange after reaction work-up, as evidenced by 1 H, 19 F and 11 B NMR spectroscopy.

The use of a biphasic mixture (CH2Cl2/saturated aqueous KHF2) incorporating the diaryliodonium salt and KPhBF3 was attempted. This biphasic system did result in improved yields; however, the residue recovered after reaction work-up was an Having encountered difficulties with bromide salt 3. 19 we thought that perhaps we could take advantage of the increased solubility of the original tetrafluoroborate salt 3.13 and attempt anion exchange directly with KPhBF3. Gratifyingly, we found that both 3.13 and KPhBF3 were soluble in MeCN. Work-up of the reaction mixture following overnight reaction, revealed that quantitative anion exchange had occurred, as evidenced by 1

Fluorination studies of unsymmetrical diaryliodonium phenyltrifluoroborates

Solvent optimisation

we began the investigation by studying the decomposition of 3.20 in various solvents at different temperatures to determine if any fluorinated products could be detected (Table 3.3). Based on selectivity rules (see section 3.1.1) we expected the major product to be 2-fluoro-1,3,5-trimethylbenzene (3.3) due to electronic and steric effects, as the mesityl group is considered electron-rich and contains an ortho substituent. Generally, low boiling solvents resulted in no conversion of 3.20 (Table 3.3, entries 1, 2 and 4); however, trace yields of 3.3 were observed in CDCl3 and THF (Table 3.3, entries 3 and 5). Otherwise, unreacted and/or deborylation of 3.20 was observed by 19 Reaction conditions: 3.20 (0.05 mmol), solvent (1.0 mL) in pressure vial with Teflon lined cap, heated at indicated temperature for 2 h. a Yields determined by 19 F NMR spectroscopy using 2,2,2-trifluoroethanol as an internal standard. b unreacted 3.20 observed by 19 F NMR. c deborylation observed by 19 F NMR spectroscopy. d 0.2 eq. TEMPO added to reaction mixture. e 1.0 eq. TEMPO added to reaction mixture.

Reaction scope and selectivity

Having determined 1,2-dichlorobenzene as the optimal solvent we investigated the decomposition of salts 3.21-3.26 under reaction conditions (Table 3 19 F NMR spectroscopy using 2,4-dinitrofluorobenzene as an internal standard.

Mechanism

The reactivity and selectivity observed in the decomposition of diaryliodonium salts 3.20-3.26 seem to implicate a different mechanism than the one proposed in the decomposition of diaryliodonium fluorides (Scheme 3.12). 182,212 Chapter 3

113 However, the results in Scheme 3.13 contradict, for the most part, experimental observations. The decomposition of 3.20 was completely selective (Table 3.3 This mechanism would also be consistent with the results observed for the decomposition of unsymmetrical diaryliodonium tetrafluoroborates 3.14 and 3.15 which displayed identical selectivity and yields as their corresponding phenyltrifluoroborate salts (Table 3.5, entries 1 and 2). Surprisingly, we did not observe any conversion of tetrafluoroborate salt 3.16 (Table 3.5, entry 3) in contrast to its corresponding phenyltrifluoroborate salt Chapter 3 116 3.24 (Table 3.4, entry 4). This result suggests that as observed in chapter 2, organotrifluoroborates may have a unique role as a fluorinating agent. 19 F NMR spectroscopy using 2,4-dinitrofluorobenzene as an internal standard.

Conclusion and Perspectives

The fluorination of unsymmetrical diaryliodonium salts is a burgeoning area of research.

These substrates have found extensive applications in radiofluorination due to their ability Short-term perspectives for this work would involve further studies to confirm the proposed mechanism and explain the selectivity observed. Additionally, the use of alternative auxiliaries that would consistently provide high yields merit investigation.

Electronic and steric properties on the organotrifluoroborates fragment could be investigated for effect on reaction efficiencies and selectivity. The counter-ion of diaryliodonium salts has been shown to have a significant effect on (radio)fluorination yields. 191 It would therefore be of interest to investigate the solution phase fluorination of diaryliodonium salts of various counter-ions with organotrifluoroborates.

Chapter 3 Experimental Section 118

Experimental

General Information

Solvents and Reagents

All chemicals were purchased from commercial sources and used as received unless otherwise noted. Solvents used were all commercial grade and used as received with no drying, all reactions were performed in oven-dried glassware under argon atmosphere unless otherwise stated. Deuterated solvents for NMR spectroscopic analysis were purchased from Euriso-top.

Analysis

NMR experiments were performed in deuterated solvents. 1 H NMR, 13 C NMR, 11 B NMR and 19 F spectra were recorded on 300 Avance (300 MHz), 400 Avance (400 MHz) and AvanceIII 400 (400 MHz) Bruker spectrometers. All spectra were recorded at ambient temperature (298 K). Chemical shifts (δ) are reported in parts per million (ppm) relative to the residual protium in the solvents ( 1 H) or the solvent carbon ( 13 C) as internal standards. 19 F spectra of aryl fluorides were referenced to 2,4-dinitrofluorobenzene or 2,2,2-trifluoroethanol as internal standards (1 equivalent). Multiplicity of signals is indicated using the following abbreviations: s (singlet), b (broad), d (doublet), t (triplet), q (quartet), qB (1:1:1:1 of peaks arising from coupling to 11 B with S=3/2, midpoint of signal reported), dd (doublet of doublets), dt (doublet of triplet), td (triplet of doublet), hept (heptet) and m (multiplet). 13 C signals arising from the quaternary carbon bearing the trifluoroborate group were not always observed and therefore were not always listed.

Reactions were monitored using Merck Silica gel 60 F254 glass backed plates. TLC plates were visualized by UV fluorescence (λ= 254 nm) and one of the following stains: KMNO4

or HBQ. Flash column chromatography was performed using VWR Chemicals Silica gel Chapter 3 Experimental Section 119 60 -200 µm or using an automated Interchim Puriflash system using pre-packed Interchim 30 µm Silica gel cartridges.

IR spectra were recorded on a PerkinElmer Frontier FT-IR spectrometer with frequencies expressed in cm -1 .

Low resolution mass spectra were obtained on Waters LC-MS and Agilent GC-MS. Highresolution mass spectra (HRMS) were recorded using either electrospray ionization (ESI)

or desorption chemical ionization (DCI) using Kratos MS-50 / Kratos Concept IIHQ spectrometers.

Synthetic procedures and characterization data for 3.11 -3.26

Iodomesitylene A 250 mL round-bottom flask was charged with a stir bar and conc. HCl (50 mL), the flask was placed in an ice-water bath and cooled to 0 °C. 2,4,6-trimethylaniline (15.4 mL, 110 mmol) was added dropwise to the stirring HCl solution, after addition the reaction mixture was vigorously stirred for 20 minutes at 0 °C. NaNO2 (7.9 g, 115 mmol) was dissolved in 35 mL of H2O and the solution transferred to an addition funnel, this nitrite solution was added dropwise to the reaction mixture at 0 °C over 20 minutes; after addition was complete the brown reaction mixture was stirred at 0 °C for 1 hour. KI (24.9 g, 150 mmol) was dissolved in 35 mL H2O and this solution transferred to an addition funnel, this solution was dropwise added to the reaction mixture over 30 minutes, maintaining the bath temperature at 0 °C. After addition was complete the reaction mixture was allowed to warm to rt and stirred overnight. The reaction mixture was transferred to a separatory funnel and the aqueous phase extracted with cyclohexane (3 x 150 mL). The organic phase was then washed with a 5% aqueous solution of Na2S2O3 (100 mL), followed by Chapter 3 Experimental Section 120 brine (150 mL). The organic phase was then dried over anhydrous MgSO4, filtered then concentrated under reduced pressure to furnish a viscous dark brown/red oil which slowly solidifies. The product was further purified by distilling at 85 °C (10 mbar), followed by Silica gel chromatography using cyclohexane as the eluent to furnish the desired product as a light-yellow oil (10.39 g, 38%). 1 H NMR (400 MHz, Chloroform-d) δ 6.94 (s, 2H), 2.50 (s, 6H), 2.31 (s, 3H). 13 General procedure for the synthesis of unsymmetrical diaryliodonium tetrafluoroborates: 117,205 A round-bottom flask was charged with a stir bar, arylboronic acid (1 eq.) and CH2Cl2 (0.1 M), the reaction mixture was stirred and cooled to 0 °C in an ice-water bath and then BF3•OEt2 (3 eq.) was added, this solution was stirred at 0 °C for 10 minutes. In a separate flask iodomesitylene diacetate (MesI(OAc)2) or phenyliodine(III) diacetate (PIDA) (1.1 eq) was dissolved in CH2Cl2 (0.37 M) and added dropwise to the reaction mixture at 0 °C.

The resulting solution was allowed to warm to rt and stirred overnight. The reaction mixture was then transferred directly onto a plug of Silica gel and washed with CH2Cl2, the product was the eluted with 9.5:0.

General procedure for the synthesis of unsymmetrical diaryliodonium aryltrifluoroborates:

A round-bottom flask was charged with a stir bar, diaryliodonium tetrafluoroborate (1 eq.)

and MeCN (0.1 M); to this stirring reaction mixture potassium phenyltrifluoroborate (1 eq.)

was added in one portion and the mixture stirred at rt for 18 h. The reaction mixture was passed through a 0.

Fluorination of unsymmetrical diaryliodonium phenyltrifluoroborates salts

General procedure for the fluorination of iodonium salts:

A 10 mL microwave vial was charged with iodonium salt (0.05 mmol) and solvent (1 mL), the vial was capped and sealed with a crimper. The vial was placed in an oil bath at the specified temperature and stirred at the designated temperature for 2 h. After allowing to cool to rt, an internal standard was added to the crude reaction mixture followed by d 6 -DMSO (0.5 mL) and the yield was determined by 19 F NMR spectroscopy.

applied towards intramolecular fluorination

Chapters 2 and 3 described the application of organotrifluoroborates in the context of intermolecular fluorination of aryl diazonium and diaryliodonium substrates, respectively.

Having proven the ability of organotrifluoroborates to serve as fluoride ion sources in an intermolecular fashion, we were intrigued by the possibility of translating this technology towards fluorination in an intramolecular fashion. This chapter will briefly discuss previous efforts in the literature towards intramolecular fluorination.

Introduction

The fluorination of organic scaffolds has been the subject of intense effort, research and scrutiny for the better part of the last century. As a result, significant advances and developments have been made towards C(sp 3 , sp 2 , sp)-F bond forming methodologies via nucleophilic, electrophilic and radical fluorination strategies. 12 2); HBF4•OEt2 has also been used in the ring-opening of epoxides. 3,216,217 The formation of syn or anti products is largely substrate dependent, where reaction outcomes are determined by the initial configuration of the starting epoxide (cis or trans) as well as the nature of the substituents α to the epoxide (R1-R4). Generally, trans-epoxides with p-or π-electrondonating groups in the α position result in syn products. 3,217 The proposed mechanism

Applying organotrifluoroborates as intramolecular sources of fluoride

The results presented in chapters 2 and 3 have identified organotrifluoroborates as viable fluoride ion sources for intermolecular fluorination. However, given the ability of incorporating trifluoroborate functionality into a diversity of organic scaffolds, we hypothesised that their integration into substrates containing an activated leaving group or functionalisable motif could allow an intramolecular fluorination process to ensue. Chapter 4 140

The biphenyl system was easily obtained in good yield through Suzuki-Miyaura crosscoupling of 2-iodoaniline and 2-bromophenylboronic acid to produce 2'-bromo-[ At this juncture we thought that perhaps issues in reactivity were due to the presence of an unprotected amine functionality, which may interfere in the catalytic cycle or participate in proton exchange processes with a lithiated species. Therefore, we proceeded to protect the amine functionality as Given our unsuccessful attempts to borylate the biphenyl system we sought to integrate the desired boron fragment in the first synthetic step. We hypothesised that this could be accomplished by re-examining the substitution of the coupling partners in the synthesis of the biphenyl fragment. Using the methodology developed by Burke et al. 231 a boronic acid can be effectively rendered unreactive towards Suzuki-Miyaura coupling conditions by rehybridizing the boron centre from sp 2 , the hybridization of boronic acids and esters, to sp 3 using methyliminodiacetic acid (MIDA) as a trivalent ligand for boron. We therefore proposed that the biphenyl fragment could be synthesized by the Suzuki-Miyaura cross- We hypothesised that poor reaction transformations were a result of the electron-rich nature of 2-aminophenol and the multiple alkylation sites available. Aminophenols are known to undergo, often unselective, N-, O-and N,O-dialkylation with alkyl halides under standard reaction conditions. 237 The presence of multiply alkylated products under reaction conditions was confirmed by 19 With the possibility of one or a combination of these pathways being responsible for the poor conversions observed we thought that masking both the nucleophilicity and activation ability of the amino functionality may lead to improved O-alkylation. Therefore, Chapter 4

154

The retention of the trifluoroborate moiety after reduction was verified through 1 H- 19 F Heteronuclear Multiple Bond Correlation (HMBC) NMR spectroscopy, which showed a correlation between the ether methylene protons and the fluorine atoms on boron (Figure 4.2). With this key starting material in hand, we could now turn our focus towards the last synthetic step, the diazotization of aniline 4.39 to the zwitterionic diazoniotrifluoroborate 4.21. We initially attempted diazotization in acidic water using aqueous KHF2 to disfavour hydrolysis of the trifluoroborate, the addition of NaNO2 caused immediate gas evolution (N2) which subsided after 5 minutes. TLC of the reaction mixture showed a complex Chapter 4

155 mixture of products, the desired product could not be detected by 19 F and 11 The formation of 4.21 was characterised by 1 H, 19 4.8, entries 1, 3 and 4); however, no fluorinated products could be observed by 19 F NMR spectroscopy.

When toluene was used as the reaction solvent, no conversion of 4.21 was observed by 19 F NMR spectroscopy ( a determined by 19 F NMR spectroscopy using 2,4-dinitrofluorobenzene as an internal standard.

We also attempted to fluorinate aniline 4.39 in a one-pot two-step method, following conditions described in chapter 2; however, this only led to complete degradation of the starting material and no fluorinated products could be detected, as observed by 19 When reaction temperatures were increased complete conversion of 4.21 was observed in all cases but one and, at best, trace yields of 2-fluoroanisole where detected in toluene and 1,2-dichlorobenzene as reaction solvents. 19 F NMR spectroscopic analysis of these reaction crudes revealed complete absence of signals that could be attributed to a trifluoroborate functionality and a prominent peak corresponding to BF4 -indicating significant deborylation under reaction conditions. With this in mind, it is important to note that we cannot exclude the attribution of trace yields observed to fluorination by BF4 -.

Based on these results it can be concluded that 4.21 is not a suitable scaffold for the intramolecular transfer of fluorine to an aryl cation.

Synthesis and fluorination studies of styrene derivative 4.22

Experimental work using substrate 4. 22 We thought that using N-bromine agents would be advantageous by virtue of the fact that these are known to slowly release Br2 into the reaction medium which may obviate the over-bromination previously observed. Unfortunately, use of N-bromosuccinimide (NBS) in various solvents at ambient temperatures did not result in any fluorinated products however, 4.42 was observed as the main product by GC-MS; 19 F and 11 B NMR spectroscopy evidenced significant deborylation (Table 4.9, entries 1-6). Similar results

were observed when reaction temperatures were increased (Table 4.9, entries 7-11).

However, in THF at 45 °C trace yields of a fluorinated product were observed. 19 F NMR spectroscopy revealed a signal at -181 ppm with a ddd splitting pattern which corresponds well with the chemical shift and coupling constants reported for (2-bromo-1-Chapter 4

162 fluoroethyl)benzene (δ = -174, ddd). 240 Fluorination yields could not be increased by changing equivalents of NBS used (Table 4.9, entries 13-15) and when reaction temperatures were increased only deborylation was observed in the absence of any fluorinated products (Table 4.9, entries 16 and17). 1,3-dibromo-5,5-dimethylhydantoin (DBH) allowed the formation of trace fluorinated product at ambient temperatures in CCl4 and in both CH2Cl2 and CCl4 with heating (Table 4.9, entries 19, 21 and 22, respectively). a determined by 19 F NMR spectroscopy using 2,4dinitrofluorobenzene as an internal standard.

As a final approach we identified bromodimethylsulphonium bromide We found that the slow addition of a solution of 4. 44 a detected by LC-MS as [M 79 Br+K] + 351 and [M 81 Br+K] + 353. b determined by 19 F NMR spectroscopy using 2,4-dinitrofluorobenzene as an internal standard.

Discussion of results with styrene derivative 4.22

In all conditions tested only trace yields of fluorinated product could be observed in the bromofluorination of 4.22. Fluorination is occurring at the benzylic position as evidenced by the chemical shift, ~ -180 ppm, and coupling pattern observed by 19 We began by investigating the ability of 4.23 towards intramolecular fluorination in the absence of epoxide activators. As expected, reactions at ambient temperatures did not result in the detection of any fluorinated product (Table 4.11, entries 1-10). Elevated reaction temperatures were not found to improve the transformation (Table 4.11, entries 11-15 and 17-22), except in MeCN where trace yield of the desired fluorohydrin was observed as a multiplet at -184 ppm in the 19

Conclusion and Perspectives

In our effort to widen the array of intramolecular fluorine delivery methodologies we synthesised a range of organotrifluoroborate containing scaffolds that position F -near an electrophilic centre. We identified organotrifluoroborates as potential candidates for this type of transformation given their proven ability to transfer fluorine intermolecularly (see We was able to successfully synthesize, isolate and characterize zwitterionic diazoniotrifluoroborate 4.21. However, attempted fluorination of this substrate only resulted in the observation of trace yields of corresponding aryl fluoride. The substrate was generally found to be stable at low temperatures (45 °C). At higher temperatures (≥100 °C), trace yields of the corresponding aryl fluoride could be observed accompanied by significant degradation of the starting material.

A perspective for this substrate class would be synthesis and study of the corresponding all carbon derivative (4.46). This derivative will not be hampered by potential stabilization of the diazonium cation, as is possible for 4.21 (see Scheme 4.18), and may therefore undergo dediazoniation in milder conditions, avoiding the degradation observed at higher temperatures. If this strategy is successful, a long-term perspective would be applying

Solvents and Reagents

All chemicals were purchased from commercial sources and used as received unless otherwise noted. Solvents used were all commercial grade and used as received with no drying, all reactions were performed in oven-dried glassware under argon atmosphere unless otherwise stated. Deuterated solvents for NMR spectroscopic analysis were purchased from Euriso-top.

Analysis

NMR experiments were performed in deuterated solvents. 1 H NMR, 13 C NMR, 11 B NMR and 19 F spectra were recorded on 300 Avance (300 MHz), 400 Avance (400 MHz) and AvanceIII 400 (400 MHz) Bruker spectrometers. All spectra were recorded at ambient temperature (298 K). Chemical shifts (δ) are reported in parts per million (ppm) relative to the residual protium in the solvents ( 1 H) or the solvent carbon ( 13 C) as internal standards. 19 F spectra of aryl fluorides were referenced to 2,4-dinitrofluorobenzene.

Multiplicity of signals is indicated using the following abbreviations: s (singlet), b (broad), d (doublet), t (triplet), q (quartet), qB (1:1:1:1 of peaks arising from coupling to 11 B with S=3/2, midpoint of signal reported), dd (doublet of doublets), dt (doublet of triplet), td (triplet of doublet), hept (heptet) and m (multiplet).

Reactions were monitored using Merck Silica gel 60 F254 glass backed plates. TLC plates were visualized by UV fluorescence (λ= 254 nm) and one of the following stains: KMNO4

or HBQ. Flash column chromatography was performed using VWR Chemicals Silica gel 60 -200 µm or using an automated Interchim Puriflash system using pre-packed Interchim 30 µm Silica gel cartridges.

IR spectra were recorded on a PerkinElmer Frontier FT-IR spectrometer with frequencies expressed in cm -1 .

Low resolution mass spectra were obtained on Waters LC-MS and Agilent GC-MS. Highresolution mass spectra (HRMS) were recorded using either electrospray ionization (ESI)

or desorption chemical ionization (DCI) using Kratos MS-50 / Kratos Concept IIHQ spectrometers. (231 mg, 0.2 mmol, 10 mol%), DME (5.7 mL) and water (2.9 ml). The reaction mixture was stirred at rt for 5 mins, then degassed (three cycles of freeze-pump-thaw), the vial sealed and placed in an oil bath at 120 °C for 4 h. After to cooling to rt the reaction mixture was dropped onto water and extracted with Et2O (3 x 25 mL). The combined organic phases were dried over anhydrous MgSO4, filtered and concentrated onto Celite. The crude was purified by Silica gel flash column chromatography using 100% cyclohexane to cyclohexane/EtOAc (9:1). Desired fractions were collected and concentrated under reduced pressure to furnish the desired product as a clear oil that solidified upon standing (413.2 mg, 82%).

Synthetic procedures and characterization

N-Phthaloyl-2'-bromo-[1,1'-biphenyl]-2-amine (4.28)

A 10 mL round-bottom flask was charged with a stir bar, 2'-bromo-[1,1'-biphenyl]-2-amine (308.5 mg, 1.21 mmol), phthalic anhydride (184.4 mg, 1.21 mmol) and toluene (3 mL);

the flask was fixed with a condenser and the mixture heated at reflux for 18 h. After allowing to cool to rt, the crude reaction mixture was concentrated onto Celite under reduced pressure and then purified by silica gel column chromatography using an eluent of cyclohexane (100%) to cyclohexane/EtOAc (4:1); the desired product was isolated as an off-white crystalline powder (347.4 mg, 74%). IR νmax/cm

2-aminophenylboronic acid (4.32)

A 10 mL flask was charged with a stir bar and flame dried, after cooling to rt the flask was purged with Ar, and left under an Ar atmosphere. The flask was then charged with 2-Chapter 4 Experimental Section 177 nitrophenylboronic acid (112.3 mg, 0.6 mmol), Pd/C (10 mg, 10% loading) and EtOH (5.5 mL). Under vigorous stirring the reaction flask was purged with H2 using a balloon three times, then left under a H2 balloon. The reaction mixture was stirred for 30 min at rt until complete consumption of starting material was determined by TLC (CH2Cl2/MeOH 9:1).

The reaction mixture was filtered through a fine glass frit, and the insoluble residue was washed with EtOH (3 x 5 mL). The filtrate was concentrated under reduced pressure to furnish the product as an off-white powder which was further dried under high vacuum (59.9 mg, 65%

2-bromophenylboronic acid MIDA ester (4.33)

A 250 mL round-bottom flask, affixed with a condenser and Dean-Stark adapter, was charged with a stir bar, 2-bromophenylboronic acid (1.0199 g, 5 mmol), methyliminodiacetic acid (748.4 mg, 5 mmol), toluene (50 mL) and DMSO (20 mL). The reaction mixture was stirred and heated at reflux for 18h. After cooling to rt, all solvent was removed under reduced pressure and the residue concentrated onto Celite. The crude reside was purified by Silica gel flash column chromatography using an eluent gradient of 100% Et2O to Et2O/MeCN (1:1). Desired fractions were collected and concentrated to furnish the desired product as a white crystalline powder (1.5291 g, 97%).

1 H NMR (300 MHz, Acetonitrile-d3) δ 7.67 (dd, J = 7.5, 1.9 Hz, 1H), 7.62 (dd, J = 7.9, 1. added dropwise to ensure that the internal temperature did not rise above -70 °C. After n-BuLi addition was completed the reaction mixture was stirred at -78 °C for 2.5 h.

Methanesulphonic acid (4.12 mL, 0.064 mol) was then added to the reaction mixture slowly at -78 °C, then the flask was removed from the dry ice-acetone bath and allowed to warm to 0 °C. At this point KHF2 (32.8595 g, 0.42 mol) was added in one portion followed by deionized water (43 mL). The reaction mixture was then stirred for an additional 30 min before all solvent was removed under reduced pressure and the remaining residue dried under high vacuum overnight. The dry white solid was then triturated with acetone (4 x 100 mL) and filtered to remove insoluble salts. The filtrate was concentrated under reduced pressure to the point of saturation after which Et2O was added leading to the precipitation of the product as a fine white crystalline powder, which was collected by filtration further washed with Et2O and dried under high vacuum (15.8322g, 62%). 1 H[ 11 B] NMR (400 MHz, Acetone-d6) δ 2.21 (q, J = 5.7 Hz). 19 A 250 mL round-bottom flask was charged with a stir bar, potassium bromomethyltrifluoroborate (3.9970 g, 20 mmol), potassium iodide (3.3856 g, 20.5 mmol) and acetone (140 ml). The flask was fitted with a condenser and the flask heated to reflux in an oil bath; the reaction mixture was stirred at reflux overnight until the reaction was determined completed by 19

N-Boc-2-aminophenol (4.42)

A 50 mL round-bottom flask was charged with a stir bar, 2-aminopehnol (1 g, 10 mmol), Boc2O (2.4 mL, 10.5 mmol) and dry THF (10 mL); the flask was purged with Ar and left to stir at rt for 18h. All solvent was removed under reduced pressure and the residue redissolved in EtOAc (50 mL) and dropped onto sat 'd aq. NH4Cl (50 mL). The phases were separated and the aqueous phase was extracted with EtOAc (3 x 50 mL). The combined organic phases were dried over anhydrous Na2SO4, then filtered and concentrated under reduced pressure to furnish the desired product as a brown powder (2.2029 g, >99%). was added in one portion then the flask was placed in an oil bath and heated at reflux for 18 h. The reaction mixture was allowed to cool to rt and then quenched with 4.5 M aq.

KHF2 (1 mL); all solvent was then removed under reduced pressure and the residue further dried under high vacuum overnight. The dry residue was triturated with acetone and filtered through a 0.2 µm PTFE filter to remove insoluble impurities, the filtrate was then concentrated to the point of saturation and dropped onto Et2O to precipitate the desired the product as an off-white powder which was collected by filtration and further washed with Et2O then dried under high vacuum overnight (324 mg, 83%). IR νmax/cm -1 (neat film): 3132, 3060, 2947, 2909, 2854, 1616, 1524, 1345, 1269, 1104, 1002, 968, A 10 mL round-bottom flask was charged with a stir bar, condenser and flame-dried, once cooled the apparatus was purged with Ar and left under Ar atmosphere. The flask was then charged with NaH (47.1 mg, 1.2 mmol) and THF (5 mL), then cooled in ice-bath, after which 2-nitrophenol (161.7 mg, 1.2 mmol) was added in one portion causing the evolution of gas and the formation of a red heterogeneous mixture. The reaction mixture was then stirred at rt for 30 minutes after which 2-(bromomethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (255 mg, 1.2 mmol) was added, the mixture was then stirred at rt for 5 h, then heated to reflux for 18 h. The reaction mixture was then cooled to rt and quenched with saturated aq. NH4Cl (1mL), the aqueous phase was extracted with Et2O

(3 x 20 mL). The organic phase was dried over Na2SO4, then filtered and concentrated under reduced pressure onto Celite. The crude was purified by Silica gel flash column chromatography using a gradient of 100% CH2Cl2 to 95:5 CH2Cl2/MeOH. Desired fractions were collected and concentrated under reduced pressure, and under high vacuum overnight to furnish the product as a brown crystalline solid (181.6 mg, 56%). IR νmax/cm -1 (neat film): 2981, 1931, 1607, 1525, 1350, 1237, 1223, 1140, 955, 844, then filtered and concentrated to furnish the desired boronic acid as a white powder (254.7 mg, 63%). 1 H NMR (300 MHz, Methanol-d4) δ 7.53 (d, J = 7.7 Hz, 1H), 7.28 (ttd, J = 14.2, 7.1, 1.6 Hz, 3H), 6.76 (dd, J = 17.5, 11.0 Hz, 1H), 5.66 (dd, J = 17.5, 1.0 Hz, 1H), 5.24 (dd, J = 11.0, 1.0 Hz, 1H). 13 A 50 mL round-bottom flask was charged with a stir bar, 2-vinylphenylboronic acid (254.7 mg, 1.72 mmol), KHF2 (444.6 mg, 5.7 mmol), MeOH (20 mL) and water (1.27 mL). The reaction mixture was sonicated for 1 min, then stirred at rt for 3 h at which point complete conversion of the boronic acid was confirmed by 11B NMR. The reaction mixture was then concentrated to dryness under reduced pressure, then further dried under high vacuum. The residue was triturated with acetone (3 x 5 mL), which was filtered to remove insoluble impurities, the filtrate was then concentrated to saturation and dropped onto Et2O to precipitate the product. The precipitate was collected by filtration and washed with Et2O to furnish the desired product as a white powder (241.4 mg, 67%). IR νmax/cm -1 (neat film): 3082, 3057, 3021, 3000, 1624, 1441, 1209, 1188, 911, 743.

Bromodimethylsulphonium bromide (4.44)

A 100 mL round-bottom flask was charged with a stir bar and addition funnel then flame dried under high vacuum and then allowed to cool to rt, the system was then purged with Ar. The round-bottom flask was then charged with dimethyl sulphide (3.7 and current developments in the imaging of such hallmarks. The design and synthesis of a series benzothiazole based B-Fn complexes, as potential bi-modal imaging agents, will then be described. The characterization of these complexes by various methods will be presented.

Introduction

The patients showed increased localisation and retention of the tracer in frontotemporal and hippocampal areas of the brain in AD patients compared to healthy controls (Figure 5.3). [269][270][271][272] Tracer uptake in brain regions known for higher Aβ deposits was confirmed via post-mortem histological staining. Therefore, the use of 18 F with a more appropriate half-life (t1/2 = 110 minutes) has been sought as a viable and necessary alternative, where centralized production and regional distribution is common practice as with Highest Occupied Molecular Orbital (HOMO) and Lowest Unoccupied Molecular Orbital (LUMO), called the HOMO-LUMO gap. The HOMO-LUMO gap is lowered through the combined effect of a conjugated π system and D-π-A motif which generates a "push-pull" system. D-π-A molecules can be described by two resonance forms, one neutral and the other zwitterionic; the zwitterionic resonance form is a closer representation of the excited state (Scheme 5.4). This renders the entire molecular increasingly polarizable, and therefore the ground state is closer in energy to the excited state hence a lower HOMO-LUMO gap. 285 NIRF probes normally display a change in emission properties once bound to Aβ aggregates, this aids in the differentiation between nonspecific and specific binding.

Binding is usually accompanied by bathochromic shifts in emissions wavelength as well as increased quantum yield (QY). To date, no NIRF probe has been approved for clinical use. However, significant research is focused on the development of probes possessing favourable photophysical properties and affinity for Aβ aggregates for in vivo applications. [285][286][287] The following section will discuss the most relevant probe from each family of reported probes and their current developments. As described for PET probes above, NIRF probes for Aβ aggregates must meet some of the same basic requirements as well as additional ones: 1) appropriate lipophilicity to allow BBB permeability, 2) selectivity and affinity for amyloid plaques, 3) bioimaging. 99,297,298 In this context, Ono et al. designed a series of BODIPY-based probes for the selective detection of Aβ aggregates. 299 These probes were designed by incorporating features in the NIAD family of dyes, namely the conjugated thiophene moiety and from this series of probes, BAP-2 emerged as the most promising. BAP-2

was shown to selectively bind Aβ aggregates in high affinity in in vitro binding assays.

However, the probe failed in in vivo experiments as differentiation between wild type and transgenic mice could not be observed due to the significant accumulation of the probe in the scalps of both. BAP-2 also displayed other disadvantages, while emission was in the NIR (708 nm), the probe displayed a small Stokes shift (57 nm) which may cause potential interference via inner filter effects and Raman and Rayleigh scattering. Before potential clinical applications of BODIPY probes can be considered their downfalls of narrow Stokes shifts and nonspecific binding in lipophilic tissues need to be addressed.

The final class of probe is structurally derived from curcumin (Scheme 5.6). It is important to note that curcumin has been shown to reduce oxidative damage and amyloid plaque accumulation in in vitro rat models. 300 The natural compound has also been studied as an in vivo probe for Aβ aggregates due to its fluorescent properties. However, due to its hydrophilic nature the compound exhibited poor BBB permeability, and emission was not in the NIR requiring invasive imaging techniques. 300 is an important observation as it is the soluble forms of Aβ (dimers and oligomers) that are considered toxic, and precede the formation of plaques. 252,255,302,303 CRANAD-58 was also shown to be capable of differentiating between wild type and transgenic mice prior to formation of insoluble Aβ deposits; highlighting the ability of this probe to detect the presence of soluble Aβ plaques in vivo.

Bi-modal Imaging Probes for AD

Dual-mode imaging probes are of interest for their ability to provide complementary information. When the dual functionality comprises the coupling of non-radiative and radiative modalities, these can be used for cross-validation of each imaging technique.

There are only a few reports on the synthesis and evaluation of bi-modal imaging probes for amyloid plaques. The first of such probes was reported in 2010 by Ono et al. where The difluoroborate moiety should allow facile access to a PET probe via IEX, as has been successfully demonstrated with BODIPY probes. 90 Benzothiazole-based B-F2 complexes are a recent development having been first reported in 2009 by Kim et al. 307 The synthesis of other derivatives was reported in the Chapter 5

205 following years, with most complexes sharing similar photophysical properties and exhibiting emissions in the blue and green region, while mostly displaying narrow Stokes shifts similar to BODIPY probes. [307][308][309][310][311][312] Only one reported benzothiazole B-F2 complex, reported by Ahn et al., emits just below the NIR cut-off. 313 In addition to synthesizing benzothiazole B-F2 complexes we were interested in the possibility of further functionalizing the benzothiazole core into a tritopic (three heteroatoms for boron coordination) ligand for monofluoroborate chelation (Scheme

5.10).

To the best of our knowledge, complexes of this nature have not been previously described, and their synthesis, characterization and investigation of photophysical properties and stability would be of interest. These monofluoroborate complexes would also be well-suited for IEX as there is only one fluoride to exchange, increasing the overall efficiency of the process.

Results and Discussion

Synthesis of Benzothiazolyl B-Fn Complexes

The benzothiazole core is considered a privileged bicyclic heterocycle in light of its applications in pharmaceutical, agrochemical and materials chemistry. [314][START_REF]3')-C(4')-C(5[END_REF][316] This has driven the development of increasingly efficient methodologies towards the synthesis of 2-aryl benzothiazole scaffolds 252,317,318 A practical and convergent strategy involves initial We began this investigation by synthesizing a series of 4-and 6-substituted 2aminobenzothiazoles. 6-Substituted-2-aminobenzothiazoles could be directly obtained, in excellent yield, from the corresponding 4-substituted anilines via Brewster thiocyanation followed by Br2 mediated oxidative cyclization in AcOH 319,320 (Scheme 5.12, a, products 5.1 and 5.2). 4-Substituted-2-aminobenzothiazoles cannot be obtained in this manner due to preferential thiocyanation at the activated para position relative to the aniline. 319,321 Therefore, the corresponding thioureas were first isolated according to conditions reported by Rasmussen and Jung (Scheme 5.12, b, products 5.3 and 5.4), 322,323 subsequent Hugershoff cyclization 324,325 with Br2 yielded the corresponding 4-Substituted-2-aminobenzothiazoles in good to excellent yields (Scheme 5.12 b, products We postulated that the instability of a B-F2 complex with 5.13 may due to the steric hindrance imposed by the methyl group at position 4 on the benzothiazole scaffold. For aniline-containing ligands, 5.14 and 5.16, we thought that if B-Fn complexation occurs, degradation via HF elimination followed by hydrolysis would restore the starting ligand (Scheme 5.16). We could not find any literature precedent for 2-(benzo [d]thiazol-2yl)aniline B-F2 complexes; indeed, the only reported analogous family of compounds incorporated carbazoles or diarylamines at the 2 position of a benzothiazole or benzoxazole scaffold, respectively (Scheme 5.17). 310,327 Chapter 5

212

Structure of B-Fn Complexes

The molecular structure of all boron complexes was determined by X-ray crystallography;

single crystals of 5.17-5.19 were obtained by slow vapour diffusion of cyclohexane into saturated solutions of complexes in CHCl3 or acetone (Figure 5.4).

Chapter 5 219 5.17 crystalized in the triclinic P-1, while 5.18 and 5.19 in the monoclinic P21/c space groups. In 5.17 and 5.19, atoms forming the six-membered chelate ring are almost all coplanar with angles between the benzothiazole and C2 attached phenol ring planes of 3.12 and 3.33°, respectively. However, 5.18 exhibited greater torsion between the two ring systems with the angle between both planes being 6.20°. All complexes display a slightly distorted tetrahedral geometry at boron with the F1 and F2 (for 5.17 and 5.18) or F1 and O1' (for 5.19) atoms above and below the main molecular plane. For both 5.17 The B1-N1 bond distances are generally consistent in 5.17-5.19, ranging from 1.580-1.589 Å. The B1-O1 bond distances are similar in 5.17 and 5.18 at 1.441 and 1.445 Å, respectively. However, in 5.19 the B1-O1 bond is slightly longer (1.450 Å) while the B1-O1' bond is the shortest of all B-O bonds (1.423 Å). This may be due to ring strain in the six-membered chelating system containing O1, while the seven-membered chelating system, containing O1', allows O1' to adopt a further optimized geometry leading to greater orbital overlap and therefore a shorter B-O bond distance. Structural characteristics for 5.17 and 5.18 are generally consistent with reported 2arylbenzothiazole B-F2 complexes. [307][308][309][310][311][312][313] To the best of our knowledge, 5.19 is the first benzothiazole-based mono-fluoroborate complex and is a new addition to the few reported examples of boron chelation in a seven-membered ring. [330][331][332][333] Chapter 5 220

Asymmetry of B-F complex 5.19

Chiral boron complexes have been the subject of intense development and study due to their important applications as asymmetric catalysts in organic transformations. 334,335 In most cases chirality is derived from an asymmetric carbon within the molecular scaffold and not by asymmetry at the boron centre. Asymmetric boron complexes that are stable and can be resolved are rare due to facile dissociation and inversion process which lead to racemization. 336,337 There are however reported examples of stable chiral oxazaborolidinone and salicylaldimine boronate complexes and more recently acylboronates (Scheme 5.24). [338][339][340][341] Scheme 5. 24 Selected examples of chiral boron complexes While there are examples of chiral boron-containing fluorophores, most examples that have been reported incorporate a chiral carbon or are axially chiral (using binaphthyl substituents for example) as opposed to an asymmetric centre at boron. 342,343 In 2010

Ulrich et al. reported the first synthesis and resolution of a chiral BODIPY (Scheme 5.25, product 5.32). 344 They achieved chirality through initial mono-substitution at boron followed by desymmetrization of the BODIPY core via oxidation of the 3-methyl group to an aldehyde. The aldehyde functionality is crucial for both asymmetry and configurational stability of the B-F complex via hydrogen bonding (H---F). The racemic mixture was successfully resolved by chiral HPLC and the enantiomers were found to be stable to inversion about the boron centre. showed no evidence of inversion, although some hydrolysis to the free ligand was observed.

Photophysical Studies of B-Fn Complexes

The absorption and emission spectra of compounds 5.11, 5.12, 5.15 and 5.17 Chapter 5

225

While the same absorption profile is maintained going from free ligand to complex, all B-Fn complexes display a significant red-shift in absorption maxima (λmax) when compared to their free ligand precursors (Table 5.1). The red-shifts observed (19, 26 and 22 nm for 5.17 maintaining a similar red-shift of 13 nm compared to 5.17; both compounds exhibit narrow Stokes shifts of 64 and 62 nm for 5.17 and 5.18, respectively. Meanwhile, 5.19 is a greenemitter with a broader emission band, with a maximum at 512 nm (ΦF = 0.10), representing a significant Stokes shift of 151 nm, more than double those of 5.17 and Chapter 5

226 5.18 (Table 5.1). It is also worthy to note that all compounds 5.11, 5.12, 5.15 and 5.17-5.19 exhibit solid-state fluorescence when irradiated with a UV-lamp (365 nm).

Generally, complexes 5.17 and 5.18 display similar photophysical properties to previously reported 2-arylbenzothiazole B-F2 complexes. [307][308][309][310]312,313 Complex 5.19 is the notable exception: while possessing similar absorption properties to previously reported benzothiazole B-F2 complexes, its emission properties resemble those of highly conjugated systems or systems with significant D-π-A architectures (Scheme 5.26). 308,309,313 More importantly, the photophysical properties observed for 5.19 approach those for previously reported NIRF imaging probes for Aβ. 285,286 The properties observed

Theoretical Calculations

To further and better understand the absorption and emission properties of the complexes synthesized, we decided to carry out time-dependant density functional theory (TD-DFT) calculations. Ground state geometries (S0) were optimized using the DFT/B3LYP method with 6-31G basis sets. TD-DFT calculations were carried out, in CH2Cl2 as the solvent according to the Polarizable Continuum Model (PCM), using the B3LYP method with 6-31G basis sets in Gaussian 09. 345 HOMO and LUMO energies, representations, transitions, oscillator strengths (f) and calculated λmax are displayed in Figure 5.9.

Calculated excitation energies for 5.17 As seen in Figure 5.9, LUMO orbitals of 5.17 and 5.19 are very similar in energy (-2.31 and -2.30 eV, respectively), while 5.18 was calculated to have the lowest LUMO energy (-2.60 eV). Larger differences are observed in the HOMO, and more notably HOMO-1 energies of 5.17-5.19. Similar electronic distribution in the HOMO orbitals of 5.17 and 5.18 are predicted, where electron density is delocalized over the entirety of the πconjugated system. The LUMO orbitals of these two complexes shows redistribution of Chapter 5

229 electron density into orbitals that are still delocalized over the entire system. However, for 5.19 HOMO orbital electron density is concentrated on the benzothiazole core as well as the phenol ring at position C4. In the LUMO, there is a significant rearrangement of electron density from the C4 to C2 phenol ring. This considerable redistribution of electron density may be a plausible explanation for the larger Stokes shift of 5.19, compared to that of 5.17 and 5.18. This shift in electron density may also be a factor in the decreased quantum yield observed for 5.19. 313 The polarized HOMO and LUMO orbitals of 5.19 may also explain the positive solvatochromism in emission observed in MeCN (Table 5.1).

Chapter

Stability Studies of B-Fn Complexes

Given prospective applications of these complexes in vivo, we briefly examined the stability of 5.17-5.19 to the presence of water. We observed that 5.18 hydrolysed to the free ligand after extended periods of time in organic solvent, exposed to moisture and air.

However, 5.17 and 5.19 were stable for months stored as solids in ambient conditions and in organic solvents (CH3CN, CH2Cl2 and CHCl3) exposed to moisture and air.

Chapter 5

231

To further probe this, we investigated the stability of 5.17 and 5.19 to increasing amounts of water and monitored the hydrolysis of the B-Fn complex by NMR spectroscopy. Each complex was dissolved in 0.6 mL CD3CN followed by 0.1 mL D2O; stability was monitored via 19 F and 11 B NMR spectroscopy (Figure 5.10). Immediate hydrolysis of 5.17 is apparent at t=0, as degradation by-products are observed in 19 F and 11 B NMR spectroscopy (BF4 - and B(OH)3); complete hydrolysis is apparent at t = 14 hours. However, 5.19 displayed exceptional stability for over 289 hours, as no hydrolysis of the B-F bond or degradation products were observed by 11 B and 19 F NMR spectroscopy.

The enhanced hydrolytic stability of 5.19 can be tentatively attributed to two factors: 1) increased steric protection, 2) tridentate chelation of boron. The second phenol ring at position 4 on the benzothiazole core provides additional hydrophobic steric bulk which may disfavour water solvation and therefore retard hydrolysis. The benzothiazole core being a tritopic ligand may also disfavour ligand dissociation, as the boron centre would require rehybridization from sp 3 to sp 2 . Rehybridization, in turn would induce geometrical reorganization at boron from tetrahedral to trigonal planar, which may be disfavoured given the geometrical restrictions imposed by the non-planar tritopic benzothiazole ligand.

These results importantly highlight that electronic factors are not a deciding factor in the stability of these complexes. The average B-F bond length in 5.19 (1.391 Å) is longer than that of 5.17 (1.381 Å) an indication that the boron centre in 5.19 is less electron deficient than in 5.17, solely based on these properties one would have predicted increased stability for 5.17 compared to 5.19.

Chapter 5

Figure 5.7 19 F and 11 B NMR spectra evolution for 5.17 With the favourable aqueous stability observed for 5.19 we continued by investigating the possibility of fluorine exchange at boron, in line with prospective applications in radiolabelling with 18 F for PET probe synthesis. Significant developments have been reported in the synthesis and 19 F -18 F IEX of BODIPY dyes for the generation of bi-modal imaging agents. These efforts have largely been driven by Gabbaï, Weissleder and

Mazitschek. These groups simultaneously demonstrated that BODIPY derivatives could be pre-activated by the abstraction of one fluorine atom at boron and replacement with labile hydroxide or trifluoromethanesulfonate (OTf, triflate). These pre-activated BODIPYs could then be facilely radiolabelled under mild aqueous or anhydrous conditions (Scheme 5.27). 87,346 Soon after, both Gabbaï and Weissleder demonstrated that pre-activation could be avoided via Brønsted or Lewis acid assisted IEX (Scheme 5.27, c). 88,90 Chapter 5

235 We thought that pre-activation with triflate would be the simplest methodology to test fluoride exchange on 5.19, as fluoride abstraction and formation of the intermediate borenium species (5.33) should be observable by 1 H, 19 The B-F signal in the 19 F NMR spectrum, (qB, 1:1:1:1) centred at -132.07 ppm, completely disappears and a new peak attributed to TMS-F, centred at -157.77 (dh, JF-Si = 14.9 Hz, JF-H = 7.4 Hz) appears. 19 F NMR spectroscopy also shows two peaks for OTf (-76. and was found to be a green light emitter with a significantly large Stokes shift (151 nm), this complex was also found to display positive solvatochromism in polar solvents.

Theoretical calculations were conducted in order to support and better understand the experimentally observed photophysical properties. The stability of complexes 5.17-5.19 were studied. 5.18 was found to degrade, via deborylation, to the starting ligand upon extended exposure to moisture and ambient conditions. Complex 5.17 was found to be more resilient, however exposure to increasing aqueous conditions resulted in rapid degradation. Complex Long-term perspectives for complexes of this architecture would be to develop a theranostic platform based on the starting ligand (Scheme 5.30). Facile interchange between both imaging modalities is envisioned via IEX, and the benzothiazole ligand itself can be used a potential metal chelator for therapeutic use, give the implication of metal ions in the aetiology of AD. 255,302,303,347 Scheme 5.30 Prospective theranostic platform based on benzothiazole ligand

Experimental General Information

Solvents and Reagents

All chemicals were purchased from commercial sources and used as received unless otherwise noted. Solvents used were all commercial grade and used as received with no drying, all reactions were performed in oven-dried glassware under argon atmosphere unless otherwise stated. Deuterated solvents for NMR spectroscopic analysis were purchased from Euriso-top.

Analysis

NMR experiments were performed in deuterated solvents. 1 H NMR, 13 C NMR, 11 B NMR and 19 F spectra were recorded on 300 Avance (300 MHz), 400 Avance (400 MHz) and AvanceIII 400 (400 MHz) Bruker spectrometers. All spectra were recorded at ambient temperature (298 K). Chemical shifts (δ) are reported in parts per million (ppm) relative to the residual protium in the solvents ( 1 H) or the solvent carbon ( 13 C) as internal standards. Multiplicity of signals is indicated using the following abbreviations: s (singlet), b (broad), d (doublet), t (triplet), q (quartet), qB (1:1:1:1 set of peaks arising from coupling to 11 B with S=3/2, midpoint of signal reported), dd (doublet of doublets), dt (doublet of triplet), td (triplet of doublet), hept (heptet) and m (multiplet).

Reactions were monitored using Merck Silica gel 60 F254 or Aluminium Oxide (Basic) 60 A 250 mL round-bottom flask was charged with a stir bar, p-toluidine (9.995 g, 93.27 mmol), NH4SCN (35.00 g, 459.8 mmol) and AcOH (100 mL). An addition funnel was then charged with Br2 (5.2 mL, 101.5 mmol), which was diluted with AcOH (20 mL). The resulting Br2 solution was then added to the reaction mixture dropwise over 10 minutes.

With the addition of Br2 a pink slurry forms. After Br2 addition is complete, the slurry is allowed to react for 18 h at rt. The reaction mixture had then formed a thick non-stirrable slurry. To this slurry a solution of NaOH was added as to adjust the pH to 7-8. The mixture was then washed with a 5% aq. Na2S2O3 solution resulting in a fine precipitate. The yellow precipitate was collected, washed with 5% aq. Na2S2O3 and water then placed in a desiccator under high vacuum to dry (14.0401 g, 92%). IR νmax/cm -1 (neat film): 3394, 3273, 3257, 3124, 1622, 1532, 1463, 1278, 806, 603. 1 H NMR (400 MHz, Acetone-d6) δ 7.43 (s, 1H), 7.28 (d, J = 8.1 Hz, 1H), 7.05 (dd, J = 8.0, 1.5 Hz, 1H), 6.67 (bs, 2H), 2.34 (s, 3H). 13 C NMR (101 MHz, Acetone-d6) δ 166.4 (Cq), 151.9 (Cq), 132.

Ethyl 4-aminobenzoate

A 250 mL round-bottom flask was charged with a stir bar, condenser, 4-aminobenzoic acid (10.055 g, 73 mmol) and 50 mL of EtOH. The resulting slurry was stirred and the flask was placed in an ice-bath at 0°C. H2SO4 (98%, 7.8 mL, 140.4 mmol) was diluted into 20 mL of EtOH and the resulting solution was added dropwise to the stirring slurry over a period of 3 min. The solution formed a thick white precipitate and was then allowed to warm up to room temperature; the reaction mixture was then heated at reflux for 3 hours. It was observed that after refluxing for 5 minutes the white precipitate dissolved, resulting in a clear light orange solution. After reflux the mixture is allowed to cool to room temperature. The reaction mixture was then basified with a saturated aqueous solution of NaHCO3 to a pH of 7-8. The aqueous phase was then extracted with Et2O (3 x 100 mL).

The combined organic phases were subsequently washed with saturated aqueous NaHCO3 (100 mL) and brine (100 mL). The combined organic extracts were collected and dried over anhydrous Na2SO4. The solution was then filtered and concentrated by rotary evaporation under reduced pressure. The product, an off-white powder, was left to dry overnight on a high vacuum pump (11.180 g, 92%). IR νmax/cm -1 (neat film): 3421, 3343, 3222, 2985, 2899, 1680, 1542, 1366, 1272, 845, 770, C, 65.44; H, 6.71; N, 8.48. Found C, 65.51; H, 6.49; N, 8.47.

Ethyl 2-aminobenzothiazole-6-carboxylate (5.2)

A 250 mL round-bottom flask was charged with a stir bar, ethyl 4-aminobenzoate (10.008 g, 60.6 mmol), NH4SCN (18.560 g, 242.4 mmol) and 50 mL AcOH. An addition funnel was then charged with Br2 (3.2 mL, 60.6 mmol), which was diluted with 20 mL of AcOH.

The resulting Br2 solution was then added to the reaction mixture dropwise over approximately 10 minutes; with the addition of Br2 a pink slurry forms. After Br2 addition is complete the reaction mixture is stirred overnight at rt. The next day the reaction mixture had formed a thick non-stirrable slurry. To this slurry a solution of NaOH was added to adjust the pH to 7-8. The mixture was then washed with a 5% aq. Na2S2O3 solution resulting in a fine precipitate. The precipitate was collected, washed with 5% aq. Na2S2O3

and water then placed in a desiccator under high vacuum to dry overnight (18.410 g, 99%). IR νmax/cm -1 (neat film): 3345, 3310, 3076, 2971, 1685, 1524, 1462, 1277, 1112, 892, 825, 765. HCl (37%, aq. solution) was then added to the stirring mixture to adjust the pH to ~2, then

NaHCO3 was then added slowly to increase the pH to ~8. The precipitate formed was collected by filtration, washed with water until washes were neutral then dried under high vacuum (26.4761 g, 80%). IR νmax/cm -1 (neat film): 3376, 3357, 3263, 3179, 1615, 1495, 1452, 1110, 824, 758, 697. 1 H NMR (400 MHz, Acetone-d6) δ 8.66 (bs, 1H), 7.37 -7.15 (m, 4H), 6.72 (bs, 2H), 2.29 (s, 3H). 13 product was then dried under high vacuum (17.3748 g, 75%). IR νmax/cm -1 (neat film): 3425, 3253, 3245, 3124, 3002, 1619, 1500, 1466, 1427, 1290, 1063, 1039, 1025, 818, 758,

2-amino-4-methylbenzothiazole (5.5)

A two-necked 500 mL round-bottom flask was charged with a stir bar, condenser (with a NaOH trap to neutralize HBr fumes), o-tolylthiourea (16.617 g, 0.10 mol) and CCl4 (80 mL). An addition funnel was charged with Br2 (6.15 mL, 0.12 mol) and dissolved in CCl4 (36 mL). This bromine solution was added dropwise to the stirring solution over 1.5 h. The solution was then heated at reflux for 2 hours until starting material was consumed by TLC. The reaction mixture was then cooled to rt and the solvent removed by rotary evaporation. The remaining residue was then suspended in water and washed with a 5% aq. Na2S2O3 solution to remove excess traces of bromine, then filtered and washed with water. The residue was then suspended in water and 25% NH4OH aq. solution was added to basify the solution to pH 10. The fine white precipitate was collected and washed with water until washes were neutral; the precipitate was dried under high vacuum (11.8534 g, 72%). IR νmax/cm -1 (neat film): 3448, 3287, 3062, 2941, 1642, 1537, 1409, 871, 733, 692. 3277, 3073, 2926, 1635, 1531, 1415, 1269, 882, 750, 725. (7.8858 g, 48.00 mmol) was then added portion-wise to the stirring reaction mixture over 5 minutes; rapid gas evolution was observed. The reaction mixture was then heated at 60°C for 1.5 h under positive Ar pressure. The reaction mixture was then allowed to cool to rt and 2 N HCl (120 mL) was added to quench the reaction mixture, with the notable evolution of gas. The mixture was then transferred into a separatory funnel and additional 2N HCl was added along with brine. The aqueous phase was extracted with EtOAc (4 x 200 mL). The combined organic extracts were dried over anhydrous Na2SO4, then filtered and concentrated under reduced pressure to produce a black/brown oil. This residue was further purified through a silica plug using EtOAc as the eluent, it was observed that a black residue was trapped by the silica and the desired product eluted out as an orange/red solution. Solvent was removed under reduced pressure to afford the desired compound as a brown crystalline material (7.4388 g, 68%).

1 H NMR (400 MHz, Chloroform-d) δ 7. 87 -7.79 (m, 1H), 7.59 -7.54 (m, 1H), 7.30 -7.27 (m, 1H), 2.47 (s, 3H). 13

2-bromo-4-methylbenzothiazole (5.9)

A 500 mL round-bottom flask was charged with a stir bar, CuBr2 (15.979 g, 73 mmol), t-BuONO (11.8 mL, 99 mmol) and MeCN (200 mL). 2-amino-4-methylbenzothiazole (9.9936 g, 61 mmol) was added portionwise to this stirring solution and evolution of gas was observed. The solution was stirred under positive Ar pressure for 2 h until all starting material was consumed by TLC. The reaction was quenched with 1 N aq. HCl (200 mL), after cessation of gas evolution, the mixture was transferred into a separatory funnel and additional 1 N HCl and brine were added. The aqueous phase was extracted with EtOAc (3 x 500 mL), the combined organic extracts were washed with additional 1 N HCl, then dried over anhydrous MgSO4. The solution was then filtered and concentrated under reduced pressure yielding a brown viscous oil. This residue was purified through a silica plug using EtOAc-pentane (1:1) as the eluent, the solvent was removed under reduced pressure to furnish a brown solid (9.3832 g, 68%). IR νmax/cm C, 42.12; H, 2.65; N, 6.14. Found C, 39.69; H, 1.96; N, 5.75.

2-iodo-4-bromobenzothiazole (5.10)

A 500 mL round-bottom flask was charged with a stir bar, 2-amino-4-bromobenzothiazole (9.85 g, 42 mmol), p-TsOH•H2O (24.9 g, 129 mmol) and MeCN (172 mL). The heterogenous reaction mixture was stirred and cooled in an ice-brine bath to 0 °C, at which point t-BuONO (15.3 mL, 129 mmol) was added dropwise, over 10 min, via an addition funnel; after the addition was complete the reaction mixture was stirred at 0 °C for 30 min. An additional funnel was then charged with a water (43 mL) solution of KI (21.4 g, 129 mmol) and CuI (819 mg, 4.3 mmol). The KI solution was added dropwise to the vigorously stirred reaction mixture at 0 °C over 20 minutes; the reaction mixture was then allowed to warm to rt overnight. The crude reaction mixture was concentrated under reduced pressure to ~70 mL and then dropped on sat 'd aq. NaHCO3 (150 mL) and the aqueous phase extracted with EtOAc (4 x 150 mL), the combined organic phases were then washed with a 5% aqueous Na2S2O3 solution (4 x 150 mL). The organic phase was dried over anhydrous MgSO4, filtered and concentrated under reduced pressure to furnish the product as a brown powder (13.1607 g, 90%). IR νmax/cm -1 (neat film): 3089, 3064, 2931, 2851, 1442, 1391, 1203, 952, 842, 764, 732. 1 H NMR (400 MHz, DMSO-d6) δ 8.12 (dd, J = 8.1, 1.0 Hz, 1H), 7.72 (dd, J = 7.8, 1.0 Hz, 1H), 7.37 (t, J = 7.9 Hz, 1H). 13 , 2985, 2908, 2920, 1708, 1593, 1480, 1268, 1213, 971, 904, 816, 767, 741, 718, 7.8, 1.6 Hz, 1H), 7.39 (ddd, J = 8.7, 7.3, 1.6 Hz, 1H), 7.34 -7.28 (m, 2H), 7.11 (dd, J = 8.4, 1.1 Hz, 1H), 6.99 -6.94 (m, 1H), 2.75 (s, 3H). 13 (100 mL), the aqueous phase was extracted with EtOAc (3 x 50 mL). The combined aqueous phases were washed with brine (3 x 50 mL), then dried over anhydrous MgSO4, filtered and the filtrate concentrated onto Celite under reduced pressure. The crude material was purified using Si gel flash chromatography using an eluent of 100% cyclohexane to cyclohexane/CH2Cl2 (7:3). Desired fractions were collected and concentrated under reduced pressure, and further under high vacuum overnight to furnish the desired compound as a yellow powder (85.4 mg, 30%). IR νmax/cm -1 (neat film): 3461, 3291, 3070, 3022, 2917, 2857, 1613, 1588, 1559, 1493, 1458, 1443, 1227, 1157, 965, 816, 746, 738. 1 H NMR (400 MHz, Chloroform-d) δ 7.85 (d, J = 8.3 Hz, 1H), 7.69 (dd, J = 7.9, 1.4 Hz, 1H), 7.67 (s, 1H), 7.26 (dd, J = 8.1, 1.4 Hz, 2H), 7.21 (ddd, J = 8.4, 7.2, 1.4 Hz, 1H), 6.78 (dd, J = 8.2, 0.9 Hz, 1H), 6.74 (ddd, J = 8.1, 7.2, 1.2 Hz, 1H), 6.37 (bs, 2H), 2.49 (s, 3H). 13 (3 mL). The reaction mixture was degassed the freeze-pump-thaw method three times and then purged with Ar. The vial was loaded into a microwave reactor and programmed to be heated at 120 °C for 1h, after which the crude was dropped onto water (50 mL) and the phases separated. The aqueous phase was extracted with EtOAc (3 x 25 mL), the combined organic phases were dried over anhydrous MgSO4, filtered and concentrated onto Celite. The crude residue was purified by Silica gel flash column chromatography using cyclohexane/EtOAc (4:2 to 1:1). Desired fractions were collected and concentrated to furnish the desired product as a tan foam which was further dried under vacuum overnight (189.5 mg, 55%).

IR νmax/cm -1 (neat film): 3377, 2926, 2855, 1613, 1583, 1489, 1470, 1450, 1350, 977, 743, 716. 1 H NMR (400 MHz, Chloroform-d) δ 7.95 (dd, J = 7.8, 1.4 Hz, 1H, H7), 7.69 (dd, J = 7.9, 1.6 Hz, 1H, H9), 7.58 (dd, J = 7.5, 1.4 Hz, 1H, H5), 7.53 (t, J = 7.6 Hz, 1H, H6), 7.43 (dd, J = 7.5, 1.7 Hz, 1H, H19), 7.37 (ddd, J = 8.7, 7.3, 1.6 Hz, 2H, H11, H17), 7.14 -7.07 the desired compound as a red powder (27.6 mg, 87%). IR νmax/cm -1 (neat film): 3457, 3372, 3305, 3055, 3024, 2924, 2853, 1698, 1614, 1593, 1494, 1223, 963, pentane and finally triturated with CHCl3; the filtrate was collected and concentrated under reduced pressure to furnish a light yellow powder (>99%). NMR analysis indicated the formation of the desired product accompanied with undesired DIPEA salts. The residue was dry loaded onto Celite and further loaded onto a plug of basic alumina. The product was eluted using dry CH2Cl2, until no fluorescence was observed in the eluent. Solvent was removed under reduced pressure and further dried under high vacuum, yielding a yellow powder (277.6 mg, 97%). IR νmax/cm -1 (neat film): 2917, 2849, 1615, 1570, 1509, 1488, 1468, 1276, 1057, 1011, 951, 914, 819, 804, 768. 1 C, 58.16; H, 3.49; N, 4.84. Found C, 59.00; H, 3.48; N, 4.48. 1714, 1506, 1484, 1405, 1273, 1238, 1138, 1099, 1072, 901, 826, 757, 629, C, 55.36; H, 3.48; N, 4.03. Found C, 55.42; H, 3.46; N, 3.95. 6a-fluoro-6aH-6,7-dioxa-1-thia-1a 1 -aza-6aborabenzo[a]benzo [5,6]cyclohepta [1,2,3,4-def]fluoren-1a 1 -ium-7-uide (5.19)

A 10 mL Wheaton vial was charged with a stir bar, 2,4-di(2-hydroxyphenyl)benzothiazole (33.8 mg, 0.1 mmol), dry CH2Cl2 (2 mL) and DIPEA (53 µL, 0.3 mmol). The mixture was allowed to stir at rt for 10 minutes at which point BF3•OEt2 (100 µL, 4.8 mmol) was added.

The clear brown reaction mixture was allowed to stir at rt for 2h, at which point complete consumption of starting material was determined by TLC (basic Alumina, cyclohexane/CH2Cl2 1:1). The mixture was then dropped onto excess pentane, causing precipitation of a white solid. The precipitate was collected by filtration, washed with pentane and finally dissolved into CHCl3; the filtrate was collected and concentrated onto Celite and purified by basic Alumina flash column chromatography using cyclohexane/CH2Cl2 (1:1) as the eluent. Desired fractions were collected and concentrated to furnish the desired product as a light-yellow powder which was further dried under high vacuum (32.4 mg, 88%). IR νmax/cm -1 (neat film): 1611, 1509, 1480, 1468, 1291, 1275, 1076, 1009, 846, 823, 747. 1 H NMR (400 MHz, Chloroform-d) δ 7.98

(dt, J = 7.8, 0.9 Hz, 1H, H5), 7.86 (dd, J = 8.0, 1.1 Hz, 1H, H7), 7.75 (dd, J = 8.0, 1.6 Hz, 1H, H19), 7.68 -7.54 (m, 3H, H6, H9, H11), 7.44 (ddd, J = 8.1, 7.1, 1.6 Hz, 1H, H17), 7.36 (dd, J = 8.0, 1.5 Hz, 1H, H16), 7.31 (dd, J = 8.5, 1.0 Hz, 1H, H12), 7.20 (ddd, J = 7.9, 7.1, 1.5 Hz, 1H, H18), 7.04 (ddd, J = 8.0, 7.3, 1.1 Hz, 1H, H10). 13 (C18), 121.1 (C7), 120.9 (C10), 120.7 (C12), 114.4 (C8). 19 The organic phase was dried over anhydrous MgSO4, then filtered and concentrated onto Celite and purified by Silica flash column chromatography (eluent: 100% cyclohexane to 9:1 cyclohexane/EtOAc). Desired fractions were combined and concentrated under reduced pressure to provide the product as a yellow powder (26 mg, 29%). Starting material could be recovered from purification (55.4 mg, 65% recovery). IR νmax/cm -1 (neat film): 3282, 2923, 2860, 2820, 1610, 1581, 1524, 1499, 1450, 1309, 1217, 1174, 960, 814, 734.. 1 H NMR (300 MHz, Chloroform-d) , 1523, 1508, 1501, 1313, 1219, 1171, 959, 746. 1 H NMR (400 MHz, Chloroform-d) δ 7.88 (dd, J = 7.8, 1.3 Hz, 1H, H5), 7.71 (dd, J = 7.9, 1.5 Hz, 1H, H15), 7.50 (dd, J = 7.4, 1.3 Hz, 1H, H7), 7.44 (t, J = 7.6 Hz, 1H, H6), 7.39 (td, J = 8.0, 1.6 Hz, 1H, H11), 7.35 -7.29 (m, 2H, H9, H17), 6.90 (t, J = 6.8 Hz, 2H, H10, H12), 6.74 -6.64 (m, 2H, H16, H18), 2.83 (s, 3H, H20), 2.81 (s, 3H, H21). 13

2-(2-hydroxyphenyl)-4-bromobenzothiazole (5.22)

A 10 mL µwave vial was charged with a stir bar, 2-iodo-4-bromobenzothiazole (35 mg, 0.1 mmol), 2-hydroxyphenylboronic acid (20.5 mg, 0.15 mmol), Pd(PPh3)4 (12 mg, 10 mol%), Na2CO3 (74 mg, 0.7 mmol), DMF (0.8 mL) and water (0.2 mL). The reaction mixture was stirred at rt for 5 minutes, while purging with Ar. The vial was then loaded into a microwave reactor and heated at 90 °C for 1h, after which TLC (cyclohexane/CH2Cl2, 3:2) showed complete conversion of starting material. The crude was dropped onto brine (10 mL) and the phases separated, the aqueous phase was extracted with EtOAc (3 x 15 mL) and the combined organic phases washed with brine

(2 x 10 mL). The organic phase was dried over anhydrous MgSO4, then filtered and concentrated on Celite. The crude was purified on Si gel flash column chromatography using 100% cyclohexane to 4:1 cyclohexane/CH2Cl2 as the eluent. Fractions were collected and concentrated to furnish the product as an off-white powder which was further dried under high vacuum (23 mg, 73%). IR νmax/cm (7.7 mL) and water (0.3 mL). The reaction mixture was degassed the freeze-pump-thaw method three times and then purged with Ar. The vial was loaded into a microwave reactor and programmed to be heated at 90 °C for 1h, after which the crude was dropped onto water (10 mL) and the phases separated. The aqueous phase was extracted with EtOAc (3 x 10 mL), the combined organic phases were dried over anhydrous MgSO4, filtered and concentrated onto Celite. The crude residue was purified by Silica gel flash column chromatography using 100% cyclohexane to cyclohexane/EtOAc (9.5:0.5). Desired fractions were collected and concentrated to furnish the desired product as a yellow oil which was further dried under vacuum overnight (31 mg, 72%). IR νmax/cm -1 (neat film): 3066, 2978, 2930, 1735, 1442, 1368, 1321, 1221, 1157, 1132, 1006, mL). TFA (1 mL) was added via syringe dropwise and the reaction mixture stirred at rt for 2h. All solvent was removed under reduced pressure and the residue dissolved in CH2Cl2 (10 mL) and dropped onto saturated aq. NaHCO3. The phases were separated and the aqueous phase extracted with CH2Cl2 (3 x 10 mL). The combined organic phases were dried over anhydrous MgSO4, filtered and concentrated onto Celite. The crude residue was purified by Silica gel flash column chromatography using 100% cyclohexane to cyclohexane/EtOAc (9:1). Desired fractions were collected and concentrated to furnish the desired product as a yellow powder which was further dried under vacuum overnight (111.3 mg, 97%). IR νmax/cm -1 (neat film): 3398, 3380, 3058, 2960, 2921, 2852, 1588, 1557, 1459, 1439, 1397, 1339, 1302, 1142, 1035, 917, 788, 766, 747, 733, After 5 days, the reaction mixture was cooled to rt, diluted with EtOAc and passed through a Silica plug in a Pasteur pipette and eluted with EtOAc. The residue was concentrated onto Celite and purified using Silica gel flash column chromatography using 100% cyclohexane to cyclohexane/CH2Cl2 (7:3). Desired fractions were collected and concentrated under reduced pressure to furnish the desired product as a yellow powder, which was further dried under high vacuum overnight (142.3 mg, 78%). IR νmax/cm -1 (neat film): 3275, 3098, 3056, 2924, 2890, 2859, 2820, 1612, 1575, 1525, 1499, 1454, 1305, 1218, 1173, 954, (0.2 mL). The reaction mixture was degassed the freeze-pump-thaw method three times and then purged with Ar. The vial was loaded into a microwave reactor and programmed to be heated at 120 °C for 1h, after which the crude was dropped onto water (10 mL) and the phases separated. The aqueous phase was extracted with EtOAc (3 x 10 mL), the combined organic phases were dried over anhydrous MgSO4, filtered and concentrated onto Celite. The crude residue was purified by Silica gel flash column chromatography using cyclohexane/EtOAc (4:2 to 1:1). Desired fractions were collected and concentrated to furnish the desired product as a yellow powder which was further dried under vacuum overnight (28.7 mg, 82%). IR νmax/cm -1 (neat film): 3466, 3371, 3211, 3057, 3021, 2920, 2250, 1936, 1612, 1577, 1482, 1467, 1219, 1151, 977, EtOAc and passed through a Silica plug in a Pasteur pipette and eluted with EtOAc. The residue was concentrated onto Celite and purified using Silica gel flash column chromatography using 100% cyclohexane to cyclohexane/EtOAc (9:1). Desired fractions were collected and concentrated under reduced pressure to furnish the desired product as a yellow powder, which was further dried under high vacuum overnight (54.7 mg, 33%).

Starting material could be recovered from purification (75 mg, 48% recovery). IR νmax/cm - 1 (neat film): 3434, 3048, 2922, 2814, 1620, 1603, 1580, 1510, 1481, 1313, 1218, 1155, 975, The vial was loaded into a microwave reactor and heated at 85 °C for 5 h. The crude was dropped onto brine (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic phases were dried over anhydrous MgSO4, filtered and all solvent removed under reduced pressure. The residue was dissolved in CH2Cl2 (1 mL) and TFA (1 mL) and stirred at rt for 2h. Solvent was removed under reduced pressure and the residue dissolved in CH2Cl2 (10 mL) and washed with saturated aq. NaHCO3 (2 x 10 mL) until pH was basic (~8) then brine (10 mL). The organic phase was dried over anhydrous MgSO4, filtered and concentrated onto Celite. The crude residue was purified on Si gel flash column chromatography using an eluent of 100% cyclohexane to 8.5:1.5 cyclohexane/EtOAc.

Desired fractions were collected and concentrated to furnish the desired product as an orange powder which was further dried under high vacuum overnight (23.6 mg, 69%). IR νmax/cm -1 (neat film): 3441, 3357, 3054, 2956, 2919, 2846, 1621, 1583, 1481, 1450, 1418, 1301, 1222, and water (0.2 mL). The reaction mixture was degassed the freeze-pump-thaw method three times and then purged with Ar. The vial was loaded into a microwave reactor and heated at 120 °C for 1 h. The crude was dropped onto water (10 mL) and the phases separated. The aqueous phase was extracted with EtOAc (3 x 10 mL), the combined organic phases were dried over anhydrous MgSO4, filtered and concentrated. The crude was dissolved in CH2Cl2 (1 mL) and TFA (1 mL) and stirred at rt for 2h. Solvent was removed under reduced pressure and the crude dissolved in CH2Cl2 (10 mL). The organic phase was washed with saturated aq. NaHCO3 (2 x 10 mL) until pH was basic (~ 8) and finally with brine (10 mL). The organic phase was dried over anhydrous MgSO4, then filtered and concentrated onto Celite. The crude residue was purified by Silica gel flash column chromatography using 100% cyclohexane to cyclohexane/EtOAc (4:1). Desired fractions were collected and concentrated to furnish the desired product as a yellow powder which was further dried under vacuum overnight (18.4 mg, 70%). IR νmax/cm -1 (neat film): 3348, 3061, 2927, 2846, 2248, 1584, 1549, 1458, 1340, 1230, 1141, 1024, 905, 728. 1 (212 mg, 2 mmol), DMF (2.4 mL) and water (0.6 mL). The reaction mixture was degassed the freeze-pump-thaw method three times and then purged with Ar. The flask was placed in an oil bath at 120 °C for 18h. The crude was dropped onto water (10 mL) and the phases separated. The aqueous phase was extracted with EtOAc (3 x 10 mL), the combined organic phases were dried over anhydrous MgSO4, filtered and concentrated onto Celite. The crude residue was purified by Silica gel flash column chromatography using 100% cyclohexane to cyclohexane/EtOAc (4:1). Desired fractions were collected and concentrated to furnish the desired product as a yellow foam which was further dried under vacuum overnight (82.7 mg, 78%). IR νmax/cm -1 (neat film): 3343, 3060, 2922, 2817, 1608, 1575, 1492, 1448, 1312, 1216, 1172, 961,

Conclusion

The work presented in this thesis has mainly focused on the use of B-F bonds, particularly organotrifluoroborates, as F -sources in the inter-and intramolecular fluorination of various substrates. This work has also applied B-F bonds in the synthesis of novel fluorophores as potential bi-modal imaging agents.

Chapter 2 described the application of organotrifluoroborates as a source of F -in the fluorodediazoniation of aryl diazonium salts. Preliminary results demonstrated that aryl diazonium salts could be fluorinated using organotrifluoroborates salts in the solutionphase. This methodology was then extended to a one-pot two-step diazotization/fluorodediazoniation protocol, avoiding the isolation of aryl diazonium salts (Scheme 6.1). This protocol allows the fluorination of anilines under unprecedently mild conditions in low to excellent yields. The transformation was particularly efficient for highly sterically hindered anilines, yields decreased as steric hindrance was removed from one or both ortho positions. L'utilisation du phényltrifluoroborate de potassium, dans MeCN, a permis un échange quantitatif d'anions mis en évidence par RMN 1 H, 19 Les complexes B-F2 5.17

Conclusion

Les travaux présentés dans cette thèse ont principalement porté sur l'utilisation des Persephonis, P. J. Org. Chem. 2011, 76 (21), 8726-8736.

Exploiting Boron-Fluorine Bonds for Fluorination and Synthesis of Potential Bi-modal Imaging Agents

The B-F bond has an expansive and rich history in chemical transformations and the versatility of the B-F bond has also shown immense utility in fields as far reaching as Positron Emission Tomography (PET) and fluorescence imaging.

The application of B-F bonds for nucleophilic Carbon-Fluorine (C-F) bond formation and the development of novel fluorophores with potential applications in PET/fluorescence bimodal imaging is reported in this document.

Organotrifluoroborates are well known as indispensable synthetic tools for the elaboration of organic molecules. However, the trifluoroborate functionality is generally regarded as an auxiliary group, and its potential as a nucleophilic fluoride (F -) source has remained untested. In this context, the ability of organotrifluoroborates to serve as competent sources of F -was investigated. In an update to the historic Balz-Schiemann reaction, that traditionally uses BF4 -as a source of F -, organotrifluoroborates were shown to mediate the fluorodediazoniation of in situ generated aryl diazonium salts under mild reaction conditions. In reactions with an analogous substrate class, unsymmetrical diaryliodonium salts could also be fluorinated using phenyltrifluoroborate via thermal decomposition of the ion pair. Finally, the ability of the trifluoroborate moiety to mediate intramolecular fluorination reactions was investigated through the synthesis of various trifluoroboratecontaining molecular scaffolds.

We also investigated novel fluoroborate (B-Fn) complexes of the 2-aryl-benzothiazole scaffold, known for its interaction with Aβ aggregates, as fluorescent probes. Three complexes were isolated, characterized and their photophysical properties are reported. A 2,4-diaryl-benzothiazole monofluoroborate complex displaying the most promising photophysical properties, was shown to be stable to aqueous conditions. Fluoride abstraction from this complex was also demonstrated, providing promising preliminary results towards the viability of radiolabelling via 19 F-18 F isotope exchange. The monofluoroborate complex also showed interesting structural properties given the asymmetric boron centre. Enantiomers of the complex were successfully resolved by chiral chromatography from the racemic mixture, characterized by Circular Dichroism and their stability to inversion investigated. Les organotrifluoroborates sont connus pour être des outils de synthèse d'importance majeure pour la conception de molécules organiques. Cependant, le groupement trifluoroborate n'est généralement utilisé qu'en tant que groupement partant, c'est à dire par rupture de la liaison C-B. Ainsi, son potentiel en tant que source de fluorure nucléophile (F -) n'est pas étudié. C'est pourquoi, nous nous sommes intéressé à l'aptitude des organotrifluoroborates à servir de source de fluorure. En effet, si historiquement la réaction de Balz-Schiemann, utilise le BF4 -comme source de F -, nous avons démontré que les organotrifluoroborates sont capables de réaliser la réaction de fluorodédiazotation de sels d'aryldiazonium générés in situ dans des conditions réactionnelles douces. De plus, dans des réactions avec une classe de substrats analogues, des sels dissymétriques de diaryliodonium pourraient être fluorés par des phényltrifluoroborates par décomposition thermique de la paire d'ion. Finalement, l'aptitude du groupement trifluoroborate à promouvoir des réactions de fluoration intramoléculaires a été étudiée par la synthèse de divers motifs contenant ce groupement.

Nous avons également étudié de nouveaux complexes fluoroborates (B-Fn) dérivés du motif 2-aryl-benzothiazole comme sondes fluorescentes. Trois complexes ont été isolés, caractérisés, et leurs propriétés photo-physiques rapportées. Un complexe monofluoroborate de 2,4-diaryl-benzothiazole présentant les propriétés photo-physiques les plus prometteuses s'est révélé stable en conditions aqueuses. De plus, l'abstraction de fluorure de ce complexe a été démontrée, fournissant ainsi des résultats préliminaires prometteurs vers la viabilité du radiomarquage par échange isotopiques 19 F-18 F. Ce complexe monofluoroborate a également montré des propriétés structurales intéressantes par la présence d'un bore stéréogène. Les énantiomères de ce complexe ont été dédoublés par chromatographie chirale à partir du mélange racémique puis caractérisés par dichroïsme circulaire. Enfin, la stabilité configurationnelle du bore a été étudiée.

323 Table 2. Atomic coordinates ( x 10^4) and equivalent isotropic displacement parameters (A^2 x 10^3) for OS-6-058. U(eq) is defined as one third of the trace of the orthogonalized Uij tensor. _______________________________________________________________ x y z U(eq) _______________________________________________________________ C (1) 2041( 2) 1790( 1) 3232( 1) 24(1) C( 2) 831( 2) 1457( 2) 3395( 1) 36( 1) C (3) -274( 2) 1965( 2) 3453( 1) 45( 1) C( 4)

-149( 2) 2781( 2) 3356( 1) 39(1) C( 5) 1078( 2) 3100( 1) 3189( 1) 33( 1) C( 6) 2199( 2) 2603( 1) 3124( 1) 28( 1) C( 7) 4787( 2) 1438( 1) 3827( 1) 26( 1) C( 8) 4503( 2) 1093( 2) 4339( 1) 35( 1) C( 9) 5191( 3) 1411( 2) 4793( 1) 47( 1) C (10) 6118( 3) 2031( 2) 4740( 1) 51( 1) C( 11) 6375( 2) 2341( 2) 4219( 1) 43( 1) C( 12) 5723( 2) 2054( 1) 3748( 1) 29( 1) C( 13) 3514( 3) 409( 2) 4411( 1) 52( 1) C( 14) 6845( 4) 2365( 3) 5241( 2) 86( 1) C( 15) 6076( 2) 2395( 2) 3192( 1) 37( 1) C( 16) 8168( 2) 9671( 1) 3457( 1) 28( 1) C( 17) 9462( 2) 9448( 1) 3285( 1) 33( 1) C( 18) 10502( 2) 9286( 2) 3659( 1) 40( 1) C (19) 10263( 3) 9351( 2) 4214( 1) 54( 1) C( 20) 9010( 3) 9588( 3) 4401( 1) 70( 1) C( 21) 7979( 3) 9747( 2) 4027( 1) 52( 1) B( 1) 6987( 2) 9827( 2) 3019( 1) 28( 1) F( 1) 7042( 2) 10623( 1) 2795( 1) 45( 1) F( 2) 7054( 2) 9295( 1) 2573( 1) 51(1) F( 3) 5688( 1) 9761( 1) 3264( 1) 37( 1) I( 1) 3712( 1) 1011( 1) 3130( 1) 26( 1) ________________________________________________________________ 1) 4907( 3) 6315( 1) 13( 1) C (1") 11457( 1) 1360( 3) 7076( 1) 18(1) C( 2) 9105( 1) 2805( 2) 6751( 1) 11( 1) C (2') 8546( 1) 2971( 2) 6722( 1) 12(1) C (3') 8231( 1) 1258( 3) 7096( 1) 15(1) C(3A) 9922( 1) 3830( 2) 6556( 1) 11( 1) C( 4)

10346( 1) 5162( 3) 6289( 1) 12( 1) C (4') 7699( 1) 1424( 3) 7061( 1) 17( 1) C( 5)

10836( 1) 4330( 2) 6457( 1) 13(1) C (5') 7473( 1) 3336( 3) 6651( 1) 17( 1) C( 6)

10919( 1) 2198( 2) 6898( 1) 13( 1) C (6') 7775( 1) 5073( 3) 6286( 1) 18( 1) C (7) 10499( 1) 890( 2) 7171( 1) 13( 1) C(7A) 10005( 1) 1716( 2) 6992( 1) 11( 1) C (10') 8487( 1) 9868( 3) 9663( 1) 14( 1) C (10") 11645( 1) 6464( 3) 8951( 1) 19( 1) C (20') 8731( 1) 7914( 2) 9287( 1) 12( 1) C( 20) 9290( 1) 7737( 2) 9295( 1) 11( 1) C (30') 8426( 1) 6196( 3) 8889( 1) 16( 1) C(30A) 10104( 1) 8818( 2) 9491( 1) 11( 1) C (40') 7894( 1) 6393( 3) 8858( 1) 18( 1) C (40) 10522( 1) 10170( 3) 9744( 1) 13( 1) C (50') 7662( 1) 8326( 3) 9237( 1) 19(1) C (50) 11016( 1) 9383( 3) 9561( 1) 14(1) C (60') 7950( 1) 10045( 3) 9636( 1) 17(1) C (60) 11103( 1) 7256( 2) 9131( 1) 14(1) C (70) 10687( 1) 5900( 2) 8876( 1) 13(1) C(70A) 10191( 1) 6688( 2) 9059( 1) 12( 1) N(3) 9409( 1) 4404( 2) 6428( 1) 12(1) N (30) 9590( 1) 9353( 2) 9618( 1) 11( 1) O( 1) 8585( 1) 6644( 2) 5945( 1) 18( 1) O (10) 8754( 1) 11596( 2) 10059( 1) 18(1) S( 1) 9417( 1) 435( 1) 7234( 1) 12(1) S (10) 9609( 1) 5385( 1) 8815( 1) 13( 1) ________________________________________________________________ 1) 37(1) C (5") 4086( 1) -1673( 1) 1693( 1) 31( 1) C (6") 3396( 1) -871( 1) 1875( 1) 24( 1) C( 4) 3652( 1) 99( 1) 1604( 1) 24(1) C( 5) 4851( 1) 502( 1) 1646( 1) 30( 1) C( 6) 5094( 1) 1409( 1) 1381( 1) 33( 1) C (7) 4154( 1) 1942( 1) 1054( 1) 29( 1) C(7A) 2951( 1) 1541( 1) 993( 1) 23( 1) C(3A) 2694( 1) 636( 1) 1266( 1) 21( 1) C( 2) 789( 1) 952( 1) 798( 1) 21( 1) C(2') -532( 1) 780( 1) 598( 1) 23( 1) C (3') -1200( 1) 1369( 1) 142( 1) 30( 1) C(4') -2446( 2) 1189(1) -49( 1) 38( 1) C (5') -3048( 1) 415( 1) 222( 1) 42( 1) C (6') -2420(1) -177( 1) 677( 1) 37( 1) C (1') -1160(1) -3( 1) 869( 1) 26( 1) N(3) 1461( 1) 331( 1) 1148( 1) 21( 1) O (1') 1828( 1) -227( 1) 2520( 1) 35( 1) O (1) -577(1) -599( 1) 1324( 1) 32( 1) S (1) 1591( 1) 2002( 1) 590( 1) 25( 1) ________________________________________________________________ 5)-C (6) 1.399(2) C( 5)-H( 5) 0.9500 C(6)-C (7) 1.378(2) C( 6)-H( 6) 0.9500 C(7)-C(7A)

1.3929( 18) C( 7)-H( 7 4)

25( 1) 30( 1) 18(1) -2(1) 4( 1) 1(1) C( 5)

24( 1) 43( 1) 23( 1) -2( 1) 1( 1) 0(1) C( 6)

24( 1) 47( 1) 27( 1) -6( 1) 4(1) -12(1) C( 7)

31( 1) 32( 1 1) 4( 1) 21( 1) 7( 1) O( 1)

29( 1) 29( 1) 41( 1) 4( 1) 10(1) -7(1) S( 1) 27( 1) 22( 1) 27( 1) 4( 1) 4(1) -3(1) _______________________________________________________________________ Table 2. Atomic coordinates ( x 10^4) and equivalent isotropic displacement parameters (A^2 x 10^3) for os1302_0m. U(eq) is defined as one third of the trace of the orthogonalized Uij tensor.

________________________________________________________________

x y z U(eq) ________________________________________________________________ S (1) 3298( 1) 2891( 1) 4585( 1) 34( 1) S (10) 2223( 1) 11701( 1) 371( 1) 33( 1) C( 2) 5148( 4) 3526( 4) 4078( 1) 30( 1) F (20) -88( 3) 5736( 3) 852( 1) 51( 1) N( 3) 6692( 3) 3353( 3) 4304( 1) 25( 1) F (10) 2824( 3) 5436( 2) 1024( 1) 49( 1) C(3A) 6487( 4) 2707( 4) 4901( 1) 30( 1) O (10) 709( 3) 6832( 3) 1669( 1) 41( 1) N (30) 1726( 3) 8354( 3) 669( 1) 25( 1) C (2') 5084( 4) 4138( 4) 3467( 1) 30( 1) C (1') 6717( 4) 4545( 4) 3101( 1) 32( 1) C(7A) 4701( 4) 2365( 4) 5131( 1) 31( 1) C (6') 6707( 4) 5075( 4) 2505( 1) 37( 1) C (7) 4207( 4) 1712( 4) 5725( 1) 33( 1) C( 6) 5558( 5) 1408( 4) 6084( 1) 38( 1) C( 5) 7361( 4) 1763( 5) 5841( 2) 42( 1) C( 4) 7864( 5) 2398( 4) 5260( 1) 39( 1) C(1") 5123( 5) 731( 5) 6727( 1) 48( 1) C (20) 1602( 4) 9906( 4) 890( 1) 26( 1) C(4') 3482( 5) 4864( 5) 2628( 2) 44(1) C (5') 5085( 5) 5227( 4) 2271( 1) 40( 1) C(70A) 2677( 4) 10274( 4) -175( 1) 30( 1) C (3') 3460( 4) 4313( 4) 3223( 1) 37(1) C(30A) 2334( 4) 8511( 4) 63( 1) 28( 1) O (1) 8304( 3) 4439( 3) 3313( 1) 43(1) C (40) 2581( 4) 7128(4) -300(1) 36( 1) B( 1) 8570( 5) 3848( 5) 3916( 2) 34(1) C (50) 3174( 5) 7576(4) -891(1) 39(1) F( 2) 9675( 2) 2298( 3) 3939( 1) 45(1) C (60) 3539( 4) 9343(4) -1139(1) 35(1) F( 1) 9336( 2) 5151( 3) 4161( 1) 48(1) C (70) 3281( 4) 10708(4) -777(1) 34(1) C (20') 1021( 4) 10025( 4) 1508( 1) 27(1) C (10') 621( 4) 8429( 4) 1877( 1) 31(1) C (60') 116( 4) 8485( 4) 2484( 1) 36( 1) C(50') -8( 4) 10113( 4) 2711( 1) 37( 1) C (40') 361( 5) 11684( 4) 2344( 1) 41( 1) C (30') 875( 5) 11654( 4) 1745( 1) 38( 1) C (10") 4164( 5) 9738( 5) -1790( 1) 45( 1) B (10) 1270( 5) 6521( 5) 1066( 2) 32( 1) ________________________________________________________________ 7)-H( 7 C(2) 2235( 1) 9084( 3) 2541( 2) 17( 1) N(3) 2782( 1) 8282( 3) 2635( 1) 16( 1) S( 1 ) 2108( 1) 9527( 1) 3440( 1) 21( 1) C( 4) 3716( 2) 7033( 4) 3743( 2) 20(1) C( 5) 3930( 2) 6818( 4) 4588( 2) 28( 1) C( 6) 3618( 2) 7446( 4) 5103( 2) 32( 1) C( 7) 3057( 2) 8323( 4) 4809( 2) 28( 1) C(7A) 2818( 2) 8534( 4) 3974( 2) 20( 1) C(3A) 3130( 1) 7912( 4) 3441( 2) 17( 1) C (2') 1799( 1) 9491( 4) 1745( 2) 20( 1) C (1') 1959( 2) 8958( 4) 1066( 2) 25( 1) C (6') 1558( 2) 9360( 4) 286( 2) 33(1) C (5') 1002( 2) 10229( 5) 188( 2) 37( 1) C(4') 828( 2) 10726( 5) 854( 2) 36( 1) C (3') 1225( 2) 10366( 4) 1626( 2) 30( 1) C (6") 4106( 1) 6324( 4) 3260( 2) 20( 1) C (1") 3862( 2) 5935( 4) 2430( 2) 24(1) C (2") 4252( 2) 5148( 4) 2050( 2) 32(1) C (3") 4894( 2) 4778( 4) 2474( 2) 33( 1) C(4") 5150( 2) 5221( 5) 3275( 2) 39(1) C (5") 4762( 2) 5973( 5) 3660( 2) 33( 1) O( 1) 2477( 1) 8028( 3) 1143( 1) 32( 1) O (1') 3224( 1) 6229( 3) 1956( 1) 25( 1) B( 1) 3014( 2) 7857( 4) 1881( 2) 19(1) F( 1) 3510( 1) 8930( 2) 1906(1) 30(1) S (10) 2871( 1) 2528( 1) 1578( 1) 24(1) C (20) 2763( 1) 2986( 4) 2488( 2) 21( 1) N (30) 2223( 1) 3805( 3) 2411( 2) 20(1) C (40) 1293( 2) 5113( 4) 1325( 2) 22(1) C (50) 1082( 2) 5367( 4) 487( 2) 27(1) C( 60) 1370( 2) 4726(4) -50( 2) 31(1) C (70) 1914( 2) 3766( 4) 228( 2) 28(1) C(70A) 2165( 2) 3561( 4) 1067( 2) 22(1) C(30A) 1870( 1) 4195( 4) 1609( 2) 21(1) C (20') 3209( 2) 2568( 4) 3277( 2) 23(1) C (10') 3081( 2) 3168( 4) 3965( 2) 27( 1) C (60') 3511( 2) 2803( 5) 4741( 2) 36( 1) C (50') 4046( 2) 1848( 5) 4806( 2) 40( 1) C (40') 4183( 2) 1293( 5) 4130( 2) 41( 1) C (30') 3766( 2) 1646( 4) 3367( 2) 34(1) C (60") 906( 2) 5802( 4) 1824( 2) 23( 1) C (10") 1148( 2) 6153( 4) 2649( 2) 24(1) C (20") 762( 2) 6927( 4) 3040( 2) 32(1) C (30") 126( 2) 7349( 4) 2621( 2) 36(1) C (40") -133( 2) 6964( 5) 1804( 2) 35(1) C (50") 248( 2) 6191( 4) 1420( 2) 30( 1) O (10) 2566( 1) 4101( 3) 3906( 1) 33( 1) O (10') 1780( 1) 5847( 3) 3108( 1) 26( 1) B (10) 2005( 2) 4238( 4) 3178( 2) 22(1) F (10) 1528( 1) 3134( 2) 3192( 1) 29( 1) ________________________________________________________________

NMR

  Spectra of selected compounds ...................................................................... Annex B: Chapter 3 ................................................................................................... NMR Spectra of selected compounds ...................................................................... X-ray Data Tables .................................................................................................... Annex C: Chapter 4 ................................................................................................... NMR Spectra of selected compounds ...................................................................... Annex D: Chapter 5 ................................................................................................... NMR Spectra of selected compounds ...................................................................... X-ray Data Tables .................................................................................................... xi

  ........................................................................................................

6

 6 Acid optimization for the one-pot reaction ..................................................... Table 2.7 Effect of temperature on reaction yields ........................................................ Table 2.8 Effect of organotrifluoroborate on reaction yields .......................................... Table 2.9 Control fluorination experiments with various 'fluoride' salts.......................... Table 3.1 Fluorination of diaryliodonium salts in solution and in the melt ...................... Table 3.2 Radiofluorination of diaryliodonium salts ....................................................... Table 3.3 Solvent optimisation for the decomposition of 3.20 ..................................... Table 3.4 Product distribution from the decomposition of salts 3.21-3.26 ................... Table 3.5 Product distribution from the decomposition of salts 3.14-3.16 ................... Table 4.1 Borylation reaction conditions for the formation of 4.26 and 4.25 ................ Table 4.2 Attempted Pd-catalysed borylation of N-protected substrates 4.27 and 4.28. Isolated yield of 4.30 ...................................................................................................

2 xx

 2 Scheme 1.1 Examples of F + /F . reagents. ........................................................................ 2

Figure 1 . 1 19 Figure 1 . 2 28 Figure 2 . 38 Figure 3 . 94 Figure 3 . 3 X

 1119122823839433 Figure 1.1 Basic schematic of PET imaging. ................................................................. 19

Figure 4 . 1 Figure 5 . 1

 4151 Figure 4.1 Selected fluorinating agents: anhydrous TBAF for nucleophilic fluorination, PhenoFluor TM for deoxyfluorination, Selectfluor ® for electrophilic fluorination. ............ 133 Figure 4.2 1 H-19 F HMBC NMR spectroscopy showing the correlation between methylene

  ..................................................................................

Figure 5 . 3

 53 Figure 5.3 Enantiomers of 5.19 in the X-ray crystal structure. Hydrogen atoms omitted for

Figure 5 . 4

 54 Figure 5.4 HPLC chromatogram of racemic 5.19 (left), 5.19a (right, top) and 5.19b (right,

Figure

  Figure 5.5 CD spectra of 5.19rac, 5.19a and 5.19b in CH2Cl2 at 25 °C ........................

  Figure 5.5 CD spectra of 5.19rac, 5.19a and 5.19b in CH2Cl2 at 25 °C ........................

Figure 5 . 6

 56 Figure 5.6 Calculated FMOs, excitation energies and corresponding oscillator strengths

Figure 5 . 7

 57 Figure 5.719 F and 11 B NMR spectra evolution for 5.17 (top two spectra) and5.19 (bottom

  Figure 5.719 F and 11 B NMR spectra evolution for 5.17 (top two spectra) and5.19 (bottom

Figure 5 . 8

 58 Figure 5.8 Evolution of 19 F (top), 11 B (middle) and 1 H (bottom) NMR spectra of 5.19 with

Figure 7 . 1

 71 Figure 7.1 Chromatogramme HPLC de racémique 5.19 (à gauche), 5.19a (à droite, en

  are Selectfluor TM and N-fluorobenzenesulphonimide (NFSI). The use of these reagents has greatly facilitated the advancement of electrophilic fluorination reactions.13

  value. b calculated values.

Scheme 1 . 3

 13 Scheme 1.3 Deoxyfluorination reagents developed by Ritter et al. (top) and postulated leaving group formed by reagents (bottom).Finally, oxidative fluorination strategies have been developed as alternatives to

6 Scheme 1 . 4

 614 Scheme 1.4 Oxidative fluorination pathways with F -.

7 Scheme 1 . 5

 715 Scheme 1.5 The Balz-Schiemann reaction.

Scheme 1 . 6

 16 Scheme 1.6 Fluorination of aryllead(IV) acetates.

1. 4 . 1 . 5 , 9 Scheme 1 . 8

 415918 Scheme 1.8 Fluorination of 3-phenylpropyl ethers.

10 Scheme 1 . 9 11 Scheme 1 . 10

 101911110 Scheme 1.9 Fluorination of gem-dichlorides/iodides and trichlorotoluene with AgBF4.A novel modification of the Mitsunobu reaction was reported byKunz and Swager, where

12 Scheme 1 . 11

 12111 Scheme 1.11 Selected examples of oxa-and aza-Prins cyclization-fluorination reactions.

Figure 1 . 1

 11 Figure 1.1 Basic schematic of PET imaging.

Scheme 1 . 18 22 .

 11822 Scheme 1.18 Aqueous radiofluorination of boronic ester 1.21 to [ 18 F]-trifluoroborate 1.22.With intended applications in vivo, the hydrolytic stability of the trifluoroborate moiety is

27 NIRF

 27 imaging relies on the detection of light emitted by the excitation of a fluorophore (Figure 1.3). Light of an appropriate energy (hν1), based on the absorption properties of the probe, is generated by a light source, this light is absorbed by the probe in its ground state. Absorption of light causes the excitation of electrons from the vibrational ground state (S0) into a vibrational excited state (S1, S2 etc.). Relaxation of these excited electrons back down to S0, without a change in electron spin, with the release of light of a longer wavelength (hν2 > hν1) is termed fluorescence. The emitted photons can then be detected by a digital camera and then processed to generate an image. Like PET, NIRF imaging

Figure 1 . 2

 12 Figure 1.2 Basic schematic of NIRF imaging.

  Scheme 1.23 a, Synthesis of PPCy-4a for in vivo imaging. b, PPCy-Arg9-8 used as a HeLa cell label.

Scheme 1 . 25 1 32 possible with 1 . 1 . 3

 125132113 Scheme 1.25 Synthesis of 1-BODIPY as an in vivo drug biodistribution probe. Antiparasitic motif highlighted in blue. O'Shea et al. developed functionalized aza-BODIPYs (nitrogen instead of carbon at meso

Chapter 2 40

 2 purity and suppress the formation of unwanted by-products.140,142 More recently, the use of ionic liquids in mediating the fluorodediazoniation process has been demonstrated; a series of substrates, both electron poor and rich, could be fluorinated in quantitative NMR spectroscopy yields.143 Interestingly, the use of ionic liquids with non-fluorinated anions resulted in anion metathesis under reaction conditions leading to products from aryl diazonium-solvent combination, affirming the importance of a tight ion pair for efficient fluorination. 1432.1.1.4 Development of one-pot and continuous flow processesThus far, advances discussed have addressed the issue of poor reproducibility and substrate scope, however many of these methods require isolation of the aryl diazonium salt prior to decomposition. Given the risk associated with the isolation of diazonium salts, vide supra, efforts in recent years have focused on developing a safer and more generally applicable methodology via one-pot two-step (diazotization-fluorodediazoniation)

  the lability of fluorine on the organotrifluoroborate has potential for ameliorating reaction conditions and increasing fluorination efficiencies by facilitating fluorine transfer within the tight ion pair intermediate (I, Figure 2.1).

  F NMR (282 MHz, DMSO-d6) δ -139.5 (bs). HRMS-ESI-TOF (m/z): found [M-K] -202.0647, calc'd C8H8 11 BF3NO requires 202.0651.

9 (

 9 C NMR (75 MHz, Chloroform-d) δ 144.0 (Cq), 135.0 (CH), 130.1 (CH), 130.0 (CH), 124.7 (CH), 72.3 (CH2), 31.7 (Cq), 22.5 (CH3), 21.CH3). 11 B NMR (96 MHz, Chloroform-d) δ 27.53 (bs). GCMS-EI (m/z): 204 [M] + . Spectroscopic data matches those previously reported. 168 round-bottom flask was charged with a stir bar and condenser and flame dried then purged with an Ar balloon. Under Ar, the flask was charged with 5,5-dimethyl-2-(otolyl)-1,3,2-dioxaborinane (2.1421 g, 10.5 mmol), N-bromosuccinimide (2.0524 g, 11.5 mmol), 2,2'-azobisisobutylnitrile (54.2 mg, 0.33 mmol) and degassed (freeze-pump-thaw x 3, then Ar bubbling) CCl4 (20 mL). The light yellow reaction mixture was heated at reflux in an oil bath for 18 h. A white precipitate develops during the course of the reaction, after Chapter 2 Experimental Section 74

  C NMR (75 MHz, Chloroform-d) δ 143.6 (Cq), 135.6 (CH), 130.6 (CH), 130.2 (CH), 127.6 (CH), 72.4 (CH2), 34.6 (CH2), 31.8 (Cq), 22.0 (CH3). 11 B NMR (96 MHz, Chloroform-d) δ 27.07 (bs). GCMS-EI (m/z): 282 [Br 79 M] + , 284 [Br 81 M] + . Spectroscopic data matches those previously reported. 169

0 (

 0 C NMR (75 MHz, Acetonitrile-d3) δ 136.5 (CH), 134.2 (CH), 132.9 (Cq), 131.0 (CH), 129.9 (CH), 72.1 (CH2), 67.7 -67.6 (m) (CH2), 53.5 -52.52 (m) (CH3), 31.4 (Cq), 21.Cq). 11 B NMR (96 MHz, Acetonitrile-d3) δ 26.70 (bs). HRMS-ESI (m/z): found [M-I] + 261.2005, calc'd C15H25 10 BNO2 + 261.2015.

  C NMR (101 MHz, DMSO-d6) δ 145.3 (Cq), 124.2 (Cq), 116.4 (CH), 107.1 (CH). MS-DCI(NH3) (m/z): 126 [M+H] + , 143 [M+NH4] + . Spectroscopic data matches those previously reported. 171

  C NMR (101 MHz, Chloroform-d) δ 147.5 (Cq), 125.4 (Cq), 116.9 (CH), 104.1 (CH), 55.8 (CH3). MS-DCI(NH3) (m/z): 154 [M+H] + . Spectroscopic data matches those previously reported. 172

  CH), 128.0 (CH), 127.6 (CH), 126.3 (Cq), 117.0 (CH), 106.1 (CH), 70.8 (CH2). HRMS-EI (m/z): found [M+H] + 306.1498, calc'd C20H20NO2 requires 306.1494.

  5 (CH), 128.1 (CH), 128.0 (Cq), 127.4 (CH), 118.2 (CH). HRMS-ESI-TOF (m/z): found [M+H] + 246.1277, calc'd C18H16N requires 246.1283.

  δ 158.9 (Cq), 141.0 (Cq), 132.1 (Cq), 130.5 (CH), 129.6 (CH), 127.8 (Cq), 118.3 (CH), 114.3 (CH), 55.4 (CH3). HRMS-ESI-TOF (m/z): found [M+H] + 306.1480, calc'd C20H20NO2 requires 306.1494. Chapter 2 Experimental Section 82

  δ 7.99 (s, 4H), 7.91 (s, 2H), 7.18(d, J = 7.6 Hz, 2H), 6.98 (dd, J = 8.0, 7.2 Hz, 1H), 3.70 (bs, 2H).13 C NMR (101 MHz, Chloroform-d) δ 141.3 (Cq), 140.4 (2 x Cq), 132.4 (q, 2 JC-F = 33.5 Hz, CH), 131.1 (CH), 129.6 (CH), 125.4 (Cq), 123.2 (q, 1 JC-F = 273.0 Hz, Cq), 121.5 (hept, 3 JC-F = 4.1 Hz, CH), 119.2 (Cq). 19 F NMR (376 MHz, Chloroform-d) δ -62.84 (s). HRMS-DCI(CH4) (m/z): found [M] .+ 517.0693, calc'd C22H11F12 requires 517.0700.

8 (

 8 1 H NMR (300 MHz, Chloroform-d) δ 7.20(d, J = 7.2 Hz, 2H), 1.40 (s, 18H), 1.30 (s, 3H).13 C NMR(75 MHz, Chloroform-d) δ 159.5(d, 1 JC-F = 249.2 Hz, Cq), 144.9(d, 4 JC-F = 3.7 Hz, Cq), 136.4(d, 2 JC-F = 13.8 Hz, Cq), 122.1(d, 3 JC-F = 6.2 Hz, CH), 34.9 (Cq),34.8 (Cq), 31.CH3),30.4 (d, 5 JC-F = 4.1 Hz, CH3).19 F NMR (282 MHz, Chloroform-d) δ -112.0 (s). HRMS-EI (m/z): found [M] .+ 264.22527, calc'd C18H29F requires 264.22533.

F

  NMR (282 MHz, DMSO-d6) δ -114.0 (s), δ (lit) -114.1 (s). Spectroscopic data matches reports in the literature.

C20H18FO2

  1 H NMR (300 MHz, Chloroform-d) δ7.53 (dd, J = 8.8, 1.8 Hz, 4H), 7.35 (t, J = 7.4 Hz, 2H), 7.23 (dd, J = 8.2, 7.0 Hz, 1H), 7.00(d, J = 8.8 Hz, 4H).13 C NMR (75 MHz, Chloroform-d) δ 159.4 (Cq), 156.7 (d, 1 JC-F = 248.4 Hz, Cq), 130.5 (d, 4 JC-F = 3.1 Hz, CH), 129.4 (d, 4 JC-F = 3.5 Hz, CH), 128.6 (Cq), 124.4 (d, 3 JC-F = 4.6 Hz, CH), 114.0 (CH). 19 F NMR (282 MHz, Chloroform-d) δ -123.6 (s, 1F). HRMS-DCI(CH4) (m/z): found [M+H] + 309.1291, calc'd

2

  JC-F = 3.0 Hz, CH),129.3 (CH), 127.4 (d, Cq), 125.4 (d, 2 JC-F = 4.7 Hz, CH), 123.2 (q, 1 JC-F = 272.8 Hz, Cq), 121.9 (hept, 3 JC-F = 3.6 Hz, CH).19 F NMR (282 MHz, 12F), 1F). HRMS-DCI(CH4) (m/z): found [M] + 520.0496, calc'd C22H9F13 requires 520.0497.

  .1, b); other intermediates (radical anions, aryl radicals and arynes) have also been proposed but will not be discussed in this chapter. Nu-I bond formation is the initial step due to the electrophilicity of the iodine atom, with release of the counter-ion. Consequent reductive elimination from this intermediate then generates the product and corresponding Ar-I (Figure 3.1, b). In metal mediated transformations, diaryliodonium salts are considered more reactive forms of aryl iodides which undergo oxidative addition to the metal centre, transferring an aryl moiety and ligand (Figure 3.1, b). The formed organometallic complex can then undergo further transformations with incoming nucleophiles leading to desired products.

Figure 3 . 3 93

 33 Figure 3.1 a, scope of nucleophiles arylated by diaryliodonium salts. b, intermediates implicated in the metal-free and metal-mediated arylation of nucleophiles with diaryliodonium salts.

Figure 3 .Scheme 3 . 1

 331 Figure 3.2 λ 3 -iodane equilibrium. a, electronic effect on equilibrium. b, steric "ortho" effect on equilibrium.3.1.2 Fluorination of diaryliodonium salts3.1.2.1 Metal-free fluorination of diaryliodonium saltsWhile diaryliodonium salts have been known since 1894 and are well known to react with

3 98Scheme 3 . 2 3 99Scheme 3 . 3 18 F 3 101Scheme 3 . 4

 33233318334 Scheme 3.2 Auxiliaries used for the selective fluorination of unsymmetrical diaryliodonium salts.

Chapter 3 103

 3 driven byOlofsson et al., have been developed.

Scheme 3 . 6

 36 Scheme 3.6 Stuart et al. one-pot diaryliodonium salt synthesis conditions.

inseparable 2 :

 2 Scheme 3.10 Attempts at anion exchange (isolated yields in parentheses). a, anion exchange in acetone or MeCN. b, anion exchange in biphasic CH2Cl2/saturated aqueous KHF2.

Figure 3 . 3 X

 33 Figure 3.3 X-ray crystal structures of 3.20, diphenyliodonium tetrafluoroborate (3.27), 209 (2methylphenyl)(phenyl)iodonium fluoride (3.28). 209 Solvent molecules omitted for clarity. Hydrogen in white, carbon in grey, iodine in purple, boron in pink, fluorine in green/yellow.

Scheme 3 . 12

 312 Scheme 3.12 Accepted mechanism for the fluorination of unsymmetrical diaryliodonium salts.

  Scheme 3.14 Proposed mechanism for the fluorination of diaryliodonium salts with phenyltrifluoroborates.

Chapter 3 117

 3 to provide both electron-poor and rich aryl fluorides. Most efforts have been directed towards unveiling underlying mechanisms of selectivity and improving reaction conditions within the context of radiochemistry. The fluorination of diaryliodonium salts has mostly been limited to alkali metal fluorides, and to the best of our knowledge the use of organotrifluoroborates for the fluorination of diaryliodonium salts is unprecedented. To this end a series of unsymmetrical diaryliodonium phenyltrifluoroborates were synthesized and fully characterised. The decomposition of these salts was investigated in various solvents and was found to be most efficient at high temperatures in non-polar solvents. All salts provided a single fluorinated product in complete selectivity in low to excellent yields. The selectivity observed seems to contrast with that observed in the decomposition of diaryliodonium fluorides; the experimental discrepancies suggest two different mechanisms. These studies are a proof of concept that organotrifluoroborates can be used in the fluorination of diaryliodonium salts. These preliminary results also expand the repertoire of organotrifluoroborates as a nucleophilic fluorine source.

  Given the difficulties encountered in C-F formation, improvements in fluorination methodologies have largely been driven by the development of novel, stable and easy to handle fluorinating agents (Figure 4.1). These reagents function as exogenous sources of fluorine for intermolecular fluorination and their delivery of fluorine is facilitated by the nature of their environment and physicochemical properties. Given the particularities of synthesizing these reagents, with regards to reaction conditions and functional complexity, their application towards intramolecular fluorination is unreasonable and would be highly inefficient. It is therefore not surprising to find that there are only a few intramolecular fluorination strategies described in the literature. Chapter 4 133

Figure 4 . 1 4 . 1 . 1

 41411 Figure 4.1 Selected fluorinating agents: anhydrous TBAF for nucleophilic fluorination, PhenoFluor TM for deoxyfluorination, Selectfluor ® for electrophilic fluorination.4.1.1 Intramolecular fluorinationThe earliest reported examples of proposed, but unconfirmed, intramolecular fluorination

Scheme 4 . 1 4 134

 414 Scheme 4.1 Proposed intramolecular fluorination for the formation of fluorinated derivatives.4.1.1.1 Intramolecular fluorine transfer to reaction intermediates Using exogenous fluorine sources, there are several examples in the literature that

Scheme 4 . 2 4 135

 424 Scheme 4.2 Intramolecular fluorine transfer in the synthesis of syn-fluorohydrins and fluoroamines.

Scheme 4 . 3

 43 Scheme 4.3 Proposed mechanism for deoxyfluorination of phenols by PhenoFluor TM .

Chapter 4 138Scheme 4 . 5 4 139Scheme 4 . 6

 445446 Scheme 4.5 Proposed substrates for intramolecular fluorination with trifluoroborates. [B] = BF3 -, B(OR)2 (R = H, alkyl).We thought that organotrifluoroborates would be well suited for intramolecular fluorination via a Balz-Schiemann type reaction. Therefore, we envisioned zwitterionic

10

 10 Scheme 4.10 Attempted borylation of 4.28 (a) and 4.29 (b) via lithium-halogen exchange.

F 14

 14 Scheme 4.14 Possible 2-aminophenol alkylation pathways. a, multiple N-and O-alkylation. b, EAS alkylation of aromatic ring.

Figure 4 .

 4 Figure 4.2 1 H-19 F HMBC NMR spectroscopy showing the correlation between methylene protons and fluorine atoms in 4.39.

  F and 11 B NMR and IR spectroscopy, and HRMS. Formation of the diazo moiety was apparent by IR as the amine N-H stretching and bending bands disappear and are replaced by a prominent peak at 2273 cm -1 corresponding to N-N triple bond stretching (Figure 4.3). 239

Figure 4 . 3

 43 Figure 4.3 ATR IR spectrum of 4.21.

Chapter 4 161

 4 Scheme 4.20 Over-brominated products observed during attempted bromofluorination of 4.22 using Br2.

Table 4 . 9

 49 Effect of N-bromine reagents on bromofluorination of 4

Scheme 4 . 21

 421 Scheme 4.21 Possible intramolecular fluorination via 4.45.

chapters 2 and 3 )

 3 Scheme 4.23 Trifluoroborate-containing scaffolds for intramolecular fluorination. Despite our efforts, 4.20 could not be synthesized due to difficulties in accessing a borylated biphenyl system (see section 4.2.1). Due to time constraints we could not continue optimization of reaction conditions towards 4.20. We do however continue to recognize the potential of 4.20 for intramolecular fluorine transfer, and therefore suggest that as perspective of this investigation further optimization towards synthesizing 4.20 continue.

Chapter 4 170

 4 Scheme 4.24 Further functionalization of aryl fluoride via boronic acid. Styrene derivatives 4.22 and 4.23 were easily obtained in moderate to excellent yields respectively. Efficient bromofluorination failed using 4.22 and various electrophilic bromine sources. Major products were over-brominated and deborylated products, at best

  round-bottom flask was charged with a stir bar and condenser and flame dried, the vessel was then purged with Ar and left under Ar atmosphere. The flask was then charged with Mg turnings(80.7 mg, 3.2 mmol) and one crystal of I2, the solids were vigorously stirred until the Mg were coated with I2 and had a purple brown colour. In a separate flame dried 5 mL round-bottom flask, under Ar atmosphere, 2-bromostyrene (342.5 µL, 2.73 mmol) was dissolved in 2.4 mL THF. The 2-bromostyrene solution was added dropwise to the flask containing the Mg turnings as to maintain constant reflux, after addition was complete the reaction mixture was heated at reflux in an oil bath for 30 min, then allowed to cool to rt. Meanwhile, a flame dried 5 mL round-bottom flask, under Ar, was charged with B(OMe)3 (353.5 µL, 3.2 mmol) and THF (2.5 mL) and cooled to -78 °C. The Grignard solution was added dropwise to the borate solution and the resulting solution was stirred at -78 °C for 1 h, then allowed to warm to rt over 5h. The reaction mixture was quenched with 1 M aq. HCl (1 mL) then transferred into a separatory funnel and extracted with Et2O (3 x 50 mL). The organic layer was dried over anhydrous Na2SO4

  1 H NMR (300 MHz, Methanol-d4) δ 7.55 (dd, J = 6.7, 2.1 Hz, 1H), 7.55 -7.46 (m, 1H), 7.41 (ddd, J = 17.8, 11.0, 1.5 Hz, 1H), 7.09 (tt, J = 6.8, 3.5 Hz, 2H), 5.61 -5.47 (m, 1H), 5.03 (dd, J = 11.0, 1.9 Hz, 1H).13 C NMR (75 MHz, Methanol-d4) δ 142.2 (Cq), 141.2 (CH), 133.34 (q, 3 JC-F = 3.2 Hz), 127.4 (CH), 127.1 (CH), 124.4 (CH), 111.2 (CH2).19 F NMR (282 MHz, Methanol-d4) δ -139.04 --140.53 (m). 11 B NMR (96 MHz, Methanol-d4) δ 3.76 (q, J = 58.0 Hz). HRMS-ESI (m/z): found [M-K] -170.0624, calc'd C8H7BF3 -requires 170.0629.

13 C

 13 NMR(75 MHz, Chloroform-d) δ26.5 (CH3). MS-ESI (m/z): [M79 Br] + 141, [M81 Br] + 143. -bottom flask was charged with a stir bar, potassium 2vinylphenyltrifluoroborate (704 mg, 3.4 mmol) and acetone (3.5 mL); the flask was then cooled to -78 °C. While stirring, a solution of DMDO in acetone (74 mM) (55.9 mL, 4.1 mmol) was added dropwise at -78 °C; the yellow colour of the DMDO solution quickly disappeared. The reaction mixture was stirred at -78 °C for 2h then allowed to warm to rt after which half of the solvent was removed under reduced pressure and the product was precipitated, with the addition of Et2O, as a white fluffy powder. The product was collected by filtration and further washed with Et2O, then dried under high vacuum overnight (646.1 mg, 85%

5 189Figure 5 . 1 5 191Scheme 5 . 1 5 192 5 . 1 . 1 PET 5 . 1 . 1 . 1 PETScheme 5 . 2

 5515515511511152 Figure 5.1 The amyloid cascade hypothesis (adapted with permission from Noël et al., Chem. Soc. Rev., 2013, 42, 7747-7762, copyright Royal Society of Chemistry)To date, there is no cure for AD. As such, disease management relies on managing

Figure 5 . 2 [

 52 Figure 5.2 [ 11 C]-PiB standardized uptake value (SUV) in healthy (left) and AD (right) patients (adapted with permission fromKlunk et al., Ann. Neurol., 2004, 55, 306-319, copyright John Wiley and Sons)

[ 18 F 5 194 5 195Scheme 5 . 3

 185553 Scheme 5.3 Chemical structures of stilbene derivatives [ 18 F]-Florbetapir and [ 18 F]-Florbetaben5.1.2 NIRF Imaging for ADFluorescence spectroscopy is emerging as an alternative and complementary non-

Scheme 5 . 4 D

 54 Scheme 5.4 D-π-A design of NIR fluorescent probes. Acceptor (A) in red, Donor (D) in blue

5 197and finally 7 )Scheme 5 . 5 5 198

 57555 Scheme 5.5 Selected structures and properties (Stokes shift = ΔSS, Quantum Yield (QY) = ΦF) of NIRF probes for Aβ. Acceptor motif in red, Donor motif in blue

Scheme 5 . 6 5 201

 565 Scheme 5.6 Chemical structure of the natural compound curcumin

5 202Scheme 5 . 7 5 203Scheme 5 . 8

 557558 Scheme 5.7 Chemical structures of BODIPY7 and [ 125 I]-BODIPY7 A year later Ono et al. developed FIAR, a bi-modal (PET/SPECT) radiotracer for in vivo imaging of Aβ plaques (Scheme 5.8). 305 FIAR was demonstrated to bind Aβ aggregates in high affinity and could distinguish between the brain sections of wild type and

Scheme 5 . 10

 510 Scheme 5.10 Chemical structure of proposed benzothiazole B-Fn complexes and potential synthesis of PET probes by IEX

generation of the 2 - 5 207Scheme 5 . 11

 25511 Scheme 5.11 Modular synthetic strategy towards functionalized 2-arylbenzothiazoles and 2,4diarylbenzothiazoles

5 209Scheme 5 . 13 12 and 5 . 5 210Scheme 5 . 5 211Scheme 5 . 15

 5513125555515 Scheme 5.12 a, Synthesis of 6-substituted-2-aminobenzothiazoles from anilines. b, Synthesis of 4substituted-2aminobenzothiazoles via arylthioureas. Isolated yields.Sandmeyer bromination of 2-aminobenzothiazoles 5.1, 5.2 and 5.5 was achieved in moderate yields via copper mediated bromination of the in situ formed diazonium cation (Scheme 5.13, products 5.7, 5.8 and 5.9) using conditions as reported by Dehaen et al.326 Similarly, one-pot iodination of 5.6 to 2-iodo-4-bromobenzothiazole (5.10) was carried out in excellent yield using a modified procedure fromFilimonov et al. 152 Given the difference in reactivities of C(sp 2 )-I and C(sp 2 )-Br bonds with respect to oxidative addition to a metal

Scheme 5 . 16 5 Scheme 5 . 21 28 . 5 216Scheme 5 . 22 5 217 5 . 2 . 1 . 1

 516552128552255211 Scheme 5.16 Possible degradation pathway of 2-(benzo[d]thiazol-2-yl)aniline B-Fn complexes via HF elimination and hydrolysis

and 5 . 18 ,

 518 the F1-B1-F2 plane dissects the six-membered chelate plane almost perpendicularly(89.7 and 89.6°, respectively), while for 5.19 the F1-B1-O1' plane is at 88.3° relative to the six-membered chelating plane. The phenol at C4 in 5.19 displays considerable torsion from the remainder of the molecule with a dihedral angle between the benzothiazole and C4 attached phenol ring of 21.44°.

Chapter 5 221 5 . 25

 5525 Scheme 5.25 Synthesis of racemic 5.32 Similarly, complex 5.19 contains an asymmetric boron centre, and the crystal structure shows the complex crystallizes as a pair of enantiomers (Figure 5.5).

Figure 5 . 3

 53 Figure 5.3 Enantiomers of 5.19 in the X-ray crystal structure. Hydrogen atoms omitted for clarityThe racemic mixture was successfully resolved by analytical HPLC using a ChiralPak IA

Figure 5 . 4 5 223Figure 5 . 5

 54555 Figure 5.4 HPLC chromatogram of racemic 5.19 (left), 5.19a (right, top) and 5.19b (right, bottom) after 1 week The enantiomeric nature of 5.19a and 5.19b was further confirmed by circular dichroism (CD) spectroscopy (Figure 5.7). The racemic mixture displays no interaction with circularly polarized light, while the spectra of the enantiomers are mirror images.

- 5 .

 5 19, inCH2Cl2, are displayed in Figure5.7; the spectra are of the free ligand overlaid with its corresponding boron complex.

, 5 . 5 . 8 .

 558 18 and 5.19, respectively) evidence increased rigidity in ring coplanarity induced by B-Fn complexation, allowing for a greater extent of π-conjugation throughout the molecular scaffold. The absorption and emission spectra of complexes 5.17-5.19, in CH2Cl2, are represented in Figure All three complexes exhibit quite similar absorptionprofiles, with λmax of 355, 370 and 361 nm for 5.17, 5.18 and 5.19, respectively. The λmax of 5.17 and 5.19 are almost identical which is expected considering their electronic similarity (see X-ray crystal structures Figure5.4). The torsion between the phenol ring system at C4 and the benzothiazole core suggest poor π-conjugation between the two systems. The λmax of 5.17 is red shifted by ~15 nm compared to 5.18 and 5.19, this is attributed to the electron-withdrawing effect of the ethyl ester substituent at position C6 (enhanced D-π-A electronics).Despite the similarity in absorption spectra of 5.17-5.19, their emission properties are markedly different (Figure5.8). Complexes 5.17 and 5.18 are potent blue-emitters displaying emissions at 419 (ΦF = 0.50) and 432 nm (ΦF = 0.58), respectively, with 5.18

thus far with 5 .

 5 19 are promising with regards to large Stokes shift and emission wavelength. Increasing conjugation and D-π-A characteristics are viable strategies to further red-shift emissions towards the NIR region. Interestingly, only 5.19 displays positive solvatochromism in polar solvents, evidenced by increased bathochromic shifts in emission as solvent polarity increases.

26

 26 Scheme 5.26 Selected examples of highly conjugated (top) and enhanced D-π-A (bottom) 2arylbenzothiazole B-F2 complexes

  (353 nm) nicely match with those observed experimentally (355 nm), both the HOMO and HOMO-1 orbitals are implicated in the transition (f=0.3624), contributing 69.4 and 11.3%, respectively. Only one transition (366 nm, HOMOLUMO, 69.8% contribution, f=0.3785) is implicated in the first excited state of 5.18 and supports the experimentally observed λmax (370 nm). The calculated λmax for 5.19 (380 nm, HOMOLUMO, 70.2% contribution, f=0.1464) is in good agreement with experimental results (361 nm).

Figure 5 . 6

 56 Figure 5.6 Calculated FMOs, excitation energies and corresponding oscillator strengths (f) for 5.17 (left), 5.18 (middle) and 5.19 (right)

  Figure 5.719 F and 11 B NMR spectra evolution for 5.17 (top two spectra) and 5.19 (bottom two spectra) in CD3CN/D2O

Scheme 5 .

 5 Scheme 5.27 BODIPY radiolabelling strategies via hydroxide (a) or triflate pre-activation (b) and Brønsted or Lewis acid-assisted IEX (c)

28

 28 Scheme 5.28 Fluoride abstraction from 5.19 to form 5.33 and proposed regeneration of 5.19 by addition of [F -] source Treatment of 5.19 with TMS-OTf (2 eq.) resulted in quantitative fluoride abstraction to provide 5.33 in CDCl3, as observed by 1 H, 19 F and 11 B NMR spectroscopy (Figure 5.11).

Figure 5 . 8 5 . 3

 5853 Figure 5.8 Evolution of 19 F (top), 11 B (middle) and 1 H (bottom) NMR spectra of 5.19 with TMS-OTf5.3 Conclusion and PerspectivesBi-modal imaging probes for Aβ are of interest given their potential in cross-validation of

Scheme 5 . 29

 529 Scheme 5.29 Isolated and characterised B-Fn complexes Complex 5.19, synthesized as a racemic pair of enantiomers, was chirally resolved and characterised by CD. The separated enantiomers were shown to be stable to

5 . 5 240

 55 19 was shown to be most stable, with exceptional stability without degradation in CD3CN/D2O solution for up to 289h. Additionally, fluoride abstraction from 5.19 was demonstrated. These studies highlight 5.19 as a promising candidate for further studies and structural elaboration with regards to the development of a bi-modal probe. In the short-term the stability of 5.19 needs to be investigated in more physiologically relevant conditions (aqueous buffered solutions). It would also be important to study the affinity of 5.19 for Aβ aggregates via in Chapter vitro assays. The further functionalization of 5.19 with electron-donating moieties or increasing conjugation would help in further red-shifting absorption and emission into the NIR.

F254

  glass backed plates. TLC plates were visualized by UV fluorescence (λ= 254, 365 nm) and one of the following stains: KMNO4 or HBQ. Flash column chromatography was performed using VWR Chemicals Silica gel 60 -200 µm or on an automated Interchim puriFlash system using pre-packed Interchim 30 µm Silica gel cartridges or Acros Aluminium Oxide (Basic) Brockmann I 50-200 µm.Chapter 5 Experimental Section 242 IR spectra were recorded on a PerkinElmer Spectrum One or Frontier FT-IR spectrometer with frequencies expressed in cm -1 . UV/Vis spectra were recorded on an Agilent 8453 Spectroscopy System using a 10 mm Quartz cuvette. Fluorescence spectra were recorded on a HORIBA Jobin Yvon FluoroMax-4 Spectrofluorometer. Quantum yield measurements were done using 9,10-diphenylanthracene as a reference (Φ=0.97 in cyclohexane, λexc = 355). Circular Dichroism spectra were recorded on a Jasco J-815 CD Spectropolarimeter using a 10 mm Quartz cuvette, with D.I.T = 0.5 sec, Scanning Speed = 100 nm/min, Band width = 1.00 nm at 25 °C. High-resolution mass spectra (HRMS) were recorded using either electrospray ionization (ESI) or desorption chemical ionization (DCI) using a Waters GCT Premier or Sciex QTRAP 4500 AB or Thermo Fisher Scientific DSQ II spectrometers. X-ray crystallography was performed on single crystal diffractometers: Agilent Gemini, Bruker Nonius and Bruker Kappa Apex II.

7 (

 7 Cq), 131.6 (Cq), 127.4 (CH), 121.6 (CH), 119.0 (CH), 21.1 (CH3). HRMS-ESI (m/z): found [M+H] + 165.0487, calc'd C8H9N2S requires 165.0486.

2 (

 2 1 H NMR (400 MHz, DMSO-d6) δ 8.27 (d, J = 1.8 Hz, 1H), 7.89 (bs, 2H),7.81 (dd, J = 8.4, 1.8 Hz, 1H), 7.37 (d, J = 8.4 Hz, 1H), 4.28 (q, J = 7.1 Hz, 2H), 1.31 (t, J = 7.1 Hz, 3H).13 C NMR (101 MHz, DMSO-d6) δ 169.8 (Cq), 165.7 (Cq), 156.9 (Cq), 131.Cq), 127.1 (CH), 122.5 (CH), 122.0 (Cq), 117.1 (CH),60.4 (CH2), 14.3 (CH3). HRMS-ESI (m/z): found [M+H] + 223.0538, calc'd C10H11N2O2S requires 223.0541. round-bottom flask was charged with a stir bar, condenser, NH4SCN (19.809 g, 0.26 mol) and acetone (100 mL). Benzoyl chloride (27.9 mL, 0.24 mol) was then added over 5 min via syringe to the stirring solution producing a thick yellow precipitate, which was then heated to reflux for 15 min. The mixture was then allowed to cool to rt at which point o-Toluidine (21.43 mL, 0.20 mol) diluted with acetone (50 mL) was added via an addition funnel over 15 min. The reaction mixture was then heated to reflux until consumption of starting material by TLC(45 min). The reaction mixture was dropped onto cold water (300 mL); the light yellow precipitate was collected and washed with cold water (3 x 100 mL), and finally with cold H2O/MeOH (1:1) producing an off-white powder. 10% aq. NaOH solution (200 mL) was prepared and heated to 80°C in an Erlenmeyer flask into which the collected precipitate was dissolved, this was left to hydrolyze for 15 min.

10 Chapter 5

 105 two-necked round-bottom flask was charged with a stir bar, 2bromophenylthiourea(2.3204 g, 10 mmol) and CHCl3(10 mL). Bromine (0.51 mL, Experimental Section 248 mmol) was dissolved in CHCl3 (5 mL) in an addition funnel and affixed to the main neck of the round-bottom flask, the second neck was connected to a base trap to neutralize HBr fumes developed during the course of the reaction. The flask was cooled to 0 °C in an ice-bath and the bromine solution was added dropwise to the vigorously stirring reaction mixture (note: often the sides needed to be scraped down as the bromine solution would coagulate on the bottom and sides of the flask). The addition funnel was then replaced with a condenser and the reaction mixture heated at reflux for 1.5 h until complete conversion of starting material was determined by TLC; with external heat HBr gas evolution became consistently rapid. During the course of the reaction a fine yellow precipitate evolved in a clear red/brown solution. After cooling to rt, solvent removed under reduced pressure. The remaining residue was dissolved in EtOAc (100 mL) and washed with sat'd aq. NaHCO3 (2 x 100 mL), 5% aq. Na2S2O3 (2 x 50 mL) and finally brine (2 x 50 mL). The organic phase was dried over anhydrous MgSO4 the filtered and concentrated under reduced pressure and further dried under high vacuum overnight to furnish the product as a yellow powder(2.1296 g, 93%). IR νmax/cm -1 (neat film): 3446,

  microwave vial was charged with a stir bar, 2-iodo-4-bromobenzothiazole (34 mg, 0.1 mmol), 2-aminophenylboronic acid (41.1 mg, 0.3 mmol), Na2CO3 (106 mg, 1 mmol), Pd(PPh3)4 (12 mg, 0.01 mmol), DMF (0.6 mL) and water (0.2 mL). The crude mixture was then degassed (3 x freeze-pump-thaw method) and purged with Ar. The vial was loaded into a microwave reactor and heated at 120 °C for 5h. The reaction mixture was cooled to rt before being transferred to a separatory funnel with sat'd aq. NaHCO3 (10 mL), the aqueous phase was extracted with EtOAc (3 x 15 mL). The combined aqueous phases were washed with brine (3 x 20 mL), then dried over anhydrous MgSO4, filtered and the filtrate concentrated onto Celite under reduced pressure. The crude material was purified using Silica gel flash chromatography using an eluent of 100% cyclohexane to 70:30 cyclohexane/EtOAc. Desired fractions were collected and concentrated under reduced pressure, and further under high vacuum overnight to furnish

  round bottom flask was charged with a stir bar, ethyl 2-(2hydroxyphenyl)benzothiazole-6-carboxylate (233.5 mg, 0.78 mmol), 2 mL CH2Cl2 and DIPEA (204 mL, 1.17 mmol). The mixture was stirred under Ar atmosphere for 10 minutes after which BF3•OEt2 (400 mL, 3.2 mmol) was added dropwise to the stirring solution. The mixture was left to react overnight at room temperature until starting material was consumed (Basic Alumina TLC). The reaction mixture was then diluted with dry pentane, which resulted in the formation of a white precipitate. The reaction mixture was filtered through a frit collecting the precipitate which was washed several times with pentane; the filtrate was discarded. The solid precipitate was then dissolved in CHCl3 and concentrated to dryness onto Celite. The crude reaction mixture was then purified on a basic alumina column, eluting with CH2Cl2/pentane (1:1) until the eluent was no longer fluorescent. The solvent was then removed by rotary evaporation to afford a light yellow powder, which was further dried under high vacuum (103.4 mg, 38%). IR νmax/cm -1 (neat film): 3000,

  F NMR (377 MHz, Chloroform-d) Chapter 5 Experimental Section 261 δ -132.09 (qB). 11 B NMR (128 MHz, Chloroform-d) δ 1.90 (d, J = 34.5 Hz). HRMS-ESI (m/z): found [M+Na] + 370.0491, calc'd C19H11BFNNaO2S requires 370.0480. An oven dried 10 mL Pyrex Wheaton vial was charged with a stir bar, [Re] (16 mg, 0.025 mmol, 5 mol%), Cs2CO3 (118 mg, 0.0.36 mmol, 100 mol%), 2-(6-methylbenzo[d]thiazol-2-yl)aniline (85.4 mg, 0.36 mmol) and dry MeOH (1.5 mL). The vial was purged with Ar, then the reaction mixture degassed (3 cycles of freeze-pump-thaw) and left under an atmosphere of Ar before being sealed with a Teflon lined cap. The vial was placed in an oil bath at 140 °C for 5 days; reaction progress monitored by LCMS and TLC (9:1 cyclohexane/EtOAc). The reaction mixture was cooled to rt, and diluted with EtOAc (10 mL) and passed through a Silica plug, and the Silica washed with EtOAc. The organic phase was washed with saturated aqueous NaHCO3 (1 x 50 mL) and brine (1 x 100 mL).

  Two oven dried 10 mL Pyrex Wheaton vials were each charged with a stir bar, [Re] (20 mg, 0.025 mmol, 5 mol%), Cs2CO3 (190 mg, 0.6 mmol, 100 mol%), 2,2'-(benzo[d]thiazole-2,4-diyl)dianiline (180 mg, 0.6 mmol) and dry MeOH (2 mL). The vials were purged with Ar, then the reaction mixtures degassed (3 cycles of freeze-pump-thaw) and left under an atmosphere of Ar before being sealed with a Teflon lined cap. The vials were placed in an oil bath at 140 °C for 5 days; reaction progress monitored by LCMS and TLC (4:1 cyclohexane/EtOAc). The reaction mixtures were cooled to rt, the content of both vials combined and the mixture diluted with EtOAc (10 mL) and passed through a Silica plug, and the Silica washed with EtOAc. The organic phase was washed with saturated aqueous NaHCO3 (1 x 50 mL) and brine (1 x 100 mL). The organic phase was dried over anhydrous MgSO4, then filtered and concentrated onto Celite and purified by Silica flash column chromatography (eluent: 100% cyclohexane to 9:1 cyclohexane/EtOAc). Desired fractions were combined and concentrated under reduced pressure to provide the product as a yellow foam (301.2 mg, 77%). IR νmax/cm -1 (neat film): 3430, 3271, 2919, 2814, 1608, Chapter 5 Experimental Section 263 1578

  An oven dried 10 mL Pyrex Wheaton vial was charged with a stir bar, [Re] (23 mg, 0.025 mmol, 5 mol%), Cs2CO3 (188.9 mg, 0.6 mmol, 100 mol%), 2-(2-aminophenyl)-4bromobenzothiazole (174.5 mg, 0.6 mmol) and dry MeOH (2 mL). The vial was purged with Ar, then the reaction mixture degassed (3 cycles of freeze-pump-thaw) and left under an atmosphere of Ar before being sealed with a Teflon lined cap. The vial was then placed in an oil bath at 140 °C and reaction progress monitored by TLC (9:1 cyclohexane/EtOAc).

  An oven dried 10 mL Pyrex Wheaton vial was charged with a stir bar, [Re] (21 mg, 0.025 mmol, 5 mol%), Cs2CO3 (170 mg, 0.5 mmol, 100 mol%), 2-(2-hydroxyphenyl)-4-(2aminophenyl)benzothiazole (156.7 mg, 0.5 mmol) and dry MeOH (2 mL). The vial was purged with Ar, then the reaction mixture degassed (3 cycles of freeze-pump-thaw) and left under an atmosphere of Ar before being sealed with a Teflon lined cap. The vial was then placed in an oil bath at 140 °C and reaction progress monitored by TLC (9:1 cyclohexane/EtOAc). After 5 days, the reaction mixture was cooled to rt, diluted with

Scheme 6 . 1 Scheme 6 . 2 Scheme 6 . 3

 616263 Scheme 6.1 Reaction summary for one-pot two-step Balz-Schiemann reaction with organotrifluoroborates. Chapter 3 reports preliminary results from the investigation of organotrifluoroborates as F -sources in the fluorination of unsymmetrical diaryliodonium salts. The work mainly

7. 1 Introduction

 1 photophysiques ont été explorées. Un complexe de monofluoroboratede 2,4-

7. 2 Chapitre 2 Schéma 7 . 3

 2273 Résume La réaction Balz-Schiemann continue d'être une méthode pertinente pour la synthèse des fluorures d'aryle en raison de sa simplicité de mise en oeuvre (Schéma 7.1). Cependant, -Effet de l'organotrifluoroborate Plusieurs organotrifluoroborates ont été employés dans la réaction pour étudier l'effet du fragment organique sur l'efficacité de la réaction. Les organotrifluoroborates aromatiques enrichis et appauvris en électrons (par rapport au PhBF3K) fonctionnaient cependant avec des rendements inférieurs. Les trifluoroborates d'alkyle ont également pu être utilisés, mais là encore avec des rendements inférieurs. Le phényltrifluoroborate de potassium s'est révélé fournir les meilleurs rendements. Les conditions de réaction ont permis la fluoration de divers substrats d'aniline avec un rendement modéré à bon, et ont permis l'accès à des fluorobenzènes 2,6-disubstitués dont les sels de diazonium correspondants sont connus pour être instables (Schéma 7.3). Contrairement aux conditions classiques de la réaction de Balz-Schiemann qui exigent habituellement une décomposition sèche stricte, les conditions décrites utilisent un acide aqueux et peuvent tolérer la présence d'équivalents d'eau ajoutés sans diminution des rendements. Ce point apparaît particulièrement important du fait de la forte propension des ions fluorures à être hydratés, et semble indiquer une non implications des fluorures libres mais plus un transfert direct du fluorure depuis l'organotrifluoroborate. De plus, la faible température (45 °C) à laquelle se produit la décomposition du diazonium et la fluoration réussie est sans précédent dans les transformations de type Balz-Schieman (à l'exception de l'utilisation de réactifs HF) faisant de cette approche une voie d'accès douce aux fluorures d'aryle. Le schéma 7.3 illustre l'étendue de la méthode développée au cours de nos travaux. Chapitre 7 Résume Français 284 Substrat de la réaction de Balz-Schiemann en un pot avec le phényltrifluoroborate de potassium. Conditions de réaction : aniline (0,25 mmol), 85% H3PO4 aq. (0,5 éq.), Phényltrifluoroborate de potassium (0,38 mmol), t-BuOH (1,3 ml) dans un flacon de pression avec capuchon doublé de téflon, purge Ar, puis t-BuONO (0,38 mmol), t.a. pendant 20 min, puis chauffé à 45-50 °C pendant 2h. Rendement déterminé par RMN 19 F en utilisant le 2,4-dinitrofluorobenzène comme étalon interne. Rendement isolé entre parenthèses. a 98% H2SO4 utilisé comme acide dans du t-BuOH à 95 ° C. Enfin, les sources traditionnelles de fluorures comme BF4 -, et d'autres sources telles que TBAF, CsF et KF ne conduisent au plus qu'à des traces de fluorure d'aryle dans des conditions établies avec l'organotrifluoroborate, démontrant ainsi le rôle critique de ces réactifs dans l'expansion des réactions de Balz-Schiemann.

7. 3

 3 Résume Chapitre 3 Dans le chapitre 2, nous avons décrit le développement d'une méthodologie pour une réaction de Balz-Schiemann en deux étapes en un pot avec des organotrifluoroborates. Compte tenu de la réactivité intéressante observée, nous avons été motivés pour élargir le profil de réaction de fluoration des organotrifluoroborates. Les sels de diaryliodonium ont présenté la classe de substrat logique suivante à étudier en tant qu'équivalents de cation aryle. La fluoration des sels de diaryliodonium dissymétriques est un domaine de recherche croissant. Ces substrats ont trouvé de nombreuses applications en radiofluoration en raison de leur capacité à fournir des fluorures d'aryle riches et pauvres en électrons. La plupart des efforts ont été orientés vers l'exploration des mécanismes sous-jacents de la sélectivité et l'amélioration des conditions de réaction dans le contexte de la radiochimie du fluor. La fluoration des sels de diaryliodonium se limite principalement aux fluorures de métaux alcalins et, à notre connaissance, l'utilisation d'organotrifluoroborates pour la fluoration de sels de diaryliodonium est sans précédent. Une série de phényltrifluoroborates de diaryliodonium dissymétriques ont été synthétisés et entièrement caractérisés. La synthèse de ces sels a commencé en utilisant un protocole modifié décrit par Olofsson et al. En utilisant cette méthodologie, sept sels de tétrafluoroborate de diaryliodonium dissymétriques ont pu être obtenus avec des rendements modérés à excellents (Schéma 7.4).

Schéma 7 . 5

 75 F et 11 B pour fournir les sels souhaités avec un rendement bon à excellent (Schéma 7.5). Sels de phényltrifluoroborate de diaryliodonium dissymétriques synthétisés.La décomposition de ces sels a été étudiée dans divers solvants et s'est avérée la plus efficace dans le 1,2-dichlorobenzène à 120 ° C. Tous les sels ont fourni un seul produit : précurseur (0,05 mmol), 1,2-dichlorobenzène (1,0 ml) dans un flacon de pression avec un capuchon doublé de téflon, chauffé à 140 °C pendant 2 heures, X = phényltrifluoroborate. a Rendements déterminés par RMN19 F en utilisant le 2,4dinitrofluorobenzène comme étalon interne.La sélectivité observée semble contraster avec celle observée dans la décomposition des fluorures de diaryliodonium ; les écarts expérimentaux suggèrent deux mécanismes différents. Ces études prouvent que les organotrifluoroborates peuvent être utilisés dans la fluoration des sels de diaryliodonium. Ces résultats préliminaires élargissent également le répertoire des organotrifluoroborates en tant que source de fluor nucléophile.

7. 4 Schéma 7 . 6 4 . 20 .. 20 . 4 . 21 .Schéma 7 . 7 Schéma 7 . 8

 476420204217778 Résume Chapitre 4 Dans notre effort d'élargir la gamme des méthodologies de transfert intramoléculaire de fluor, nous avons synthétisé une gamme de motifs contenant des organotrifluoroborates qui positionnent F -près d'un centre électrophile. Nous avons identifié les organotrifluoroborates comme candidats potentiels pour ce type de transformation, compte tenu de leur capacité avérée à transférer le fluor de façon intermoléculaire (voir les chapitres 2 et 3). Dans ce contexte, nous avons tenté de synthétiser quatre substrats différents contenant du trifluoroborate et d'enquêter ensuite sur la fluoration intramoléculaire (Schéma 7.6). Ces substrats seraient intéressants, car dans tous les cas, le C-B devrait être maintenu et permettre une fonctionnalisation ultérieure après la fluoration. Substrats proposés pour la fluoration intramoléculaire avec des trifluoroborates. [B] = BF3 -, B(OR)2 (R = H, alkyle). Malgré des efforts synthétiques conséquents, 4.20 n'a pas pu être obtenu en raison des difficultés d'accès à un système biphényle borylé (voir section 4.2.1). En raison des Chapitre 7 Résume Français 290 contraintes de temps, nous n'avons pas poursuivi nos tentatives d'accéder de manière efficace à Cependant nous percevons un grand potentiel de 4.20 pour le transfert intramoléculaire de fluor et conservons des perspectives quant à l'optimisation de la synthèse 4Nous avons pu synthétiser, isoler et caractériser le diazoniotrifluoroborate zwitterionique Ce substrat a été synthétisé par alkylation du 2-nitrophénol avec du bromométhyltrifluoroborate de potassium, suivi par la réduction du groupe nitro en amine. L'étape finale consistait en une diazotation et une précipitation du produit à basse température (Schéma 7.7). Synthèse du diazoniotrifluoroborate 4.21. Cependant, fluoration de 4.21 n'a conduit qu'à l'observation de rendements en traces de fluorure d'aryle correspondant. Le substrat s'est révélé généralement stable à basse température (45 °C). A des températures plus élevées (≥ 100 °C), des traces de fluorure d'aryle correspondant ont pu être observées, accompagnées d'une dégradation significative du produit de départ. Les dérivés de styrène 4.22 et 4.23 ont été facilement obtenus avec des rendements modérés à excellents, respectivement. La bromofluoruration efficace a échoué en utilisant 4.22 et diverses sources de brome électrophiles. Les principaux produits étaient des produits de polybromation et de deborylation, seules des traces de (2-bromo-1fluoroéthyl)benzène ont été observés. De manière similaire, 4.23 ont échoué dans l'ouverture du cycle époxyde intramoléculaire par le fluor, la fluorohydrine désirée n'a été observée que dans un cas, alors que la majorité des conditions de réaction examinées ont conduit à la dégradation du produit de départ. 7.5 Résume Chapitre 5 La maladie d'Alzheimer (MA), la principale cause de démence, est de plus en plus préoccupante dans une population mondiale vieillissante et en croissance rapide. À ce jour, aucun biomarqueur validé n'a été identifié pour le diagnostic de la MA. La preuve définitive n'est disponible que par des preuves histopathologiques à l'autopsie. Un domaine de recherche intense est le développement d'outils d'imagerie non invasifs pour la détection précoce des caractéristiques de la maladie. La plupart des stratégies se sont concentrées sur les traceurs d'imagerie TEP et fluorescence proche infrarouge (NIRF) ciblant le peptide amyloïde-β (Aβ). À ce jour, le développement d'outils d'imagerie bimodale est resté quelque peu limité et présente un intérêt considérable. Les sondes d'imagerie bi-modales pour Aβ présentent un intérêt compte tenu de leur potentiel de validation croisée des techniques d'imagerie et des informations complémentaires qu'elles peuvent fournir. Alors que les sondes fluorescentes ont été couramment utilisées en biologie comme colorants sélectifs, la translation de ces sondes en applications in vivo a nécessité le développement de sondes émettrices proches infrarouge (NIR). Les longueurs d'onde d'émission peuvent être déplacées vers le NIR en augmentant le degré de conjugaison π au sein de la structure moléculaire de la sonde. Une autre stratégie réussie implique la rigidification des échafaudages moléculaires par la complexation B-F2, ce qui rend la structure entière de plus en plus plane et augmente l'étendue de la conjugaison π. Une rigidité structurelle accrue et une conjugaison π induisent généralement des profils d'absorption et d'émission nets, des rendements quantiques élevés et augmentent la durée de vie de la fluorescence. De plus, le complexe cyclique B-F2 peut fonctionner comme un accepteur dans les architectures électroniques Donneur-π-Accepteur. Dans ce contexte, nous avons étudié la synthèse de divers nouveaux fluorophores B-Fn à base de motif benzothiazole. Une série de 2-arylbenzothiazoles et de 2,4-diarylbenzothiazoles substitués ont été synthétisés en utilisant des couplages Suzuki-Miyaura. À partir de ces ligands, trois complexes B-Fn ont été isolés avec succès et complètement caractérisés par divers moyens spectroscopiques (Schéma 7.8). Complexes B-Fn isolés et caractérisés. Les propriétés photophysiques de ces complexes ont ensuite été étudiées (Figure 7.1).

Figure 7 . 1

 71 Figure 7.1 Chromatogramme HPLC de racémique 5.19 (à gauche), 5.19a (à droite, en haut) et 5.19b (à droite, en bas) après 1 semaine. La stabilité des complexes 5.17-5.19 en présence d'eau a été étudiée. 5.18 s'est avéré se dégrader, par deborylation, en ligand de départ lors d'une exposition prolongée à

Schéma 7 . 11 Schéma 7 . 12

 711712 liaisons B-F, en particulier des organotrifluoroborates, en tant que sources F -dans la fluoration inter et intramoléculaire de divers substrats. Ces travaux ont également appliqué des liaisons B-F dans la synthèse de nouveaux fluorophores en tant qu'agents d'imagerie bimodale potentiels. Le chapitre 2 décrit l'application des organotrifluoroborates comme source de F -dans la fluorodediazoniation des sels d'aryle diazonium. Les résultats préliminaires ont montré que les sels d'aryle diazonium pouvaient être fluorés en utilisant des sels d'organotrifluoroborates en solution. Cette méthodologie a ensuite été étendue à un protocole de diazotation / fluorodediazoniation en deux étapes et un seul pot, en évitant l'isolement des sels d'aryle diazonium (Schéma 7.10). Ce protocole permet la fluoration des anilines dans des conditions sans précédent, avec des rendements modérés à excellents. La transformation était particulièrement efficace pour les anilines fortement stériquement encombrées, les rendements diminuants lorsque l'encombrement stérique était diminué sur l'une ou les deux positions ortho. Résumé de la réaction pour la thermolyse de sels de phényltrifluoroborate de diaryliodonium dissymétriques. À la suite des résultats observés dans les chapitres 2 et 3 avec l'application de composés organotrifluoroborés en tant que sources de F -pour la fluoration intermoléculaire, le chapitre 4 explore nos tentatives pour traduire cela en fluoration intramoléculaire. Quatre motifs moléculaires différents ont été identifiés et leur synthèse tentée (Schéma 7.12). Nous avons essayé de synthétiser 4.20, cependant toutes les méthodes employées n'ont pas abouti à atteindre plus que des traces du précurseur de l'aniline. Le zwitterion 4.21 a été synthétisé et entièrement caractérisé, et la fluoration via une réaction intramoléculaire de type Balz-Schiemann a été étudiée ; le fluorure d'aryle correspondant ne peut être détecté qu'à l'état de traces. Le dérivé de styrène 4.22 a été synthétisé, entièrement caractérisé et étudié en ce qui concerne les réactions de bromofluoration en utilisant divers agents de bromation électrophiles ; seuls des rendements en trace du produit souhaité pouvaient être détectés. Le dérivé d'oxyde de styrène 4.23 a également été synthétisé et entièrement caractérisé, mais la fluoration par ouverture de cycle époxyde intramoléculaire n'a pu être détectée qu'à l'état de traces. Motifs moléculaires pour la fluoration intramoléculaire utilisant un groupement trifluoroborate. Enfin, le chapitre 5 décrit la synthèse de nouveaux fluorophores, incorporant un complexe B-Fn, basé sur le motif benzothiazole. Une série de 2-arylbenzothiazoles et de 2,4diarylbenzothiazoles diversement substitués a été synthétisée à partir de laquelle trois complexes B-Fn ont pu être isolés et complètement caractérisés (Schéma 7.13). Le complexe 5.19 s'est avéré avoir les propriétés photophysiques les plus prometteuses : émission proche du NIR et grand décalage de Stokes. La stabilité aqueuse de ces complexes a été étudiée, à partir de laquelle 5.19 est apparu comme le plus stable. Schéma 7.13 Complexes B-Fn isolés et caractérisés. De plus, 5.19 contenant un centre de bore asymétrique a été synthétisé sous forme d'un mélange racémique d'énantiomères, pouvant être dédoublé par HPLC chirale et les énantiomères caractérisés par spectroscopie CD ; les énantiomères se sont révélés stables à la racémisation par inversion. Finalement, abstraction de F -de 5.19 a été démontrée, avec la formation de l'ion borénium correspondant (Schéma 7.14), mettant en évidence la possibilité d'effectuer un échange d'isotopes 19 F-18 F sur ce substrat.

  Exploitation du Couple Bore-Fluor pour la Fluoration et la Synthèse d'Agent d'Imagerie Bimodaux Potentiels La liaison Bore-Fluor (B-F) a une longue et riche histoire dans le domaine des transformations chimiques. De plus, cette liaison B-F est utilisée dans une grande diversité de domaines tel que la médecine nucléaire avec l'imagerie de Tomographie par Émission de Positrons (TEP) ou l'imagerie de fluorescence. Dans le cadre de cette thèse, nous nous intéressons à l'utilisation de la liaison B-F pour la formation nucléophile de liaison Carbone-Fluor (C-F) et le développement de nouveaux fluorophores ayant des applications potentielles dans les domaines de l'imagerie bimodale TEP et l'imagerie de fluorescence.

  system, space group Orthorhombic, P b c a Unit cell dimensions a = 9.8952(9) A alpha = 90 deg. b = 16.6269(15) A beta = 90 deg.

  460

  -C(6)-C(5) 121.25(13) C(7)-C(6)-C(1") 118.31(12) C(5)-C(6)-C(1") 120.44(13) C(6)-C(7)-C(7A) 117.54(12) C(6)-C(7)-H(7) 121.2

Table 1 .

 1 2 Fluorination of various substrates using fluoroborate 1.17 ............................

Table 2 .

 2 1 Selected yields of aryl fluorides using different "fluoro-ate" anions ...............

Table 2 .

 2 2 Effect of perfluoroorganotrifluoroborates on the yield of 1,4-difluorobenzene

Table 2 .

 2 3 Initial optimization of Balz-Schiemann reaction using organotrifluoroborates

Table 2 .

 2 4 Optimization of one-pot Balz-Schiemann reaction solvent ............................

Table 2 .

 2 5 Effect of diazotizing agent on reaction yields.................................................

Table 2 .

 2

Table 4 .

 4 3 Cross-coupling conditions for synthesis of biphenyl fragment using 4.33 ...

Table 4 .

 4 4 Conditions tested for the alkylation of 2-aminophenol .................................

xii

Table 4 .

 4 5 Attempted alkylation ofN-protected aminophenols 4.41 and 4.42 ..............

Table 4 .

 4 6 Optimisation of parameters for the reduction of 4.43 ...................................

Table 4 .

 4 7 Optimisation of parameters for the diazotization of 4.39 .............................

Table 4 .

 4 8 Decomposition conditions for intramolecular fluorination of 4.21 .................

Table 4 .

 4 9 Effect of N-bromine reagents on bromofluorination of 4.22 .........................

Table 4 .

 4 10 Effect of bromodimethylsulphonium bromide on bromofluorination of 4.22

Table 4 .

 4 11 Conditions tested for activator-free intramolecular fluorination of 4.23 ......

Table 4 .

 4 12 Effect of epoxide activators on the intramolecular fluorination of 4.23 .......

Table 5 .

 5 1 Photophysical properties of

Table 1 . 2

 12 Fluorination of various substrates using fluoroborate 1.17

	Entry	substrate-X	reaction conditions	substrate-F	Yield (%) a
	1		1.17 (1.4 eq.) CD3CN, rt, 5 min		>95
	2		1.17 (1.4 eq.) CD3CN, rt, 5 min		>95
	3		1.17 (1.2 eq.) CD3CN, rt, 2h		>95
	4		1.17 (2.0 eq.) CD3CN, 70 °C, 1 h		80
	5		1.17 (2.0 eq.) CD3CN, 70 °C, 1 h		45

a Yield determined by integration of 1 H NMR spectra Inspired by this work, Gras and Perrio et al. demonstrated the extension of F -

18

  18

  18

  18

  18

  18

  18

  18

  18

Table 2 .

 2

1 Selected yields of aryl fluorides using different "fluoro-ate"

anions Aromatic Amine Yield (%) ArN2 + BF4 -ArN2 + SiF6 -ArN2 + PF6 -ArN2 + SbF6 -ArN2 + AsF6 -

			Chapter 2
	4-nitroaniline	40-58	34-43	63	60	0
	2.1.1.
	Aniline	51-90	30	-	50	0
	o-toluidine	45-65	69	58	21	0
	m-toluidine	69-87	60	57	30	trace
	p-toluidine	70	64	71	47	2
	2-aminobenzoic acid	9	-	60	62	0
	4-aminophenol	0	6.5	10-20	trace	-
	2-aminopyridine	34	0	34	50	-
	2-nitroaniline	9-17	-	10-20	40	31
	3-nitroaniline	43-54	22	10-20	60	51
						42

6 Organotrifluoroborates as anions in Balz-Schiemann reaction

Table 2 . 2

 22 Effect of perfluoroorganotrifluoroborates on the yield of 1,4-difluorobenzene

	Entry	RnBF4-n -	Yield (%) a
	1		54
	2		65
	3		80
	4		90

Table 2 .

 2 3, entries 12 and 13) resulted in decreased yields.

2)

with 2,4,6-trimethylphenyldiazonium p-toluenesulphonate

(2.1)

in various solvents (Table

2

.3); aryl diazonium p-toluenesulphonates are known to be safely isolable and benchstable. 152 Gratifyingly, decomposition of 2.1 in the presence of potassium phenyltrifluoroborate in t-BuOH provided 2-fluoro-1,3,5-trimethylbenzene

(2.3)

in moderate yield (Table

2.3, entry 1

). Changing the substituent on 2.2 resulted in a decrease in yield for both electron withdrawing and donating groups (Table

2.3, entries 2 and 3

), although the decrease was more marked using an electron-rich aryl trifluoroborate. Moderate yields were also observed in low-boiling halogenated solvents (Table

2

.3, entries 4 and 5), most notably the 34% yield obtained in CH2Cl2 at 50 °C.

These results are surprising as generally, aliphatic chlorinated solvents are incompatible Chapter 2 with the Balz-Schiemann reaction as they react with the diazonium salt to generate chloroaromatics. 140 A significant improvement in yields, 57% (Table

2

.3, entry 6), was observed with THF as the solvent. Similar to results in t-BuOH, the use of electron-poor 2.2 resulted in diminished yields (Table

2.3, entries 7-10

). Lowering of the reaction temperature (Table

2.3, entry 11

) and decreasing or increasing equivalents of 2.2 (

Table 2 . 3

 23 Initial optimization of Balz-Schiemann reaction using organotrifluoroborates (0.25 mmol), 2.2 (0.38 mmol), solvent(1.3 mL) in pressure vial with Teflon lined cap, heated at indicated temperature for 2 h.

	Entry	R	Solvent	Temperature (°C)	Yield (%) a
	1	H	t-BuOH	95	39
	2	4-methoxy	t-BuOH	95	10
	3	4-formyl	t-BuOH	95	25
	4	H	CHCl3	71	38
	5	H	CH2Cl2	50	34
	6	H	THF	75	57
	7	4-formyl	THF	75	35
	8	3,4,5-trifluoro	THF	75	35
	9	4-trifluoromethyl	THF	75	34
	10	2-nitro	THF	75	29
	11	H	THF	50	39
	12 b	H	THF	75	39
	13 c	H	THF	75

a Yield determined by

Table 2 .5 Effect of diazotizing agent on reaction yields Entry [NO] + source 2.5 (eq.) Yield (%) a

 2

	1	t-Butyl nitrite	1.5	55
	2	n-Butyl nitrite	1.5	52
	3	Iso-Amyl nitrite	1.5

.3,

	Chapter 2
	entry 1). Weak acids resulted in poor yields (Table 2.6, entries 9 and 10), however H3PO4
	significantly increased yields to 76% (Table 2.6, entry 11). These results strongly suggest
	that both pKa and nature of the acid are important for efficient transformations; the ion
	pair [aryl diazonium dihydrogen phosphate] may undergo a more facile anion metathesis
	to the productive [aryl diazonium organotrifluoroborate] when compared to other [aryl
	diazonium conjugate base] ion pairs. Gratifyingly, equivalents of 2.5 could be decreased,
	as similar yields were obtained using 1.5 or 3 equivalents (Table 2.6, entries 11 and 12).
	50

Table 2 .6 Acid optimization for the one-pot reaction Entry Acid (eq.) Yield (%) a

 2

	1	-
	2	95% H2SO4 (1.0)
	3	55-58% aq. HI (1.0)	9
	4	48% aq. HBr (1.0)
	5	37% aq. HCl (1.0)
	6	p-Toluenesulfonic acid•H2O (1.0)
	7	65-70% aq. HNO3 (1.0)
	8	Trifluoroacetic acid (1.0)
	9	97% Formic acid (1.0)	6
	10	Glacial acetic acid (1.0)
	11	85% aq. H3PO4 (1.0)
	12 b	85% aq. H3PO4 (1.0)
	13	85% aq. H3PO4 (2.0)
	14	85% aq. H3PO4 (0.5)
	15	85% aq. H3PO4 (0.25)
	Reaction conditions: 2.4 (0.25 mmol), acid (xx eq.), 2.5 (0.38 mmol), t-BuOH
	(1.3 mL) in pressure vial with Teflon lined cap, Ar purge, then t-BuONO
	(0.38 mmol), rt for 20 min, then heated at 95 °C for 2 h. a Yield determined
	by 19 F NMR spectroscopy using 2,4-dinitrofluorobenzene as an internal
	standard. b 3 equivalents of potassium phenyltrifluoroborate used.

Table 2 .7 Effect of temperature on reaction yields Entry Temperature (°C) a Yield (%) b

 2

	1	rt	33
	2	45-50	73
	3	55-60	70
	4	75-80	66
	5	95-100	72
	6	105-110	68

Table 2 .8, entries 14 and 15). Alkyl trifluoroborates could mediate fluorination as well, albeit at lower yields (Table 2.8, entries 17-19).

 2

Table 2 .8 Effect of organotrifluoroborate on reaction yields

 2

	Entry	R	Yield (%) a
	1	4-methoxyphenyl	34

a Yield determined by

Table 2 .9 Control fluorination experiments with various 'fluoride' salts Entry [F] - Yield (%) a

 2

	1	KBF4	6
	2	KF	0
	3	TBAF (1M in THF)	0
	4	CsF	0
	5	KHF2	0
	Reaction conditions: 2.4 (0.25 mmol), 85% aq. H3PO4 (0.5 eq.), [F] -(0.38 mmol), t-BuOH (1.3
	mL) in pressure vial with Teflon lined cap, Ar purge, then t-BuONO (0.38 mmol), rt for 20 min,
	then heated at 45-50 °C for 2 h. a Yield determined by 19 F NMR spectroscopy using 2,4-
	dinitrofluorobenzene as an internal standard.
	Having established an effective protocol, we turned to exploring the substrate scope of
	the transformation. Sterically hindered anilines were successfully fluorinated in good to
	high yields (Scheme 2

.2, products 2.8, 2.9, 2.12 and 2.13). Interestingly

	Chapter 2
	bulk from the ortho positions of the starting aniline was observed to correlate with
	decreasing yields of the corresponding aryl fluoride. While 2.8 was produced in 62%
	isolated yield, ortho tert-butyl substituted aniline decreased yields to 39% (2.13),
	progressively moving the substituent to the meta and para positions further diminished
	yields to 26% (2.14) and 14% (2.15), respectively. The same trend is observed for
	isopropyl substituents with decreasing yields observed in the series 2.12 (78%), 2.16
	(31%), and 2.17 (14%). The sensitivity of the transformation towards steric bulk at both
	ortho positions is highlighted by the differences in reaction efficiencies observed between
	di and mono-ortho substituted anilines; yields are halved when comparing 2.9 (50%) to
	2.10 (26%). Even more drastic is the yield obtained with 2.12 (78%) compared to 2.16
	(31%). To support the hypothesis of required steric bulk at both ortho positions of the
	starting aniline, three substituted anilines were synthesized and efficiently fluorinated in
	good yields (
	, removing steric
	55

Scheme 2.2, products 2.24, 2.25 and 2.26), additionally

	showing that the
	transformation could tolerate the presence of heteroelements at auxiliary sites on the
	parent phenyl ring. The reaction conditions also allowed the fluorination of heterocycle

2.18 in moderate yield. Attempts to introduce heteroelement-containing steric bulk at ortho positions of the aniline resulted in only trace yields of the fluorinated product (Scheme 2.2, products 2.19, 2.20, 2.21, 2.22 and 2.23).

	Chapter 2 Chapter 2
	Scheme 2.2 Substrate scope of the one-pot Balz-Schiemann reaction with potassium
	phenyltrifluoroborate. Reaction conditions: aniline (0.25 mmol), 85% aq. H3PO4 (0.5 eq.), potassium
	phenyltrifluoroborate (0.38 mmol), t-BuOH (1.3 mL) in pressure vial with Teflon lined cap, Ar purge, then t-
	BuONO (0.38 mmol), rt for 20 min, then heated at 45-50 °C for 2 h. Yield determined by 19 F NMR
	spectroscopy using 2,4-dinitrofluorobenzene as an internal standard. Isolated yield in parentheses. a 98%
	H2SO4 used instead of 85% aq. H3PO4 in t-BuOH at 95 °C.
	56 57

.2, products 2.10 vs. 2.9 and 2.16 vs. 2.12) corroborate

	Chapter 2 Chapter 2
	We hypothesise that the reaction outcome is determined by the delicate balance between
	the kinetic and thermodynamic stability of the generated aryl cation. We therefore propose
	that under reaction conditions, tight ion pair III is formed in solution, SN1 heterolytic
	decomposition produces intermediate IV. Intermediate IV can then either undergo
	fluorodediazoniation with the phenyltrifluoroborate anion or react with other nucleophiles
	in solution (Scheme 2.3). Aryl cations of appropriate stability could persist long enough
	within the tight ion pair, IV, to be fluorinated producing V. Destabilized aryl cations may
	react more readily with other nucleophiles present in solution, namely water to produce
	unwanted by-products VI. The main side product observed was the corresponding Scheme 2.3 Proposed reaction mechanism.
	phenol; however, in some cases biaryls from homocoupling of the substrate were
	observed (detected by GC-MS). The use of radical scavengers was investigated to
	suppress the formation of these wanted side-products and increase yields. Employing
	2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) had no effect on yields. Results using
	sodium ascorbate were inconsistent with yields either being unaffected or completely
	diminished; the ascorbate can behave as a single electron donor and therefore promote
	the homolytic decomposition of the aryl diazonium salt.
	My results
	with mono-and di-ortho-substituted anilines (Scheme 2past findings to suggest that the mechanism for
	organotrifluoroborate engagement is likely consistent with a heterolytic reaction
	mechanism proceeding by a solvated ion pair.
	58 59

61 2.4 Experimental General Information Solvents and Reagents

	Chapter 2 Chapter 2 Experimental Section
	diminishing yields. Furthermore, the low temperature (45 °C) at which diazonium
	decomposition and successful fluorination occur is unprecedented in Balz-Schiemann
	type transformations, excluding the use of HF reagents, presenting a mild route to aryl
	fluorides. Neither BF4 -, KHF2/HF, nor other fluoride ion sources afford more than trace
	quantities of aryl fluoride under conditions where the organotrifluoroborate does, thus
	Solvents (t-BuOH, Et2O, MeOH, THF and acetone) used were all commercial grade and
	demonstrating the critical role of these reagents in expanding the reaction manifold of the used as received with no drying. However, t-BuOH was degassed prior to its use and all
	Balz-Schiemann reaction. reactions were performed under argon atmosphere unless otherwise stated.
	Commercially available compounds were used without further purification. Deuterated
	A short-term perspective involves further mechanistic studies and theoretical calculations solvents for NMR spectroscopic analysis were purchased from Cambridge Isotopes
	to try to rationalize the substrate scope observed and the role of the organotrifluoroborate. Limited.
	With a firm understanding of the underlying selectivity and reactivity, reaction conditions
	can be tuned towards developing a generally applicable methodology for the fluorination
	of aromatic amines under operationally simple and mild experimental conditions. We
	foresee extending this methodology towards cartridge-based and continuous flow
	systems. Solid-supported boronic acids are commercially available, they can be
	converted to the corresponding trifluoroborate through standard methods and applied to
	our developed methodology. Solid-supported systems of this type would represent a
	recyclable fluorination reagent that can be easily collected from reaction mixtures by
	simple filtration. A more long-term perspective is to translate this methodology towards
	monofluoroborate systems. Monofluoroborates would be a more atom-economical
	fluorinating agent and have potential applications in radiofluorination. Work is currently
	underway towards expanding the application of organofluoroborates towards these two
	aims.
	aqueous acid and can tolerate the presence of added equivalents of water without
	60

Table 3 . 1

 31 Fluorination of diaryliodonium salts in solution and in the melt

	Product distribution (%)*

a reaction in DMF (115-150 °C) with KF (2 eq,). b reduced product (benzene) observed (2-9%). c neat (211-233 °C) no KF. d neat (160-235 °C) with KF

(3.5 eq.)

. * yields for symmetrical diaryliodonium salts are in the centre column.

Soon after, Grushin et al. described the near quantitative fluorination (96% yield) of diphenyliodonium tetrafluoroborate with KF and catalytic amounts of 18-crown-6 under mild conditions. 188 A decade later, Pike and Aigbirhio pioneered the application of this methodology towards the production of [

  18

Table 3 .

 3

	Entry	R1	R2	X	A	B
	1 a	H	H	CF3SO3	80
	2 a	4-OMe	H	CF3SO3	-	96
	3 a	2,4,6-(CH3)3	H	CF3SO3	96	-
	4 a	4-Br	H	CF3SO3	66.5	28.5
	5 a	4-OMe	H	Br	-	88
	6 b	2,4,6-(CH3)3	2-CH3	CF3SO3	52	13

2 Radiofluorination of diaryliodonium salts Product distribution/RCY (%)* a [ 18 F]-KF/K222. b [ 18 F]-CsF. * yields for symmetrical diaryliodonium salts are in the centre column.

Table 3 . 3

 33 Solvent optimisation for the decomposition of 3.20

	Product distribution (%) a

Table 3 . 4

 34 Product distribution from the decomposition of salts 3.

21-3.26

	Chapter 3
	2
	3
	4
	5
	6
	Reaction conditions: precursor (0.05 mmol), 1,2-dichlorobenzene (1.0 mL) in pressure vial with
	Entry Teflon lined cap, heated at 140 °C for 2 h, X = phenyltrifluoroborate. Precursor Product distribution a
	1
	112

a Yields determined by

Table 3 . 5

 35 Product distribution from the decomposition of salts 3.

14-3.16

	Entry	Precursor	Product distribution (%) a
	1
			62
	2
			89
	3		no conversion
	Reaction conditions: precursor (0.05 mmol), 1,2-dichlorobenzene (1.0 mL) in pressure vial with
	Teflon lined cap, heated at 140 °C for 2h.

a Yields determined by

2-thienyl)(phenyl)iodonium tetrafluoroborate (3.26)

  high vacuum for 6h. The remaining residue was triturated with CH2Cl2 and the solution passed through 0.2 µm PTFE filter to remove insoluble solids. The filtrate was then concentrated to saturation and then dropped onto Et2O to precipitate the product. 323.0293, calc'd C15H16I + requires 322.0297, found [M-C15H16I] -144.0474, calc'd C6H5BF3 -requires 144.0473. Anal. calc'd for C21H21BF3I: C, 53.88; H, 4.52; N, 0.00. Found C, 52.85; H, 4.32; N, 0.02.DMSO-d6) δ 143.5 (Cq), 141.8 (Cq), 135.0 (CH), 134.9 (CH), 131.3 (q, 3 JCF = 1.9 Hz) (CH), 130.0 (CH), 126.2 (CH),124.8 (CH), 122.7 (Cq), 119.4 (Cq), 117.4 (Cq), 114.4 (Cq), 26.3 (CH3), 20.5 (CH3).19 F NMR (376 MHz, DMSO-d6) δ -139.12 (qB).11 B NMR (128 MHz, Hz, 1H), 7.67 (ddt, J = 8.5, 7.0, 1.1 Hz, 1H), 7.54 (ddt, J = 8.2, 7.3, 1.3 Hz, 2H), 2H), 7.18 (dd, J = 5.3, 3.8 Hz, 1H), 7.07 (dddt, J = 7.4, 5.9, 1.4, 0.7 Hz, 2H), 1H).13 C NMR (101 MHz, DMSO-d6) δ 140.4 (CH), 137.4 (CH), 134.6

	(2,4,6-trimethylphenyl)(phenyl)iodonium phenyltrifluoroborate (3.20) DMSO-d6) δ 3.12 (q, J = 51.5 Hz). HRMS-ESI (m/z): found [M-C6H5BF3] + 348.0250, calc'd C16H15IN + requires 348.0249, found [M-C16H15IN] -144.0477, calc'd C6H5BF3 -requires 144.0473. Anal. calc'd for C22H20BF3IN: C, 53.59; H, 4.09; N, 2.84. Found C, 53.30; H, 3.84; N, 2.82. (2,6-difluorophenyl)(2,4,6-trimethylphenyl)iodonium phenyltrifluoroborate (3.23) Isolated as a white powder (520 mg, 92%). IR νmax/cm -1 (neat film): 3067, 3046, 3022, 3004, 2924, 1593, 1468, 1239, 1205, 1016, 995, 942, 925, 901, 892, 749. 1 H NMR (400 MHz, DMSO-d6) δ 7.80 (tt, J = 8.5, 6.7 Hz, 1H), 7.44 (dd, J = 8.3, 7.3 Hz, 2H), 7.31 (d, J = 6.7 Hz, 2H), 7.22 (s, 2H), 7.07 (t, J = 7.3 Hz, 2H), 7.03 -6.97 (m, 1H), 2.61 (s, 6H), 2.28 (s, 3H). (CH), 126.2 (CH), 124.9 (CH), 122.9 (Cq), 113.52 -113.03 (m) (CH), 91.7 (t, 2 JCF = 28.1 Hz) (Cq), 25.9 (t, 6 JCF = 2.1 Hz) (CH3), 20.5 (CH3). 19 F NMR (376 MHz, DMSO-d6) δ -95.84 (t, J = 7.0 Hz, 2F), -138.46 --139.68 (qB, 3F). 11 B NMR (128 MHz, DMSO-d6) δ 3.13 (q, J = 52.8 Hz). HRMS-ESI (m/z): found [M-C6H5BF3] + 359.0112, calc'd C15H14F2I + requires 359.0108, found [M-C15H14F2I] -144.0473, calc'd C6H5BF3 -requires 144.0473. Anal. calc'd for C21H19BF5I: C, 50.04; H, 3.80; N, 0.00. Found C, 49.97; H, 3.43; N, 0.04. Chapter 3 Experimental Section (2,6-difluorophenyl)(phenyl)iodonium phenyltrifluoroborate (3.24) Isolated as a white powder (132.9 mg, 77%). IR νmax/cm -1 (neat film): 3080, 3066, 3049, (4-methoxyphenyl)(phenyl)iodonium phenyltrifluoroborate (3.25) 3007, 1593, 1467, 1242, 1206, 998, 946, 898, 788, 753, 706. Chapter 3 Experimental Section Isolated as a light grey powder (93.9 mg, 81%). IR νmax/cm -1 (neat film): 3070, 3009, 2971, 2936, 2840, 1581, 1571, 1488, 1442, 1300, 1255, 1200, 1179, 1009, 990, 951, 904, 754. 1 H NMR (400 MHz, DMSO-d6) δ 8.22 -8.13 (m, 4H), 7.68 -7.62 (m, 1H), 7.56 -7.49 (m, 2H), 7.33 -7.27 (m, 2H), 7.11 -7.04 (m, 4H), 7.03 -6.97 (m, 1H), 3.79 (s, 3H). Isolated as a light pink powder (318.7 mg, 92%). IR νmax/cm -1 (neat film): 3096, 3006, 124.8 (CH), 119.3 (Cq), 100.7 (Cq). 19 F NMR (376 MHz, DMSO-d6) δ -139.11 (qB). 11 B NMR (128 MHz, DMSO-d6) δ 3.09 (q, J = 52.6 Hz). HRMS-ESI (m/z): found [M] + 286.9396, calc'd C10H8 127 IS + requires 286.9391, found [M] -144.0475, calc'd C6H5 10 BF3 -requires 144.0473. Anal. calc'd for C16H13BF3IS: C, 44.48; H, 3.03; N, 0.00. Found C, 1470, 1442, 1435, 1383, 1199, 1014, 1007, 988, 970, 890, 758, 736, 707. (CH), 132.1 (CH), 131.7 (CH), 131.3 (d, 4 JC-F = 1.7 Hz) (CH), 129.7 (CH), 126.2 (CH), 44.16; H, 2.32; N, 0.00.
	129 130

2 µm PTFE filter to remove insoluble solids, and the filter washed with MeCN. The filtrate was then concentrated to dryness under reduced pressure, and then left under Isolated as an off-white powder

(54.7 mg, >99%)

. Colourless, single crystals suitable for X-ray analysis were grown by slow evaporation of a CHCl3 solution. IR νmax/cm -1 (neat film):

3071, 3049, 3009, 2984, 1441, 1200, 1005, 986, 937, 906, 752, 743, 707

.

1

H NMR (400 MHz, DMSO-d6) δ 7.

99 -7.95 (m, 2H), 7.65 -7.60 (m, 1H), 7.53 -7.46 (m, 2H), 7.32 (d, J = 6.6 Hz, 2H), 7.23 -7.19 (m, 2H), 7.07 (dddt, J = 7.3, 5.9, 1.4, 0.7 Hz, 2H), 7.04 -6.97 (m, 1H)

, 2.60 (s, 6H), 2.29 (s, 3H).

13

C NMR (101 MHz, DMSO-d6) δ 143.1 (Cq), 141.6 (Cq), 134.5 (CH), 131.9 (CH), 131.8 (CH), 131.3 (q, 3 JCF = 1.7 Hz) (CH), 129.8 (CH), 126.2 (CH), 124.9 (CH), 122.6 (Cq), 114.5 (Cq),

26.3 (CH3), 20.5 (CH3)

.

19

F NMR (376 MHz, DMSO-d6) δ -139.06 (qB). 11 B NMR (128 MHz, DMSO-d6) δ 3.15 (q, J = 52.0 Hz). HRMS-ESI (m/z): found [M-C6H5BF3] + 13 C NMR (101 MHz, DMSO-d6) δ 160.6 (dd, 1 JCF = 250.7, 3 JCF = 6.0 Hz) (Cq), 143.5 (Cq), 141.6 (Cq), 137.0 (t, 3 JCF = 10.1 Hz) (CH), 131.3 (q, 3 JCF = 1.7 Hz) (CH), 129.9 1 H NMR (400 MHz, DMSO-d6) δ 8.20 (d, J = 7.7 Hz, 2H), 7.80 (tt, J = 8.5, 6.7 Hz, 1H), 7.70 (t, J = 7.4 Hz, 1H), 7.55 (t, J = 7.8 Hz, 2H), 7.49 -7.43 (m, 2H), 7.31 (d, J = 6.9 Hz, 2H), 7.07 (t, J = 7.2 Hz, 2H), 7.00 (t, J = 7.1 Hz, 1H). 13 C NMR (101 MHz, DMSO-d6) δ 160.1 (dd, 1 JCF = 251.0, 3 JCF = 5.5 Hz) (Cq), 137.2 (t, 3 JCF = 9.9 Hz) (CH), 135.2 (CH), 132.5 (CH), 132.2 (CH), 131.3 (q, 3 JCF = 1.8 Hz) (CH), 126.2 (CH), 124.8 (CH), 117.1 (Cq), 113.1 (dd, 2 JCF = 22.9, 4 JCF = 2.8

Hz) (CH), 94.4 (t, 2 JCF = 28.1 Hz) (Cq).

19

F NMR (377 MHz, DMSO-d6) δ -96.41 (t, J = 7.0 Hz, 2F), -137.

87 --140.92 (qB, 3F)

.

11

B NMR (128 MHz, DMSO-d6) δ 3.12 (q, J = 50.6 Hz). HRMS-ESI (m/z): found [M-C6H5BF3] + 316.9644, calc'd C12H8F2I + requires 316.9639, found [M-C12H8F2I] -144.0474, calc'd C6H5BF3 -requires 144.0473. Anal. calc

'd for C18H13BF5I: C, 46.80; H, 2.84; N, 0.00. Found C, 46.41; H, 2.25; N, 0.19

.

13

C NMR (101 MHz, DMSO-d6) δ 162.0 (Cq), 137.2 (CH), 134.8 (CH), 131.8 (CH), 131.6 (CH), 131.3 (q, 4 JC-F = 1.7 Hz) (CH), 126.1 (CH), 124.8 (CH), 117.5 (CH), 117.0 (Cq), 105.3 (Cq), 55.7 (CH3). 19 F NMR (376 MHz, DMSO-d6) δ -139.14 (qB). 11 B NMR (128 MHz, DMSO-d6) δ 3.10 (q, J = 52.9 Hz). HRMS-ESI (m/z): found [M] + 310.9929, calc'd C13H12 127 IO + requires 310.9933, found [M] -144.0456, calc'd C6H5 10 BF3 -requires 144.0473. Anal.

calc

'd for C19H17BF3IO: C, 50.04; H, 3.76; N, 0.00. Found C, 49.91; H, 3.18; N, 0.06

.

(1 H NMR (400 MHz, DMSO-d6) δ 8.

28 -8.22 (m, 2H), 8.06 (dd, J = 3.8, 1.3 Hz, 1H)

, 7.97 (dd, J = 5.3, Chapter 3 Experimental Section 131 1.3

Table 4 . 1

 41 Borylation reaction conditions for the formation of 4.26 and 4.25

	conversion of starting material to a different product was verified by TLC for most
	reactions, 1 H NMR spectroscopic analysis of reaction crudes and isolated reaction
	products suggested that protodebrominated 4.26' was the major reaction product. This is
	supported by the observation that only BF4 -could be detected by 19 F and 11 B NMR
	spectroscopy when crude borylation reaction mixtures were submitted to trifluoroborate
	forming conditions (aq. KHF2).

1,1'biphenyl]-2-amine 4.24 (Scheme 4.7). Scheme 4.7 Synthesis of 4.24 via Suzuki-Miyaura cross-coupling. Isolated yield.

We next turned our attention towards the borylation step. When 4.24 was submitted to classical Miyaura borylation conditions we could not detect formation of the borylated product (4.26 or 4.25) by

11

B NMR spectroscopy or MS (Table

4.1, entries 1-3)

. We found only one instance in the literature for the borylation of substrate 4.24, wherein the authors report the preparation of 4.26 in 74% using bis(pinacolato)diboron, catalysed by [PdCl2(PPh3)2] in PEG 600 as the solvent.

229

However, in our hands this protocol could not be reproduced; no trace of borylated product could be detected by

11

B NMR spectroscopy or MS (Table

4

.1, entry 4). Additionally, microwave heating of the reaction mixture did not promote borylation (Table

4.1, entries 5 and 6

). While quantitative a microwave heating Attempts to borylate 4.24 via lithium-halogen exchange and trapping with B(iOPr)3 failed (Scheme 4.8, a). Similarly, no borylated product could be detected via reported photoinduced borylation protocols (Scheme 4.8, b). 230 Chapter 4 142 Scheme 4.8 Attempted borylation of 4.24 via a, lithium-halogen exchange. b, photolysis.

Table 4 .

 4 Subjecting 4.27 or 4.28 to classical Miyaura coupling conditions did not result in the formation of any borylated product as indicated by11 B NMR spectroscopy and MS (2, entries 1 and 2). In fact, under reaction conditions 4.27 intramolecularly cyclised to produce N-Boc-carbazole 4.30 in 34% (Table4.2, entry 1).

	Chapter 4

t-butyl carbamate 4.27 or phthalimide 4.28 (Scheme 4.9). Scheme 4.9 Protection of 4.24 as carbamate 4.27 or phthalimide 4.28. Isolated yields.

Table 4 . 2

 42 Attempted Pd-catalysed borylation of N-protected substrates 4.27 and 4.28. Isolated yield of 4.30

	Entry Substrate	[Pd]	Solvent	Temperature (°C) 4.29 formation?
	1	4.27	[PdCl2(PPh3)2] 1,4-dioxane	100	no, 4.30

Table 4 .3, entry

 4 8). The use of potassium 2-nitrophenyltrifluoroborate did not improve yields as only trace amounts of the desired product were observed; 1 H,19 F and 11 B NMR spectroscopy and MS indicated that the recovered residue was mostly unreacted trifluoroborate.

	coupling of 2-nitrophenylboronic acid (4.31) or 2-aminophenylboronic acid (4.32) and 2-
	bromophenylboronic acid MIDA ester (4.33) (Scheme 4.11).

145 Scheme 4.11 Proposed synthesis of biphenyl scaffold using 4.33.

We started by applying reaction conditions first developed by Burke et al.

231

which should allow formation of biphenyl 4.34 (Table

4

.3). However, in our hands the desired product could not be detected by TLC or NMR spectroscopy whether the nitro or amino boronic acid was used (Table

4

.3, entries 1-3). Coupling conditions described by Watson et al.

232- 235

which should have delivered boronic acid 4.35, were then tested (Table

4.3, entries 4-

7)

. Unfortunately, no desired product could be detected by

11

B NMR spectroscopy or MS, microwave heating had no effect on the transformation (Table

4.3, entries 5 and 7

). When reaction crudes were treated with aq. KHF2 trace amounts of desired trifluoroborate 4.36 could be detected only when 2-nitrophenylboronic acid was used (

Table 4 . 3

 43 Cross-coupling conditions for synthesis of biphenyl fragment using 4.33 microwave heating. b potassium 2-nitrophenyltrifluoroborate used.Having exhausted synthetic efforts and in the interest of time we decided to abandon the pursuit of further strategies towards obtaining biphenyl scaffold 4.20.

						Coupling
	Entry	R	Catalyst	Solvent	Work-up	product
						formed?
	1	NO2	Pd(OAc)2, SPhos	THF	-	no
	2	NO2 [Pd2(dba)3]•CHCl3, SPhos	THF	-	no
	3	NH2	Pd(OAc)2, SPhos	THF	-	no
	4	NO2	[PdCl2(dppf)]•CH2Cl2	THF/H2O	-	no
	5 a	NO2	[PdCl2(dppf)]•CH2Cl2	THF/H2O	-	no
	6	NH2	[PdCl2(dppf)]•CH2Cl2	THF/H2O	-	no
	7 a	NH2	[PdCl2(dppf)]•CH2Cl2	THF/H2O	-	no
	8	NO2	[PdCl2(dppf)]•CH2Cl2	THF/H2O	aq. KHF2	trace 4.36 detected by MS
	9	NH2	[PdCl2(dppf)]•CH2Cl2	THF/H2O	aq. KHF2	no
	10 b	NO2	[PdCl2(dppf)]•CH2Cl2, SPhos	THF/H2O	aq. KHF2	trace 4.36 detected by MS

a

methyltrifluoroborate 4.21 4.2.1.2.1 Synthesis of 4.21

  We planned to prepare 4.21 over two synthetic steps, starting with the alkylation of 2aminophenol with potassium halomethyltrifluoroborate (4.37 or 4.38) to provide 4.39 which can then be diazotized to afford zwitterion 4.21 (Scheme 4.

12). Scheme 4.12 Proposed synthesis of 4.21.

  Molander et al. were the first to describe the alkylation of various substrates with 4.37.236 However, under standard reported conditions we could not detect the formation of desired product 4.38 (Table4.4, entry 1). Changing reaction conditions (i.e. solvent, base, temperature) generally had no effect on reaction transformations, at best trace amounts of 4.39 could be detected by MS. Attempts to drive the reaction forward by precipitation of halide salts (AgBr or KBr) were generally ineffective giving only trace yields of 4

.39 (Table 4 .4, entries

 4 2-5). No improvements were observed using strong bases KH and n-

	BuLi (

Table 4 .4, entries

 4 3 and 6). Using the more electrophilic potassium iodomethyltrifluoroborate(4.38) did not result in any improvement in conversions (

Table 4 . 4 ,

 44 entries 12-19). Additives, such as TBAI and 15-crown-5 were explored in attempts to increase solvation and reactivity of the intermediate phenoxide ion however, these additives had no effect on reaction yields (Table4.4, entries3, 13 and 14).

	Chapter 4

Table 4 . 4

 44 Conditions tested for the alkylation of 2-aminophenol Similarly, attempts to alkylate 2-aminophenol with electrophilic bromo or iodomethylboronic acid pinacol ester did not work. The expected product 4.40 could not be detected by 11 B NMR spectroscopy or MS (Scheme 4.13).

	Entry X Solvent Base Temperature (°C)	Additive	4.39 formed?
	1	Br	THF	NaH	rt	-	no
	2	Br	THF	NaH	rt	AgOTf	no
	3	Br	THF	KH	rt	TBAI	no
	4	Br	THF	t-BuOK	50	AgOTf or AgOAc	trace
	5	Br	DMF	t-BuOK	50	AgOTf or AgOAc	trace
	6	Br	THF	n-BuLi	-78 to rt	-	no
	7	Br	DMF	NaH	90	-	trace
	8	Br Acetone K2CO3	reflux	-	no
	9	Br	THF	t-BuOK	rt	-	no
	10	Br	THF	t-BuOK	reflux	-	trace
	11	Br	DMF	t-BuOK	90	-	no
	12	I	THF	t-BuOK	rt	-	no
	13	I	THF	t-BuOK	rt	TBAI	no
	14	I	THF	NaH	rt	15-crown-5	no
	15	I	DMF	t-BuOK	rt	-	no
	16	I	THF	t-BuOK	reflux	-	no
	17	I	DMF	t-BuOK	50	-	no
	18 a	I	THF	t-BuOK	110	-	no
	19 a	I	DMF	t-BuOK	120	-	trace
	a pressure vial used.

Scheme 4.13 Failed alkylation using boronic ester.

Table 4 . 5

 45 Attempted alkylation of N-protected aminophenols 4.41 and 4.42 Given these results we sought to further deactivate the aromatic ring and chose to investigate the effect of substituting the amino group for nitro, which could be reduced back to the amine after alkylation. Gratifyingly, deprotonation of 2-nitrophenol with NaH in THF followed by the addition of trifluoroborate 4.37 and refluxing overnight allowed the We thought that heterogenous reduction of the nitro group by Pd/C and H2 would allow for a clean transformation and simplify reaction work-up. When MeOH was used as reaction solvent,

	Entry Substrate X Solvent	Base	Temperature (°C)	Additive	O-alkylated product?
	1	4.41	Br	THF	NaH	rt	-	no
	2	4.41	Br	THF	t-BuOK	reflux	-	trace
	3	4.41	I	Acetone	K2CO3	reflux	-	trace
	4	4.41	I	THF	NaH	reflux	-	no
	5	4.41	I	THF	NaH	rt	15-crown-5	no

recovery of mono O-alkylated trifluoroborate 4.43 in excellent yield (Scheme 4.16). Alkylation could also be achieved using bromomethylboronic acid pinacol ester to produce nitrobenzene derivative 4.44 with albeit lower yields (Scheme 4.16). Scheme 4.16 Synthesis of 4.43 and 4.44 by alkylation of 2-nitrophenol. Isolated yields. With 4.43 in hand, we turned towards optimising conditions for reduction of the nitrobenzene derivative into the corresponding aniline 4.39.

complete conversion of 4.43 was observed by TLC after 30 min, work-up of the reaction crude yielded 4.39 in 67% as a mixture of inseparable impurities observed by 1 H,

19 F and

Table 4 .

 4 6, entry 1). Degradation of 4.43 may arise from hydrolysis of the trifluoroborate to the boronic acid and eventual deborylation via transmetalation with Pd. We thought hydrolysis could be disfavoured in the presence of high concentrations of F -in the reaction medium. Consequently, when a homogenous solution of MeOH and saturated aqueous KHF2 (4.5 M) was used as the reaction solvent 4.39 could be cleanly isolated in quantitative yield (Table4.6, entry 2). When reaction pH was decreased to ~1 using 1N HCl, yields decreased and inseparable impurities were observed by 1 H,19 F and 11 B NMR spectroscopy (

Table 4 . 6

 46

, entry 3). Reduction was equally efficient in EtOH, however slightly longer reaction times were required for complete conversion (Table

4

.6, entry 4). Extended reaction times led to a decrease in yields, most probably due to Pd-mediated deborylation, therefore reaction mixtures need to be worked-up once complete conversion of starting material is determined.

Table 4 . 6

 46 Optimisation of parameters for the reduction of 4

.43 Entry Solvent Time (h) Yield (%)

	1 a	MeOH	0.5	67
	2	MeOH/aq. KHF2 (20:1)	1	99
	3 a	MeOH/aq. KHF2 + 1N HCl (10:1)	1	84
	4	EtOH/aq. KHF2 (10:1)	1.5	99

a product isolated with inseparable impurities.

  B NMR spectroscopy and MS (Table4.7, entry 1). Diazotization in organic solvents in the absence (Table4.7, entries 2-5) and presence of acid (entry 6) did not yield 4.21.However, conducting the diazotization at low temperature (-40 °C) in MeCN using p-TsOH as an acid was successful, although the desired product precipitated along with inseparable impurities (Table4.7, entry 7). Similar impurities were observed when isolation of the product was attempted by cold precipitation, impurities could not be

removed by Silica gel flash column chromatography; 4.21 was found to be stable under purification conditions (Table

4

.7, entry 8). During experiments, we had observed that t-BuONO, synthesized or purchased, was acidic (pH ~4-5) likely due to its slow hydrolysis into nitrous acid (HONO) and t-BuOH.

238

The presence of additional equivalents of acid (HONO) could be causing the observed impurities and degradation products. Gratifyingly, when t-BuONO was neutralized by basic aqueous wash then dried (anhydrous MgSO4) prior to use, 4.21 could be obtained cleanly after cold precipitation, albeit in moderate yield (Table

4

.7, entry 9).

Table 4 . 7

 47 Optimisation of parameters for the diazotization of 4.39 Et2O precipitation was conducted at rt, unless otherwise indicated. b precipitate contained 4.21 along with inseparable impurities. c attempted purification of precipitated crude by Silica gel flash chromatography.d t-BuONO washed with saturated aqueous NaHCO3 and dried over anhydrous MgSO4 immediately prior to use.

	Entry	Solvent	[NO] +	Acid	Temperature (°C) a	Yield (%)
	1	Water	NaNO2	KHF2/HCl	0	0
	2	THF	t-BuONO	-	0	0
	3	AcOH	t-BuONO	-	0	0
	4	1,4-dioxane	t-BuONO	-	0	0

a

Table 4 . 8

 48

	entries 13 and 16). 19 F NMR spectroscopy revealed a multiplet at -136.7 ppm which
	corresponds well with literature reports for 2-fluoroanisole at -135 ppm. 240,241 However,
	yields could not be improved by increasing reaction temperatures to 120 °C (entries 14

, entry 2). Similarly, low conversions with no fluorination products were also observed when more polar ethereal solvents were used (Table

4

.8, entries 5-8). Using HFIP resulted in 86% conversion of 4.21 without the formation of fluorinated products; significant deborylation producing BF4 -was observed by

19

F NMR spectroscopy (Table 4.8, entry 9). High stability was also observed in MeCN, where only 3% of 4.21 was converted (Table 4.8, entry 11). Ethylene glycol resulted in complete degradation of 4.21 (Table 4.8, entry 12). Given the low conversions observed at 45 °C we thought that elevated decomposition temperatures may encourage the fluorodediazoniation step to occur. Decomposition in toluene and 1,2-dichlorobenzene at 100 °C resulted in complete conversion of 4.21 accompanied by trace (~5%) yields of the desired 2-fluoroanisole derivative (Table 4.8, and 17). Conversely, in cyclohexane 4.21 displayed remarkable stability after 2h at 100 °C where only 24% conversion was observed (Table 4.8, entry 15). All other solvents Chapter 4 158 tested resulted in complete degradation of the starting material (Table 4.8, entries 18-23). Heating 4.21 neat resulted in complete conversion with only trace yield of the 2fluoroanisole derivative (Table 4.8, entry 24).

Table 4 . 8

 48 Decomposition conditions for intramolecular fluorination of 4.21

	Entry	Solvent	Temperature (°C)	Conversion of 4.21 (%) a	Yield of Ar-F (%) a
	1	Hexane	45	26
	2	Toluene	45	<1
	3	Cyclohexane	45	33
	4	1,2-dichlorobenzene	45	19
	5	Et2O	45	50
	6	THF	45	13
	7	1,4-dioxane	45	10
	8	1,2-dimethoxyethane	45	24
	9	HFIP	45	86
	10	t-BuOH	45	23
	11	MeCN	45	3
	12	Ethylene glycol	45	>99
	13	Toluene	100	>99
	14	Toluene	120	>99
	15	Cyclohexane	100	24
	16	1,2-dichlorobenzene	100	>99
	17	1,2-dichlorobenzene	120	>99

.39. 4.2.1.2.3 Discussion of results with 4.21

	Chapter 4
	Scheme 4.18 Resonance stabilization of 4.21.
	Generally, reactions at low temperatures resulted in low conversions of 4.21, decreased
	rates of dediazoniation could be explained by resonance stabilization of the diazonium
	cation (Scheme 4.18). 140,242
	160

F NMR spectroscopy (Scheme 4.17). Scheme 4.17 Attempted one-pot two step fluorination of 4

  detected after extended stirring at 0 °C, ambient temperatures and eventually heating. Additionally, all attempts to isolate and characterize 4.45 failed.

	Table 4.10 Effect of bromodimethylsulphonium bromide on bromofluorination of 4.22
	Entry Solvent	4.45 formation? a	Yield of fluorinated product (%) b
	1	CH2Cl2	yes	0
	2	CHCl3	yes	0
	3	CCl4	yes	0
	4	MeCN	yes	0

into cold reaction mixtures did allow the formation of 4.45 as observed by MS (Table 4.10, entries 1-4). However, no Chapter 4 164 fluorinated products were

  F NMR spectroscopy of crude reaction mixtures. In most cases, the major products detected were results of complete bromination of the alkene and deborylation. As stated above for studies with 4.21, we cannot exclude BF4 -as the fluorine source for trace yields observed.

		Chapter 4
	4.2.1.4	Synthesis and fluorination studies of styrene oxide derivative 4.23
	As alkene activation, via a halonium ion failed, efforts were focused towards the more
	stable epoxide derivative. Potassium 2-(oxiranyl)phenyltrifluoroborate (4.23) was
	obtained in excellent yield via epoxidation of styrene derivative 4.22 using
	dimethyldioxirane (DMDO), applying reaction conditions reported by Molander et al.
	With these observations we conclude that 4.22 is not a suitable substrate for
	intramolecular halofluorination.
		165

(Scheme 4.22). 243 Scheme 4.22 Epoxidation of 4.22 to 4.23 using DMDO.

Table 4 .

 4 11 Conditions tested for activator-free intramolecular fluorination of 4.23

	consistent with literature values for 2-fluoro-2-phenylethanol (-187 ppm). 221 Thermolysis
	in high-boiling solvents resulted in significant starting material degradation, evidenced by
	deborylation to BF4 -, without the formation of fluorinated products (Table 4.11, entries 23-
	27).

F NMR spectrum (Table 4.11, entry 16

), -as observed by

19

F NMR spectroscopy. The use of Brønsted and Lewis acids for epoxide activation led to starting material degradation via deborylation.

With these observations, we conclude that 4.23 is not a suitable substrate for intramolecular fluorination of epoxides.

data for 4.21 -4.44

	2'-bromo-[1,1'-biphenyl]-2-amine (4.24)
	A 35 mL pressure vial was charged with a stir bar, 2-iodoaniline (442.6 mg, 2 mmol), 2-
	bromophenylboronic acid (482.8 mg, 2.4 mmol), NaHCO3 (532.5 mg, 6 mmol), Pd(PPh3)4

Phthaloyl-2-aminophenol (4.41)

	Chapter 4 Experimental Section
	mL) followed by brine (3 x 100 mL). The organic solution was then dried over anhydrous
	Na2SO4, then filtered and concentrated under reduced pressure to furnish a light pink
	solid (1.6717 g, 35%). IR νmax/cm -1 (neat film): 3377, 1698, 1684, 1223, 1192, 719. 1 H
	NMR (300 MHz, DMSO-d6) δ 9.85 (s, 1H), 7.99 -7.88 (m, 4H), 7.31 (ddd, J = 8.1, 7.3,
	1.7 Hz, 1H), 7.26 (dd, J = 7.8, 1.7 Hz, 1H), 6.99 (dd, J = 8.2, 1.3 Hz, 1H), 6.92 (td, J =
	7.6, 1.3 Hz, 1H). 13 C NMR (75 MHz, DMSO-d6) δ 167.2 (Cq), 154.0 (Cq), 134.6 (CH),
	131.9 (Cq), 130.4 (CH), 130.4 (CH), 123.3 (CH), 119.1 (CH), 118.9 (Cq), 116.6 (CH).
	HRMS-ESI (m/z): found [M-H] -238.0506, calc'd C14H8NO3 -requires 238.0504.
	A 250 mL round-bottom flask was charged with a stir bar, 2-aminophenol (2.1831 g, 20
	mmol), phthalic anhydride (2.9622 g, 20 mmol), AcOH (100 ml) and a condenser. The
	180

F NMR spectroscopy. The reaction had developed a white precipitate (KBr) which was filtered out, and the filtrate concentrated to saturation under reduced pressure. Et2O (~150 mL) was added to induce precipitation of the desired product as a white crystalline powder. This was collected by filtration and further washed with Et2O then dried under high vacuum overnight (4.8052 g, 97%). IR νmax/cm -1 (neat film): 1398, 1163, 1073, 1056, 951, 930, 721.

1

H NMR (300 MHz, Acetone-d6) δ 1.87 -1.72 (m).

19

F NMR (282 MHz, Acetone-d6) δ -144.14 (qB).

11

B NMR (96 MHz, Acetone-d6) δ 2.66 (q, J = 50.7 Hz). MS-ESI (m/z): [M-K] -209. Spectroscopic data consistent with those previously reported.

236

N-

reaction mixture was vigorously stirred at reflux for 2 h after which it was allowed to cool to rt. The homogenous yellow solution was then dropped on cold water and extracted with CHCl3 (3 x 50 mL). The combined organic phases were then washed with water (1 x 100

  mL, 50 mmol) Chapter 4 Experimental Section 187 and dry CH2Cl2 (10 mL). The addition funnel was charged with Br2(2.56 mL, 50 mmol) and dry CH2Cl2 (10 mL). The reaction flask was cooled to 0 °C in an ice bath and stirred rapidly to which, the bromine solution was added dropwise over a periodof 30 min. With

	the addition of Br2 an orange precipitate was observed developing. After 4 h the orange
	precipitate was collected by filtration and washed with Et2O (4 x 20 mL) then left to dry
	under high vacuum to furnish a light orange powder (76%, 8.4860 g). IR νmax/cm -1 (neat
	film): 2983, 2902, 1417, 1308, 1035, 983. 1 H NMR (300 MHz, Chloroform-d) δ 2.63 (s).

5 Benzothiazole B-F n Complexes as Potential Bi-modal Imaging Agents for Alzheimer's Disease Alzheimer

  's Disease (AD), the leading cause of dementia, is of increasing concern in a rapidly growing and ageing world population. To date, no validated biomarkers have been identified for the diagnosis of AD, definitive proof is only available via histopathologic evidence at autopsy. A domain of intense research resides in the development of noninvasive imaging tools for early-detection of disease features. Most strategies have focused on PET and NIRF imaging tracers targeting the amyloid-β (Aβ) peptide. To date, the development of bi-modal imaging tools has remained somewhat limited and is of considerable interest. This chapter will briefly introduce AD, its main molecular features

Table 5 .

 5 Measured using 9,10-diphenylanthracene as a reference (ΦF = 0.97 in cyclohexane). b Stokes shift. c λexc = 366. d λexc = 373. e λexc = 368.

		Solvent	λabs(max) (nm)	ε (10 3 M -1 cm -1 )	λem (nm)	ΦF a	Δss (nm) b
	5.11	CH2Cl2	336	15.8	519	-	183
	5.17	CH2Cl2	355	12.6	419	0.50 c	64
	5.17	THF	364	20.0	423	-	59
	5.17	MeCN	359	15.8	422	-	63
	5.12	CH2Cl2	344	15.8	531	-	187
	5.18	CH2Cl2	370	15.8	432	0.58 d	62
	5.18	THF	357	50.1	436	-	79
	5.18	MeCN	363	25.1	436	-	73
	5.15	CH2Cl2	339	15.8	513	-	174
	5.19	CH2Cl2	361	31.6	512	0.10 e	151
	5.19	THF	360	20.0	514	-	154
	5.19	MeCN	356	20.0	527	-

1 Photophysical properties of 5.11, 5.12, 5.15 and 5.17-5.19 a

  700. 1 H NMR (400 MHz, Chapter 5 Experimental Section 244 Chloroform-d) δ 7.85 (d, J = 8.6 Hz, 2H), 6.63 (d, J = 8.6 Hz, 2H), 4.31 (q, J = 7.1 Hz, 2H), 4.03 (bs, 2H) 1.35(t, J = 7.1 Hz, 3H).13 C NMR (101 MHz,

	(Cq), 150.9 (Cq), 131.6 (CH), 120.1 (Cq), 113.9 (CH), 60.4 (CH2), 14.5 (CH3). MS-
	DCI(NH3) (m/z): 166 [M+H] + . Anal. calc'd for C9H11NO2:

  The mixture was allowed to stir at rt for 10 minutes at which point BF3•OEt2 (502.4 μL, 4 mmol) was added; evolving a white precipitate. The mixture was allowed to stir at rt for 12 hours. The mixture was then dropped onto excess pentane, causing further evolution of a white precipitate. The precipitate was collected by filtration, washed with

	Chapter 5 Experimental Section
	6,6-difluoro-10-methyl-6H-benzo[e]benzo[4,5]thiazolo[3,2-c][1,3,2]oxazaborinin-7-
	ium-6-uide (5.17)
	A 10 mL round bottom flask was charged with a stir bar, 2-(2-hydroxyphenyl)-6-
	methylbenzothiazole (239.2 mg, 1 mmol), dry CH2Cl2 (10 mL) and DIPEA (216.5 μL, 1.5
	mmol).
	748. 1 H NMR
	(300 MHz, Acetone-d6) δ 8.03 (dq, J = 5.8, 3.6 Hz, 1H), 7.68 (dd, J = 8.0, 1.5 Hz, 1H),
	7.50 (dd, J = 4.6, 0.8 Hz, 2H), 7.28 -7.10 (m, 3H), 6.95 (bs, 2H), 6.91 -6.83 (m, 2H),
	6.74 (td, J = 7.4, 1.2 Hz, 1H), 6.66 (ddd, J = 8.1, 7.1, 1.2 Hz, 1H), 4.46 (bs, 2H). 13 C NMR
	(75 MHz, Acetone-d6) δ 156.5 (Cq), 152.6 (Cq), 148.8 (Cq), 146.4 (Cq), 134.9 (Cq), 134.6
	(Cq), 132.5 (CH), 131.9 (CH), 130.7 (CH), 129.5 (CH), 128.4 (CH), 126.2 (CH), 125.4 (Cq),
	121.6 (CH), 117.8 (CH), 117.5 (CH), 116.9 (CH), 116.4 (CH), 114.9 (Cq). HRMS-ESI
	(m/z): found [M+H] + 318.1062, calc'd C19H16N3S + requires 318.1065.
	258

ray Data Tables (2,4,6-trimethylphenyl)(phenyl)iodonium phenyltrifluoroborate (3.20)Table 1 .

 1 C NMR Crystal data and structure refinement for OS-6-058.

	(2-thienyl)(phenyl)iodonium tetrafluoroborate (3.18) 19 F NMR (2,4,6-trimethylphenyl)(phenyl)iodonium bromide (3.19) 19 F NMR (2,4,6-trimethylphenyl)(phenyl)iodonium phenyltrifluoroborate (3.20) 19 F NMR (4-methoxyphenyl)(2,4,6-trimethylphenyl)iodonium phenyltrifluoroborate (3.21) 19 F NMR (4-cyanophenyl)(2,4,6-trimethylphenyl)iodonium phenyltrifluoroborate (3.22) 19 F NMR (2,6-difluorophenyl)(2,4,6-trimethylphenyl)iodonium phenyltrifluoroborate (3.23) 19 F NMR (2,6-difluorophenyl)(phenyl)iodonium phenyltrifluoroborate (3.24) 19 F NMR (4-methoxyphenyl)(phenyl)iodonium phenyltrifluoroborate (3.25) 19 F NMR (2-thienyl)(phenyl)iodonium tetrafluoroborate (3.26) 19 F NMR
	1 H NMR 1 H NMR 1 H NMR 1 H NMR 1 H NMR 1 H NMR 1 H NMR 1 H NMR 1 H NMR
	13 C NMR 11 B NMR 13 C NMR 11 B NMR 13 C NMR 11 B NMR 13 C NMR 11 B NMR 13 C NMR 11 B NMR 13 C NMR 11 B NMR 13 C NMR 11 B NMR 13 C NMR 13 C NMR 11 B NMR 11 B NMR
	396 397 398 399 400 401 402 403 404 405 406 407 408 409 410 411 412 413

414

X-

Table 3 .

 3 Bond lengths [A] and angles [deg] for OS-6-058. _____________________________________________________________

Table 4 .

 4 Anisotropic displacement parameters (A^2 x 10^3) for OS-6-058. The anisotropic displacement factor exponent takes the form: -2 pi^2 [ h^2 a*^2 U11 + ... + 2 h k a* b* U12 ] ___________________________________________________________________

	U11	U22	U33	U23	U13	U12
	___________________________________________________________________
	C(1) 25(1)	20(1)	28(1)	-2(1)	-3(1)	2(1)
	C(2) 26(1)	26(1)	56(2)	2(1)	-2(1)	-1(1)
	C(3) 22(1)	37(1)	76(2)	6(1)	5(1)	0(1)
	C(4) 25(1)	32(1)	59(2)	-1(1)	2(1)	7(1)
	C(5) 30(1)	23(1)	46(1)	-2(1)	-1(1)	3(1)
	C(6) 25(1)	24(1)	35(1)	-1(1)	-1(1)	2(1)

Table 2 .

 2 Atomic coordinates ( x 10^4) and equivalent isotropic displacement parameters (A^2 x 10^3) for map. U(eq) is defined as one third of the trace of the orthogonalized Uij tensor.

	________________________________________________________________
		x	y	z	U(eq)
	________________________________________________________________
	C(1')	8311(

Table 4 .

 4 Anisotropic displacement parameters (A^2 x 10^3) for map. The anisotropic displacement factor exponent takes the form: -2 pi^2 [ h^2 a*^2 U11 + ... + 2 h k a* b* U12 ]

	_______________________________________________________________________
		U11	U22	U33	U23	U13	U12
	_______________________________________________________________________
	C(1')	14(1)	13(1)	13(1)	2(1)	0(1)	-1(1)
	C(1")	12(1)	21(1)	20(1)	0(1)	-2(1)	3(1)
	C(2)	14(1)	9(1)	9(1)	0(1)	-2(1)	0(1)
	C(2')	15(1)	12(1)	10(1)	-2(1)	0(1)	-1(1)
	C(3')	15(1)	14(1)	16(1)	1(1)	1(1)	-2(1)
	C(3A)	13(1)	9(1)	9(1)	-1(1)	-1(1)	1(1)
	C(4)	14(1)	11(1)	12(1)	1(1)	1(1)	-1(1)
	C(4')	16(1)	17(1)	19(1)	1(1)	2(1)	-4(1)
	C(5)	12(1)	14(1)	13(1)	1(1)	1(1)	-2(1)
	C(5')	13(1)	22(1)	18(1)	-1(1)	0(1)	0(1)
	C(6)	13(1)	14(1)	11(1)	-2(1)	0(1)	1(1)
	C(6')	15(1)	19(1)	18(1)	2(1)	-1(1)	2(1)
	C(7)	16(1)	12(1)	12(1)	0(1)	-1(1)	2(1)
	C(7A)	13(1)	10(1)	10(1)	0(1)	0(1)	-2(1)
	C(10')	16(1)	13(1)	12(1)	-1(1)	-1(1)	-1(1)
	C(10")	17(1)	19(1)	21(1)	0(1)	3(1)	3(1)

Table 2 .

 2 Atomic coordinates ( x 10^4) and equivalent isotropic displacement parameters (A^2 x 10^3) for omar2. U(eq) is defined as one third of the trace of the orthogonalized Uij tensor.

	________________________________________________________________
		x	y	z	U(eq)
	________________________________________________________________
	C(1")	2468(1)	-1016(1)	2319(1)	26(1)
	C(2")	2230(2)	-1937(1)	2552(1)	32(1)
	C(3")	2916(2)	-2720(1)	2353(1)	36(1)
	C(4")	3851(2)	-2588(1)	1926(

Table 3 .

 3 Bond lengths [A] and angles [deg] for omar2.

	_____________________________________________________________
	C(1")-O(1')	1.3656(16)
	C(1")-C(2")	1.3897(19)
	C(1")-C(6")	1.4002(19)
	C(2")-C(3")	1.383(2)
	C(2")-H(2B)	0.9500
	C(3")-C(4")	1.381(2)
	C(3")-H(3B)	0.9500
	C(4")-C(5")	1.382(2)
	C(4")-H(4B)	0.9500
	C(5")-C(6")	1.3942(19)
	C(5")-H(5B)	0.9500
	C(6")-C(4)	1.4840(19)
	C(4)-C(5)	1.3899(19)
	C(4)-C(3A)	1.4055(18)
	C(

Table 4 .

 4 Anisotropic displacement parameters (A^2 x 10^3) for omar2. The anisotropic displacement factor exponent takes the form: -2 pi^2 [ h^2 a*^2 U11 + ... + 2 h k a* b* U12 ]

	_______________________________________________________________________
		U11	U22	U33	U23	U13	U12
	_______________________________________________________________________
	C(1")	30(1)	24(1)	23(1)	-1(1)	2(1)	3(1)
	C(2")	40(1)	28(1)	28(1)	3(1)	4(1)	-2(1)
	C(3")	53(1)	23(1)	32(1)	1(1)	-6(1)	2(1)
	C(4")	49(1)	32(1)	29(1)	-5(1)	-5(1)	15(1)
	C(5")	32(1)	39(1)	23(1)	-2(1)	0(1)	9(1)
	C(6")	26(1)	28(1)	19(1)	0(1)	-2(1)	2(1)
	C(

Table 3 .

 3 Bond lengths [A] and angles [deg] for os-2-127_a.

	_____________________________________________________________
	C(3")-C(2")	1.500(2)
	C(3")-H(3B)	0.9800
	C(3")-H(3C)	0.9800
	C(3")-H(3D)	0.9800
	C(2")-O(3)	1.4466(18)
	C(2")-H(2A)	0.9900
	C(2")-H(2B)	0.9900
	C(1")-O(2)	1.2123(17)
	C(1")-O(3)	1.3339(17)
	C(1")-C(6)	1.494(2)
	C(6)-C(7)	1.386(2)
	C(6)-C(5)	1.4115(19)
	C(7)-C(7A)	1.3957(19)
	C(

Table 4 .

 4 Anisotropic displacement parameters (A^2 x 10^3) for os-2-127_a.

	The anisotropic displacement factor exponent takes the form:
	-2 pi^2 [ h^2 a*^2 U11 + ... + 2 h k a* b* U12 ]
	_______________________________________________________________________
		U11	U22	U33	U23	U13	U12
	_______________________________________________________________________
	C(3")	58(1)	17(1)	22(1)	1(1)	4(1)	1(1)
	C(2")	30(1)	13(1)	17(1)	-3(1)	3(1)	0(1)
	C(1")	14(1)	16(1)	17(1)	-1(1)	3(1)	1(1)
	C(6)	12(1)	16(1)	15(1)	-1(1)	2(1)	1(1)

Table 2 .

 2 Atomic coordinates ( x 10^4) and equivalent isotropic displacement parameters (A^2 x 10^3) for test2_a. U(eq) is defined as one third of the trace of the orthogonalized Uij tensor.

	________________________________________________________________
	x	y	z	U(eq)
	________________________________________________________________

Table 4 .

 4 Anisotropic displacement parameters (A^2 x 10^3) for test2_a. The anisotropic displacement factor exponent takes the form: -2 pi^2 [ h^2 a*^2 U11 + ... + 2 h k a* b* U12 ]

	_______________________________________________________________________
		U11	U22	U33	U23	U13	U12
	_______________________________________________________________________
	C(2)	17(1)	16(2)	21(2)	-4(1)	11(1)	-3(1)
	N(3)	17(1)	18(1)	15(1)	-1(1)	7(1)	-2(1)
	S(1)	23(1)	23(1)	23(1)	-1(1)	14(1)	1(1)
	C(4)	22(2)	20(2)	20(2)	-1(1)	9(1)	-2(1)
	C(5)	29(2)	34(2)	22(2)	6(1)	8(1)	7(2)
	C(6)	45(2)	37(2)	17(2)	7(1)	12(2)	9(2)
	C(7)	42(2)	27(2)	21(2)	0(1)	19(2)	5(2)
	C(7A)	24(2)	20(2)	22(2)	1(1)	13(1)	1(1)
	C(3A)	21(2)	19(2)	15(1)	-1(1)	10(1)	-3(1)
	C(2')	15(1)	19(2)	23(2)	-1(1)	5(1)	-5(1)
	C(1')	25(2)	24(2)	23(2)	0(1)	5(1)	3(1)
	C(6')	35(2)	38(2)	22(2)	-1(2)	4(2)	3(2)
	C(5')	31(2)	38(2)	30(2)	7(2)	-5(2)	-1(2)
	C(4')	22(2)	37(2)	42(2)	4(2)	1(2)	2(2)
	C(3')	21(2)	33(2)	33(2)	-3(2)	7(1)	0(1)

B NMR(96 MHz, J = 54.8, 54.4 Hz). HRMS-ESI (m/z): found [M-H] -201.1049, calc'd C9H12 10 BF3N -requires 201.1049.

F NMR (282 MHz, DMSO-d6) δ -128.1 (s), δ (lit) -128.0 (s). Spectroscopic data matches reports in the literature.173

la transformation reste limitée par les conditions de réaction dures, de faibles rendements et la nécessité d'isoler les intermédiaires potentiellement explosifs. Bien que plusieurs améliorations aient été apportées au fil des ans et que de multiples sources de fluor aient été étudiées, l'utilisation des organotrifluoroborates comme médiateurs de cette réaction s'est limitée à un seul rapport. Schéma 7.1 La réaction Balz-Schiemann. Afin de révéler le potentiel des organotrifluoroborates en tant que sources F -, nous avons démontré qu'ils pouvaient médier la fluorodediazoniation en solution avec des sels d'aryle diazonium préformés (Schéma 7.2). Schéma 7.2 Fluoration du sel d'aryle diazonium avec du phényltrifluoroborate.Cela a pu être étendu avec succès à un procédé en deux étapes évitant l'isolement des sels de diazonium potentiellement explosifs. Pour cela, plusieurs paramètres de réaction ont été étudiés.

Schéma 7.9 Abstraction du fluorure de 5.19 à la forme 5.33.

Schéma 7.10 Résumé de la réaction de Balz-Schiemann en deux étapes en un pot avec des organotrifluoroborates. Le chapitre 3 présente les résultats préliminaires des recherches sur les organotrifluoroborates en tant que sources F -dans la fluoration de sels de diaryliodonium dissymétriques. Les travaux ont principalement porté sur la synthèse, l'isolement et la caractérisation de sels de phényltrifluoroborate de diaryliodonium dissymétriques, qui n'ont pas été décrits précédemment (7 exemples). La fluoration de ces sels, en solution, a ensuite été étudiée (Schéma 7.11). Ces sels ont conduits à des fluorures d'aryles avec des rendements allant de faibles à excellent, et ce avec une sélectivité totale de l'introduction du fluor sur l'un des deux motifs aryles de l'iodonium. La sélectivité de la fluoration observée contrastait avec la distribution du produit prédite par le mécanisme accepté de fluoration asymétrique du sel de diaryliodonium avec F -, qui est sous le contrôle de Curtin-Hammett. Ces résultats suggèrent que la fluoration utilisant des organotrifluoroborates est soumise à un contrôle cinétique simple et que la fluoration résulte du transfert direct de F -phényltrifluoroborate et non de la libération de F -dans le milieu réactionnel.

Schéma 7.14 Abstraction du fluorure de 5.19.

B NMR

B NMR19 F NMR

F NMR

F NMR 1-tert-butyl-2-fluorobenzene, 2.13, using 2,4-dinitrofluorobenzene as the I.S.19 F NMR 1-tert-butyl-3-fluorobenzene, 2.14, using 2,4-dinitrofluorobenzene as the I.S.

F NMR 1-tert-Butyl-4-fluorobenzene, 2.15, using 2,4-dinitrofluorobenzene as the I.S.19 F NMR 1-fluoro-4-isopropylbenzene, 2.16, using 2,4-dinitrofluorobenzene as the I.S.

F NMR 1-fluoro-4-isopropylbenzene, 2.17, using 2,4-dinitrofluorobenzene as the I.S.19 F NMR3-fluoro-2-methylpyridine, 2.18, using 2,4-dinitrofluorobenzene as the I.S.

C NMR

H-19 F HMBC NMR

2-amino-6-methylbenzothiazole (5.1) 1 H NMR13 C NMR

C NMREthyl 2-aminobenzothiazole-6-carboxylate(5.2)

2-amino-4-methylbenzothiazole (5.5) 1 H NMR

2-amino-4-bromobenzothiazole(5.6)

Acknowledgements I would firstly like to express my sincere gratitude to my supervisors Prof. David M. Perrin and Dr. Emmanuel Gras. I would like to thank them for taking a chance on me and accepting me into their research groups. Their dedication towards their research programs and students is admirable and it has been a real privilege to observe and participate in. They have allowed me to freely explore chemistry, to make mistakes and most importantly to learn. They have been exceptional mentors, who have been supportive throughout this experience. It has been my pleasure to experience their creativity, enthusiasm and passion for chemistry and research. I would also like to sincerely thank my supervisory committee, Prof. Ed Grant, Prof. Jason Hein and Prof. Laurel Schafer. I am particularly grateful to Prof. Hein and Prof. Schafer for their time in reviewing this thesis and their useful comments. Their support throughout is greatly appreciated. None of this work would have been possible without the excellent support of exceptional people in the offices, shops and services of both institutions. I would particularly like to thank Isabelle Fabing for help with preparative chiral HPLC and Dr. Charles-Louis Serpentini for help with CD spectroscopy. Sincere thanks to our secretary at UBC Sheri Harbour for her tireless and amazing work. Sincere thanks to Catherine Stasiulis and Sandra Geminiano at our Human Resources and International Relations offices at UPS for all their help with cotutelle PhD contracts, visas and residency permits.

I would have not been able to finish this work without the financial support of the French Canada Research Fund (FCRF), they are gratefully acknowledged. Financial support from the Arnold By fellowship is also gratefully acknowledged.

We continued by synthesizing products of selective mono-arylation of 5.10, which was achieved by initial cross-coupling at the 2-position with concomitant release of iodide. We found that by lowering reaction temperatures to 90 °C selective arylation could be achieved while keeping the carbon-bromine bond at position-4 intact. As such, 2hydroxyphenylboronic acid and N-Boc-indole-2-boronic acid could be coupled to 5.10 furnishing 2-aryl-4-bromobenzothiazoles 5. 22 Coupling of 2-aminophenylboronic acid proved to be more challenging, as standard reaction conditions resulted in low yields (~50%) of the desired product, which unfortunately could not be separated from impurities. However, we found that employing XantPhos as a ligand allowed the clean isolation and high yield of 5.25, which was subsequently N-methylated (5.26) Additionally, 5.19 containing an asymmetric boron centre was synthesized as a racemic mixture of enantiomers, could be chirally resolved and the enantiomers characterised by CD spectroscopy; the enantiomers were found to be stable to racemization via inversion.

Finally, F -abstraction from 5.19 was demonstrated, with the formation of the corresponding borenium ion (Scheme 6.5), highlighting the possibility to perform 19 F- 18 F isotope exchange on this substrate. 3) 9484( 1) 5007( 1) 33( 1) C (2") 8219( 2) 8928( 1) 5953( 1) 21( 1) C(1") 8250( 2) 7544( 1) 6215( 1) 16( 1) C( 6) 7911( 2) 6771( 1) 5635( 1) 14( 1) C( 7) 8102( 2) 6089( 1) 6255( 1) 15(1) C(7A) 7814( 2) 5371( 1) 5700( 1) 13( 1) C(3A) 7315( 2) 5342( 1) 4557( 1) 13( 1) C( 4) 7122( 2) 6036( 1) 3941( 1) 16( 1) C( 5) 7427( 2) 6743( 1) 4485( 1) 15(1) C( 2) 7437( 2) 4033( 1) 4933( 1) 13( 1) C(2') 7271( 2) 3208( 1) 4684( 1) 14( 1) C (3') 7724( 2) 2622( 1) 5492( 1) 17( 1) C(4') 7472( 2) 1837( 1) 5218( 1) 20( 1) C (5') 6769( 2) 1626( 1) 4124( 1) 19( 1) C (6') 6335( 2) 2192( 1) 3316( 1) 18( 1) C(1') 6584( 2) 2989( 1) 3583( 1) 15( 1) B( 1) 6511( 2) 4358( 1) 2891( 1) 16( 1) N( 3) 7098( 2) 4578( 1) 4152( 1) 13( 1) O( 3) 7968( 2) 8140( 1) 5505( 1) 19( 1) O( 2) 8725( 2) 7621( 1) 7196( 1) 21( 1) O( 1) 6116( 2) 3523( 1) 2782( 1) 21( 1) F( 2) 4862( 1) 4784( 1) 2428( 1) 21( 1) F( 1) 8056( 1) 4572( 1) 2423( 1) 19(1) S( 1) 8017( 1) 4421( 1) 6231( 1