DEVELOPMENT OF TRANSION-METAL-CATALYZED C—S AND C—C CROSS-COUPLING REACTIONS

SADANANDA RANJIT

NATIONAL UNIVERSITY OF SINGAPORE

2011

Development of Transition-Metal-Catalyzed C—S and C—C Cross-Coupling Reactions

SADANANDA RANJIT (M. Sc., Chemistry, Indian Institute of Technology, Madras)

A Thesis Submitted for the Degree of Doctor of Philosophy

Department of Chemistry

National University of Singapore

2011

Acknowledgement i

ACKNOWLEDGEMENT

First of all, I gratefully and sincerely thank my advisor, Prof. Dr. Liu Xiaogang, for his encouragement and supervision throughout my PhD study. His valuable scientific advices, suggestions, and discussions, and his sincere never ending care make my graduation project successful. Being his first batch of student, I have learnt a lot from him apart from the scientific and good article writing skills. Very especially for reading and correcting almost everything I “produced”, thanks a lot Dr. Liu! I would also like to thank Dr. Zhongyu Duan for her assistance during first two years of my PhD studies. Her support and motivation for completing this thesis was priceless. She has always treated me as a friend/brother and helped me during my ups and downs in research and also in personal life. Without her support this thesis would not have been possible. I also express my gratitude to Prof. Dr. Kuo-Wei Huang and Mr. Richmond Lee for the fruitful and enjoyable collaborative work on mechanistic study of C―S Cross-Coupling reaction (Chapter 4) and hope we continue with such projects in future. I would also like to thank Prof. Dr. Pengfei Zhang who helped us understand the mechanism of decarboxylative C―S cross-coupling reactions. I thank to Dr. Changlong Jiang for his helps and supports. He provided palladium nanowires which are used for Suzuki coupling reaction (Chapter 6). My sincere gratitude also goes to Prof. Dr. Weiping Su for his valuable suggestions during our preparation of manuscript for publications. To successfully complete this work the contribution from technical and administrative part of the department was very important. I therefore thank Wong Lai Kwai, Lai Hui Ngee, Han Yanhui, Wong Chee Ping, Suriawati Binte Saad, Tan Geok Kheng and Lim May Lee for their excellent technical support and useful discussions. My gratitude also goes to all the past and present members in the Liu group, Dr. Jiang Changlong , Dr. Wang Feng, Dr. Duan Zhongyu, Dr. Deng Hong, Dr. Zhang Qian, Dr. Chandra Sekhar Rout, Dr. Debapriya Banerjee, Mr. Xue Xuejia, Ms. Wang Juan, Ms. Xu Wei, Mr. Wang Hongbo, Ms. Nguyen Thi Van Thanh, Ms. Zhang Wenhui, Mrs. Su Qianqian, Mr. Xie Xiaoji, Mr. Deng Renren, Mr. Du Guojun, Mr. Han Sanyang, for providing support and cordial atmosphere, which made my stay in the lab a pleasant one. All of them deserve great thanks for support, nice discussions concerning everything and for making my stay enjoyable in NUS. I was very lucky to have a smart person like Wang Feng as a labmate, who always be there to share with me the happiness and difficulties. The discussions with him were always enjoyable and useful as well. I am also thankful to Mr. Mir Mohammad Hedayetullah, Mrs. Jhinuk Gupta, Mr. Dipak Maity, Dr. Sudipta Samanta, Mr. Acknowledgement ii

Sandip Pasari, Mr. karthik sekar, Mr. Animesh Samanta, Mr. Anukul Jana, Mr. Ajoy Kapat, Mr. Vamsikrishna, Mr. Saravanan, Mrs. Kanimozhi, Mr. Sanjay Samanta, Mr. Krishnakanta Ghosh, Mr. Raj kumar Das, Mr. Hriday Bera, and Mr. Sudipta Saha for the help and contributions you all have made during these years. I would like to mention my appreciation to all of my previous teachers who educated me with great effort and patience to prepare me for the future. Perticularly, I am very greatful to Prof. T. Pradeep (Master thesis supervisor) and Prof. U. V. Varadaraju (Research project supervisor) for their trust, support and hand-on-training. I am also grateful to Mr. Arabinda Maity, Mr. Dipankar Sahoo, my teachers in high school for their trust, support and encouragement that stimulated my interest in chemistry. I am also thankful to my uncle, Mr. Bisweswar Pradhan whose continuous guidances and help through out the carrier in my education are worthwhile. There remain many unmentioned members whose work ethics, scientific inputs and friendship I deeply valued and I thank them all! I am grateful to all my family member and friends for their support and encouragements. Particularly, my deepest and most sincere gratitude goes to my paprents, Mr. Subimal Ranjit and Mrs. Sandhya Ranjit for their constant encouragement, unconditional support and endless love. The financial support from the National University of Singapore (NUS) is gratefully acknowledged.

iii

To my parents, this thesis is dedicated: Mr. Subimal Ranjit and Mrs. Sandhya Ranjit

Table of Contents iv

TABLE OF CONTENTS

ACKNOWLEDGEMENTS i TABLE OF CONTENTS iv SUMMARY vi LIST OF ABBREVIATIONS viii LIST OF FIGURES x LIST OF SCHEMES xiii LIST OF TABLES xiv

CHAPTER 1: GENERAL INTRODUCTION 1 1.1 Non-Metal-Mediated C―S bond formation 1 1.2 Transition metal-catalysed cross-coupling reactions 3 1.3 Motivation & objective of my research 16 1.4 Outline 18

CHAPTER 2: SYNTHESIS OF (Z)-VINYL SULFIDES BY COPPER CATALYSED DECARBOXYLATIVE C—S CROSS-OUPLING 20 2.1 Introduction 21 2.2 Results and Discussion 22 2.3 Mechanistic Considerations 30 2.4 Conclusion 32 2.5 Experimental Section 33

CHAPTER 3: COPPER-MEDIATED C―H ACTIVATION/C―S CROSS-COUPLING OF HETEROCYCLES WITH THIOLS 47 3.1 Introduction 48 3.2 Results and Discussion 50 3.3 Mechanistic Studies 59 3.4 Conclusion 68 3.5 Experimental Section 69 3.6 Computational Details 78

CHAPTER 4: DIRECT ARYLATION OF BENZOTHIAZOLES AND BENZOXAZOLES WITH ARYLBORONIC ACIDS 98 4.1 Introduction 99 4.2 Results and Discussion 101 4.3 Conclusion 115 Table of Contents v

4.4 Experimental Section 117

CHAPTER 5: NANOCONTACT-INDUCED CATALYTIC ACTIVATION IN PALLADIUM NANOPARTICLES 126 5.1 Introduction 127 5.2 Results and Discussion 129 5.3 Conclusion 143 5.4 Experimental Section 144

REFERENCES AND NOTES 148

CURRICULUM VITAE 171

APPENDIX 174

1H and 13C NMR spectra for all the compounds resulted in Chapter 2 174 1H and 13C NMR spectra for all the compounds resulted in Chapter 3 231 1H and 13C NMR spectra for all the compounds resulted in Chapter 4 269

Summary vi

Development of Transition-Metal-Catalyzed C—S and C—C Cross-Coupling Reactions

SUMMARY

The transition-metal-catalyzed carbon-carbon and carbon-heteroatom bond forming reactions are important and fundamental transformations in synthetic organic chemistry. These reactions have been widely used for a variety of cross-coupling reactions of aryl halides in the processes of C—C, C—N and C—S bond forming reactions. In this dissertation, we have developed new cross-coupling protocols for the synthesis of vinyl sulfides, benzothiazoles and benzoxazoles, using transition-metal-based catalysis. Furthermore, the mechanism of these cross-coupling reactions has also been investigated. Although numerous methods have been developed for the stereoselective synthesis of (E)-vinyl sulfides, it has been challenging to prepare Z-isomers. Chapter 2 describes a novel method for the synthesis of vinyl sulfides by the decarboxylative cross-coupling of arylpropiolic acids with thiols using copper(I) salts as catalysts. In the presence of CuI and

Cs2CO3, a number of thiols reacted with arylpropiolic acids to afford the corresponding vinyl sulfides in high yields with high stereoselectivity for Z-isomers. This work suggests the potential for broad generality and promotes an economically feasible route to large scale synthesis of vinyl sulfides without the need of organohalide reagents. Chapter 3 deals a general and highly efficient method for direct thiolation of heterocyclic C–H bond with thiols. Without the need of organohalide precursors, a variety of 2-thio-substituted benzothiazoles, imidazoles and indoles are synthesized in one step in the

presence of CuI, 2,2′-bipyridine, and Na2CO3. Both aliphatic and aromatic thiols are compatible with this method, resulting in the formation of corresponding cross-coupling heterocycles in good yields. In addition, we present detailed mechanistic investigations on the Cu(I)-mediated direct thiolation reactions. Both computational studies and experimental results reveal that the copper-thiolate complex [(L)Cu(SR)] (L: nitrogen-based bidentate ligand such as 2,2′-bipyridine; R: aryl or alkyl group) is the first reactive intermediate responsible for the observed organic transformation. Furthermore, our computational studies suggest a stepwise reaction mechanism based on a hydrogen atom abstraction pathway, which is more energetically feasible than many other possible pathways including β-hydride elimination, single electron transfer, hydrogen atom transfer, oxidative addition/reductive elimination and σ-bond metathesis. A new transition metal-catalyzed C―C bond-forming reaction between benzothiazoles (or benzoxazoles) and arylboronic acids is presented in Chapter 4. This new Summary vii method provides a simple means to access aryl-substituted benzothiazole and benzoxazole compounds, a task that otherwise requires several synthetic steps or harsh reaction conditions. Besides my main project on homogeneous catalysis, we have also studied the nanoparticle-based catalysis reactions. The synthesis and catalytic studies of novel palladium nanostructures assembled from small nanoparticles by a surfactant-templated method are described in Chapter 5. The nanomaterials were characterized by several techniques including XRD, SEM, and HRTEM, which reveal that these one-dimensional nanomaterials comprise high density nanocontacts of ~1 nm in contact length at the particle–particle interface. In contrast to palladium nanoparticles, the palladium nanowires exhibit enhanced catalytic activities towards C―C cross-coupling (e.g., Suzuki and Heck couplings) reactions under mild conditions. The recyclability of the nanowires for catalytic reactions has also examined and it has found that the catalysts exhibit essentially unaltered catalytic activity (~ 99%) over six recycles.

List of Abbreviations viii

LIST OF ABBREVIATIONS

Abbreviation Actual name

δ chemical shift λ wavelength σ sigma Δ heat µL micro liter Ar aryl br broad Bipy 2,2'-bipyridine BHE β-hydride elimination C celsius Calcd. calculated Conv conversion d doublet dd doublet of doublet DFT density functional theory DMEDA N1,N2-dimethylethane-1,2-diamine DMF dimethylformide DMSO dimethyl sulfoxide dppe 1,2-bis(diphenylphosphino)ethane EG ethylene glycol equiv equivalent eV electron volt Et ethyl g grams GC-MS gas chromatography-mass spectrometry h hours HAA hydrogen atom abstraction HATU O-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate HAT hydrogen atom transfer HR EIMS high resolution electron ionization mass spectroscopy Hz hertz iPr iso-propyl J coupling constant Kcal kilocalorie m multiplet MBT 2-Mercaptobenzothiazole Me methyl List of Abbreviations ix

MECP minimum crossing energy point mg milligram MHz mega Hertz mL milliliter mol molar mmol milli molar MS mass spectrometry, mass spectra Mw molecular weight m/z mass/charge NMP N-Methylpyrrolidone NMR nuclear Magnetic Resonannce OA oxidative addition PEG polyethylene glycol Ph phenyl Phenanthr 1,10-phenanthroline

PPh3 triphenylphosphine ppm parts per million PVP poly(N-vinyl pyrrolidone) q quartet quint quintet R organic substituents RA reductive elimination s singlet SEM scanning electron microscopy sept septet SET single electron transfer t triplet t time tBu tert-butyl TEA triethylamine TEM transmission electron microscopy temp temperature THF tetrahydrofuran TMEDA N1,N1,N2,N2-tetramethylethane-1,2-diamine v volume XPS X-ray photoelectron spectroscopy XRD X-ray diffraction

List of Figures x

LIST OF FIGURES

Figure 1.1: Phosphine ligands used in Pd-catalysed C―C cross-coupling reactions. 5

Figure 1.2: Bidentate phosphine ligands used in Pd-catalysed C―S bond formation. 11

Figure 2.1: (a) GC analysis of decarboxylative C―S Cross-Couplings of phenylpropiolic acid with 4-methoxybenzenethiol. (b) Corresponding mass spectra of the peaks shown in GC spectrum at 14.58 minute, confirming the high stereoselective formation of (Z)-(4-Methoxyphenyl)(styryl)sulfane with excellent yield. 24

Figure 3.1: Examples illustrating the significance of the 2-thio-1,3- benzothiazole scaffold. 49

Figure 3.2: Effect of ligand on the cross-coupling of benzothiazoles with thiols. Reaction conditions: 1a (1.0 mmol), 2a (1.5 mmol), CuI/ligand (1.0 equiv/1.0 equiv), Na2CO3 (2.5 equiv) in DMF (3 mL) at 100 oC for 24 h. 53

Figure 3.3: Synthesis of cathepsin-D analogues 56

Figure 3.4: 1H NMR characterizations in deteurated DMF confirming the failed attempt to the synthesis of the Cu-benzothiazole complex. (a) Room-temperature (~23 oC) 1H NMR spectrum of a solution containing the benzothiazole compound. (b) Room- temperature 1H NMR spectrum of a solution containing benzothiazole, 2,2′-bipyridine, CuI, and Na2CO3. (c) 1H NMR spectrum, obtained at 110 oC, of a solution in the presence of benzothiazole, 2,2′-bipyridine, CuI, and Na2CO3. 61

Figure 3.5: Schematic representation (energy vs reaction coordinate) of the Cu(I) mediated C―S cross-coupling reaction. 64

Figure 3.6: Optimized structure of transition states and intermediates showing key bond lengths. 66

Figure 3.7: Comparative control experiments showing the yield of the disulfide product for octanethiol oxidation reaction as a function of reaction time under pure oxygen and aerobic condition, respectively. The results show that the oxidation of octanethiol to disulfide product is facilitated by oxygen in the presence of copper. 67

Figure 4.1: Representative examples of aryl-substituted benzothiazoles and benzoxazoles in medicinal chemistry. 100

List of Figures xi

Figure 4.2: (a) GC Analysis of the cross-coupling reaction of benzothiazole with phenylboronic acid in the presence PdII/CuII catalyst under aerobic conditions. (b) The corresponding mass spectrum of the peak shown in GC spectrum at 13.56 min, confirming the formation of 2-phenylbenzothiazole in high yield. 103

Figure 4.3: Optimization of the reaction conditions with respect to the ligand. 106

Figure 4.4: (a) GC Analysis of the cross-coupling reaction of benzothiazole with phenylboronic acid in the presence PdII/CuII catalyst under aerobic conditions. (b) The corresponding mass spectrum of the peak shown in GC spectrum at 13.56 min, confirming the formation of 2-phenylbenzothiazole in high yield. 109

Figure 5.1: Control experiments for the synthesis of Pd MPNs as a function of PVP concentration. (a) SEM image of the Pd nanoparticles synthesized with 0.0025-mmol PVP. (Inset) TEM image of the as-synthesized particles. (b) SEM image of the reaction product obtained with 0.005-mmol PVP. (c) SEM image of the nanowires formed with optimum PVP concentration (0.01 mmol). 130

Figure 5.2: Characterization of Pd nanowires. (a) SEM image of the assynthesized nanowire. (b) High-magnification SEM image showing surface morphology of the nanowire. (c) X-ray powder diffraction pattern of the nanowire. (d) TEM image of a single Pd nanowire. (e) High-magnification TEM image of the nanowire shown in Fig. 1D. The space between neighboring particles is indicated by arrows. (f) XPS spectrum of the nanowire. 133

Figure 5.3: Pore-size distribution of the MPNs measuremed by Barrett- Joyner-Halenda analysis. 134

Figure 5.4: (a) Optical image of the reaction set-up for the room- temperature MPN-catalyzed Suzuki coupling between iodobenzene and phenylboronic acid in water. (b) Optical image of the reaction after 24 h. (c) TEM image of a recovered catalytic nanowire from the Suzuki reaction. (d) High- magnification TEM image of the nanowire shown in Figure 6.4c. 136

Figure 5.5: (a) Formation of biphenyl product in ethanol as a function of time at room temperature by different catalysts including Pd nanowires, Pd nanoparticles, Pd foil, commercial Pd/C particles, and Pd(OAc)2. The data points (average of two runs) were derived by acquiring the biphenyl absorption band (centered at 247 nm) for aliquot samples taken from the reaction at different time intervals. (b) Linear regression plot for the determination

List of Figures xii

of the observed rate constants kobs. The values were determined from a ln plot of the change in iodobenzene concentration versus time for respective reactions. 141

List of Schemes xiii

LIST OF SCHEMES

Scheme 1.1: Non-Metal-Mediated preparation of aryl sulfides. 2

Scheme 1.2: Palladium catalyzed C―C and C-heteroatom bond formations. 6

Scheme 1.3: The generally accepted catalytic cycle of C―C cross-coupling reactions. 8

Scheme 1.4: Preparation of palladium thiolato aryl complexes and its dissociation to aryl sulfides. 9

Scheme 1.5: General mechanism for the palladium-catalyzed C―S bond forming reactions. 12

Scheme 2.1: Proposed Mechanism. 31

Scheme 3.1: Classical routes for the synthesis of 2-arylthiobenzothiazoles. 49

Scheme 3.2: Working hypothesis. 60

Scheme 3.3: Control experiments supporting the formation of thio- substituted benzothiazole via path B. 61

Scheme 3.4: Plausible Ullmann type reaction pathways: single electron transfer (SET), hydrogen atom transfer (HAT), and σ-bond metathesis, and oxidative addition/reductive elimination (OA/RE). 62

Scheme 3.5: Proposed reaction mechanism. 64

Scheme 4.1: Proposed mechanism for the arylation of benzothiazole via C―H activation. 111

Scheme 4.2: Scaled-up phenylation of benzothiazole 1a (5 mmol) in the presence of 2a (10 mmol), Pd(OAc)2 (5 mol%), Cu(OAc)2 (10 mol%), 1,10-phenanthroline (30 mol%) and K3PO4 (15 equiv) in DMSO at 100 oC under aerobic conditions. Product 3a was isolated in 80 % yield. 116

Scheme 5.1: A schematic illustration of formation of Pd nanocontacts and nanowire growth. 131

Scheme 5.2: Proposed catalytic cycle for the coupling reaction between aryl halides and phenylboronic acids in the presence of Pd MPNs. The dotted cycles shown in the scheme indicate grain boundaries that are possible active sites for the catalytic reaction. 142

List of Tables xiv

LIST OF TABLES

Table 2.1: Decarboxylative C―S cross-coupling under different conditions. 23

Table 2.2: Decarboxylative C―S cross-couplings of phenylpropiolic acid with different concentrated 4-methoxybenzenethiol. 25

Table 2.3: Decarboxylative coupling of phenylpropiolic acid with thiols. 27

Table 2.4: Decarboxylative coupling of substituted phenylpropiolic acids with thiols. 29

Table 3.1: Optimization of the C―S cross-coupling of benzothiazole with 4-methoxythiophenol. 51

Table 3.2: CuI/Bipy-mediated direct thiolation of benzothiazole with thiols. 55

Table 3.3: Scope of heteroarene coupling partners. 58

Table 3.4: Effect of atmosphere on the cross-coupling reactions. 67

Table 4.1: Reaction condition screening for the direct arylation of benzothiazole with phenylboronic acid. 102

Table 4.2: Optimization of the reaction conditions with respect to the [Cu] source. 105

Table 4.3: Influence of atmosphere on the yield of 3a. 108

Table 4.4: Reduction Direct arylation of benzothiazole 1a with various arylboronic acids 2b-2k. 113

Table 4.5: Direct arylation of benzoxazole 1b with various arylboronic acids 2a-2k. 114

Table 5.1: Palladium nanowire-catalyzed Suzuki coupling of aryl halides and henylboronic acids at room temperature. 137

Table 5.2: Palladium nanowire-catalyzed Heck coupling of aryl halides and alkenes. 139

Table 5.3: Recycling test of the Pd nanowires for room-temperature Suzuki coupling. 139

Chapter 1: General Introduction 1

CHAPTER 1: GENERAL INTRODUCTION

The formation of carbon―sulfur bond is one of the most essential organic transformations in synthetic organic chemistry due to it’s prevalence in many molecules that are of pharmaceutical, biological, and materials interest.1-5 For example, a large number of aryl sulfides are used for various clinical applications such as the treatment of

Alzheimer’s and Parkinson’s diseases,6,7 treatment of cancer,8 and treatment of human immunodeficiency virus diseases.9 Furthermore, aryl sulfides sever as a starting material for the synthesis of heterocycles, and for the chemical synthesis of many interesting molecules.10,11

1.1 Non-Metal-Mediated C―S bond formation

Non metal mediated routes for the synthesis for aryl sulfides involves anti-

Markovnikov addition of aryl thiols on alkene, by nucleophilic aromatic substitutions of an activated aromatic halides, by Sandmeyer-type reaction of diazonium salts with thiols, and by Leuckert thiophenol reaction of aryl diazonium salt with a potassium alkyl xanthate (Scheme 1.1).12-15 However, due to the harsh reaction conditions required by these methods (e. g. strong acid or base, and high reaction temperatures,) and the lack of obtaining high regioselectivity make these methods unsuitable for preparing certain target molecules.

These limitations have led to the development of new complementary methods based on transition-metal-catalyzed cross-coupling reactions between thiols or disulfides and aryl halides. The newer copper and palladium based methodologies allow for the rapid, direct and efficient preparation of a wide variety of S-aryl compounds under that are mild enough to tolerate sensitive functional groups.

Chapter 1: General Introduction 2

Scheme 1.1: Non-Metal-Mediated preparation of aryl sulfides.

Chapter 1: General Introduction 3

1.2 Transition metal-catalyzed cross-coupling reactions

The use of transition-metals as catalysts has brought a dramatic revolution in synthetic organic chemistry. Since the discovery of the Ni-catalyzed reaction of Grignard reagents with alkenyl or aryl halides in 1972,16,17 the transition metal-catalyzed cross- coupling reactions of organometallics or organic reagents with organic halides or related electrophiles have been developed as a powerful synthetic tool for a wide range of C―C,

C―S, C―N, and C―O bond forming processes.18-21 The importance of the cross- coupling reactions is steadily growing due to their mild reaction conditions, and making them compatible with a wide variety of functional groups. These recently developed transition metal-catalyzed cross-coupling reactions provide a revolutionary method to access aryl-aryl/alkyl and aryl/alkenyl-heteroatom bonds which are often difficult and sometimes impossible to form by other methods.

1.2.1 Palladium-catalyzed C―C and C―S bonds formation

Of the metals that have been used in cross-coupling reactions, palladium stands out both as the most often used and general of these, which can be partially, attributed to its ability for the formation of a large variety of C―C and C―heteroatom bonds (scheme

1.2. eq. 1). Organometallic complexes derived from the palladium exhibit a variety of reactivity patterns such as 1,1-, 1,2- insertion, transmetallation, β- hydride elimination, and reductive elimination.22 Various combinations of these individual steps constitute a catalytic cycle in which organic substrate undergoes to desired transformation and palladium catalyst is regenerated. The palladium catalyzed reactions are highly functional group tolerant. For example, heteroatoms (-SR, -NR2, -OR), carbonyl groups (-COR, -

COOR), and acidic and basic functional groups are tolerated without the needed for

Chapter 1: General Introduction 4 protecting groups.22 In addition, organopalladium complexes are fairly stable and non- toxic, which explain the recent development of efficient industrial processes including palladium-promoted steps. The commercial availability of palladium precatalysts along with the development of new phosphine ligands further facilitates the use of Pd-catalyzed reactions. In the palladium catalyzed reaction the most popular palladium precursors used are Pd(PPh3)4, PdCl2(dppf), Pd2(dba)3, PdCl2(PPh3)2, PdCl2, Pd(OAc)2, and PdCl2(RCN)2.

The most frequently used ligand is triphenylphosphine. However, a number of new ligands, which have different steric and electronic effects, have been designed and synthesized to attain high catalyst efficiency or selectivity and to expand the reaction scope (Figure 1.1).

Cross-coupling reactions are usually classified according to the nature of the organometallic substrate applied and are often named after their discoverers (scheme 1.2).

The most important instances include the Grignard cross-coupling (or Kumada coupling,

M = Mg),23 the Suzuki-(M = B),24,25 the Stille-(M = Sn),26 the Negishi-(M = Zn)27 and the

Hiyama reaction (M = Si).28-30 These reactions are often employed for C―C bond formation. Sonagashira31 and Tuji-Trost22,32,33 cross-coupling reactions are also used for the C―C bond forming reaction. In these two methods, the carbon nucleophiles generated in situ by mixing a base and active C―H containing compounds such as terminal alkynes (Sonagashira) and carbonyl compounds (Tuji-Trost). This direct coupling of active C―H with organic halides has a significant advantage in that the need of the synthesis of organometallic starting materials would be eliminating, thereby making the synthetic schemes shorter and more efficient. Similarly, heteroatom―H

Chapter 1: General Introduction 5

Figure 1.1: Phosphine ligands used in Pd-catalysed C―C cross-coupling reactions.

Chapter 1: General Introduction 6

Scheme 1.2: Palladium catalyzed C―C and C―heteroatom bond formations.

Chapter 1: General Introduction 7 compounds containing S―H, N―H, and O―H directly couple with organic halides in the presence of a base and transition metal-catalyst to form C―S,34,35 C―N,36 and

C―O37,38 bonds respectively. These recently developed cross-coupling reactions have been used as a regular basis in industries as well as in academic research laboratories.

The general accepted mechanism for palladium catalyzed cross-coupling involves three main elementary processes39 (Scheme 1.3), which are: (1) Oxidative addition of an electrophile, typically an organic halide (mostly iodides and bromides, rarely chlorides) or triflate to a Pd(0) species to form the corresponding Pd(II) complex. (2)

Transmetallation of an (organometallic) nucleophilic coupling partner to this complex. (3)

Reductive elimination to yield the cross-coupling product together with the starting Pd(0) complex that can re-enter the catalytic cycle.

While palladium based catalysts have been utilized extensively for C―C bond forming reactions (sp2-sp2, sp2-sp, sp2-sp3), very few reports of the analogous C―S bond forming reactions had appeared in the literature. This is mainly due to the two reasons; first, thiols are readily undergo to oxidative S―S coupling reactions, resulting in the formation of undesired disulfides byproduct, and second, thiols have strong affinity to bind with metal centre, which lead to catalyst deactivation. In 1978 and 1980 Migita and coworkers reported the first palladium-catalyzed C(aryl)―S bond formation from the corresponding aryl halides and thiols (eq. 2).40,41 This original report represented a significant and untouched advanced in the literature until the mid 1990’s when Hartwig’s

Chapter 1: General Introduction 8

Scheme 1.3: The generally accepted catalytic cycle of C―C cross-coupling reactions.

Chapter 1: General Introduction 9 group reported the preparation of palladium thiolato aryl complexes [(DPPE)Pd(SR)(Ar)] that undergo reductive elimination of alkyl aryl sulfides (Scheme 1.4).42,43 From then on, palladium-catalyzed C―S bond formation received particular interests.

Scheme 1.4: Preparation of palladium thiolato aryl complexes and its dissociation to aryl sulfides.

Following Hartwig’s mechanistic studies on the reductive elimination of palladium(II) arylthiolate complexes with chelating phosphines, in 1998, Zheng and co- workers44 developed the first general palladium-catalyzed synthesis of aryl sulfides from aryl triflates and alkyl thiols (eq. 3). This protocol further expands the scope of palladium-catalyzed formation of carbon-heteroatom bonds and provides mild conditions for the conversion of phenols to alkyl aryl sulfides via aryl triflates.

After the initial discovery of the Pd/Tol-BINAP catalyst system for the C―S bond forming reactions, it was found that bidentate phosphines and dialkylphosphine oxides ligands were also quite effective.45,46 Nevertheless, these protocols have limited application due to their three major drawbacks. First, the lifetimes of these catalysts are very short; low turnover numbers (TON ≤ 50) are typically achieved. Second, these catalytic systems are not sufficiently reactive with aryl chlorides, although aryl chlorides

Chapter 1: General Introduction 10 are most attractive as starting materials because of their wider availability and lower cost.

Third, these protocols suffer from limited substrate scope and functional group compatibility.

Subsequent research in the Buchwald, Li, Schopfer and Hartwig group dramatically improved the scope and efficiency of the Pd-catalyzed C―S bond forming reactions, allowing the coupling of a range of aryl chlorides, triflates and flurides.47-55 Of the many palladium catalyst systems that have been developed, most require the use of a supporting ligand. Common ligands used in Pd-catalyzed C―S cross-coupling reactions are chelating phosphines as shown in Figure 1.2. These ligands have not only been shown to stabilize palladium-centre, they also can easily be modified to increase the reactivity of the catalyst. Bulkier electron-rich ligands not only facilitate oxidative addition by increasing the electron-density on palladium, they also speed up reductive elimination.

The catalytic cycle for this process was postulated to involved oxidative addition of the aryl halide to Pd(0), followed by transmetallation with metal-thiolate complex, and reductive elimination to generate the aryl thiol cross-coupling product with concomitant regeneration of the Pd(0) catalyst (scheme 1.5). Detailed studies of the mechanistic investigation were conducted by the group of Hartwig.42,43,53,54 Based on the mechanistic studies it was anticipated that palladium thiolates form easily and undergo relatively fast reductive eliminations with aryl groups. For that reason, the main limitation on the C―S cross-coupling could be resulted from the strong affinity of late metal catalysts to thiol substrate. Most of the metal catalysts used for the coupling of haloarenes with thiols is likely to be undergo displacement of dative ligands by thiolates to form anionic thiolate complexes I or the formation of bridging thiolate complexes II that go through slow

Chapter 1: General Introduction 11

Figure 1.2: Bidentate phosphine ligands used in Pd-catalysed C―S bond formation.

Chapter 1: General Introduction 12

Scheme 1.5: General mechanism for the palladium-catalyzed C―S bond forming reactions.

Chapter 1: General Introduction 13 reductive elimination (scheme 1.5).43 Therefore, for the efficient C―S cross-coupling, it is essential to use a chelating ligands that binds the metal strongly enough to avoid the formation of thiolate complexes I and II, while simultaneously promoting oxidative addition and reductive elimination.

1.2.2 Copper-catalyzed C―S bond formation

Copper is another noteworthy transition metal that has been used for over a century in cross-coupling reactions. Before the advent of palladium catalysts, copper- mediated cross-coupling reactions such as Ullmann condensation55-59 and Goldberg reaction60 were widely used for the formation of aryl-carbon and aryl-heteroatom bonds.

However, these reactions suffer several drawbacks: use of stoichiometric amount of copper reagents, high temperature, strong bases, and often the use of toxic polar solvents such as hexamethylphosphoramide (HMPA). As a result, further developments of copper- mediated cross-coupling reactions have lagged behind that of Nickel and specially palladium. However, studies on copper-mediated/catalyzed cross-coupling reactions have again begun to appear in the literatures at the turn of this century. Most noteworthy, the copper-mediated/catalyzed heteroatom cross-coupling reactions (C―S,61-69 C―N,70-73 and C―O74-76) are an excellent complement to those transformations catalyzed by palladium due to low cost of copper and functional group capability displayed by those reactions.

Recent work initiated by Lam, Chan and Evans has employed arylboronic acids as alternative arylating agent in the copper-catalyzed arylation of thiols. However, the reaction provides very low yield of desired cross-coupling product with significant amount of disulfide as byproduct. In 2000, Guy and co-workers77 have modified the

Chapter 1: General Introduction 14 reaction condition of Lam-Chan cross-coupling reactions and they have discovered that the reaction of thiolate substrates with arylboronic acids proceeded well when the reaction mixtures are heated to 155 oC in DMF solvent to afford the S-aryl compounds in satisfactory yields (eq. 4). A wide range of thiolate substrates with electronically and structurally diverse arylboronic acids provided the corresponding thioethers with good to moderate yields. Unfortunately, tertiary thiols, thioacetic acids, and α- methoxycarbonylthiolates are not compatible with the reaction conditions.

In the last decade, a plethora of new hard-chelating ligands has been reported, which allow the Ullmann reaction to be run under significantly milder conditions- typically rt-120 oC using weak inorganic bases. Some of the most useful ligands that promote the copper catalyzed C―S coupling reactions are phosphazene, BINAM, neocuproine, N-methylglycine, tripod ligand, benzotriazole, ethylene glycol, 1,2- diamino-cyclohexane, β-ketoester, L-proline, and oxime-phosphine oxide ligand. It is believed that these ligands increased solubility of copper salts in common solvents such as DMF, DMSO, alcohols, and toluene. This development significantly improved the substrate scope, functional groups tolerances and selectivity of these reactions (eq. 5).

For examples, in 2000, Palomo and co-worker78 reported an attractive method for the synthesis of diaryl sulfides from aryl Iodides and thiophenols using 20 mol% of CuBr and phosphazene ligands (eq. 6). The method shows high level of functional groups

Chapter 1: General Introduction 15 tolerances with respect to coupling substrates. However, high loading of catalyst and use of the expensive phosphazene ligand make this method uneconomical. Moreover, aryl chlorides are not compatible with this reaction condition.

After this work, in 2002, Venkataraman67 reported an interesting method for the synthesis of aryl sulfides. The method is based on Cu(I)-catalyzed coupling of aryl iodides with aryl- and alkyl-thiols in the presence of neocuproine ligand. The neocuproine ligand plays a vital role for this transformation, while the desired product is not formed without the ligand. NaOtBu and K3PO4 are suitable bases for this transformation, whereas Cs2CO3, Et3N and K2CO3 are inferior. However, aryl bromides are not reactive under this reaction condition.

Almost in the same time, the Buchwald’s group79 has developed an alternative synthetic protocol for the same transformation which is simpler than the previous methods, and displays wide scopes of the reaction (eq. 8). In this protocol, a variety of thiophenols and alkylthiols reacted with aryl iodides in the presence of CuI, ethylene

o glycol, and K2CO3, in isopropanol at 80 C under inert atmosphere.

Chapter 1: General Introduction 16

Very recently, Sperotto et al.63 have reported a ligand-free copper catalyzed method for the synthesis diaryl sulfides (eq. 9). This synthetic method provides general applicability and simplicity, and avoiding the use of expensive ligands. However, the scope of the reaction is further limited by the fact that aryl bromides do not react.

1.3 Motivation and objective of my research

Based on pioneering studies by Ullmann and Goldberg, syntheses of aryl sulfides predominantly make use of transition-metal-catalyzed cross-coupling reactions between aryl halides (mainly aryl iodides) and thiols. Such cross-coupling reactions have grown enough to being reliable tools for the formation of C―S bonds. However, many of these reactions required the use of toxic reagents and harsh conditions as well as the production of potentially hazardous by-products. In addition, organohalides are a health and environmental concern and require costly waste remediation, particularly on an industrial scale. Therefore, the developments of environmentally friendly and economical path ways for C―S cross-coupling reactions are of high priority among the current challenges for catalytic chemistry.

An alternative to these more established methods is a nature-inspired decarboxylative cross-coupling reaction in which decarboxylation of carboxylic acids

Chapter 1: General Introduction 17 serves the function of transmetallation. We decided to use this decarboxylative strategy for C―S bond forming reactions. This approach would have obvious advantages: (1) carboxylic acids are non-toxic, prevalent and readily prepared reagents. (2) Importantly, in theory carbon dioxide is the only by-product in these reactions. In this thesis, the recent advances of decarboxylative C―S cross-coupling reactions were described.

On the other hand, the transition-metal-catalyzed direct arylation through cleavage of C―H bonds represent another alternative to the traditional cross-coupling reactions with organometallic reagents. It is becoming an environmentally and economically more attractive strategy for streamlining organic synthesis. Importantly, this strategy does not need the synthesis of prefunctionalized precursors, thereby making the synthetic schemes shorter and more efficient. Over the past decades, extensive efforts have been undertaken to develop synthetic strategies which directly functionalize C―H groups of arenes to construct C―C bond by using transition-metal-catalysts. However, an important challenge in C―H activation lies in the direct installation of sulfur moiety on aryl (heterocycle) C―H bonds. This is partly due to the propensity of thiols toward oxidative dimerization and their affinity for metals, resulting in reduced catalytic efficiency. Herein, we reported for the first time a synthetic strategy for direct formation of C―S bond through transition-metal-catalyzed heterocycle C―H group functionalization. Furthermore, the mechanism of the new C―S cross-coupling reaction was also investigated. A better insight into the catalytic reaction mechanism can help us design better catalysts.

Chapter 1: General Introduction 18

Besides, as one part of our research project on development of transition metal catalyzed cross-coupling reactions, we have developed two novel and important synthetic methods for C―C cross-coupling reactions through the use of transition-metal-catalyst.

1.4 Outline

Chapter 2 explores a novel method for the synthesis of vinyl sulfides by the decarboxylative cross-coupling of arylpropiolic acids with thiols using copper(I) salts as catalysts. In the presence of CuI and Cs2CO3, a number of thiols reacted with arylpropiolic acids to afford the corresponding vinyl sulfides in high yields with high stereoselectivity for Z-isomers.

In Chapter 3, the development of a new Cu(I) catalyzed direct thiolation of heterocycle C—H bonds is describes. In presence of CuI, 2,2′-bipyridine and cheaper base Na2CO3, a variety of thiols can directly reacted with benzothiazoles to afford various substituted 2-mercaptobenzothiazoles (MBTs). Thiazole, 4,5-Dimethylthiazole and 1-

Methylbenzimidazole are also applicable as heteroarene coupling substrates. In addition, a mechanistic studies concerning this Cu(I) catalysed direct thiolation reactions is presented. Both computational studies and experimental results reveal that copper thiolato complexe [(L)Cu(SR)], within which L is a bidentate N,N- ligand such as 2,2′- bipyridine, phenanthroline, DMEDA, or TMEDA, and R is an aryl or alkyl group, is the first important active intermediate formed during the course of reactions. Furthermore, the computational studies suggest a possible mechanism involving hydrogen atom abstraction (HAA) pathway which is more energetically feasible than the other possible pathways like β-hydride elimination (BHE), single electron transfer (SET), hydrogen

Chapter 1: General Introduction 19 atom transfer (HAT), oxidative addition/reductive elimination (OA/RE) and σ-bond metathesis.

Chapter 4 addresses a new transition metal-catalyzed C―C bond-forming reaction between benzothiazoles (or benzoxazoles) and arylboronic acids. This new method provides a simple means to access aryl-substituted benzothiazole and benzoxazole compounds, a task that otherwise requires several synthetic steps or harsh reaction conditions.

In Chapter 5, the synthesis and catalytic studies of novel palladium nanostructures assembled from small nanoparticles by a surfactant-templated method have been presented. The nanomaterials were characterized by several techniques including XRD,

SEM, and HRTEM, which reveal that these one-dimensional nanomaterials comprise high density nanocontacts of ~1 nm in contact length at the particle–particle interface. In contrast to palladium nanoparticles, the palladium nanowires exhibit enhanced catalytic activities towards C―C cross-coupling (e.g., Suzuki and Heck couplings) reactions under mild conditions.

Chapter 2: Decarboxylative C―S Cross-Coupling 20

CHAPTER 2 Synthesis of Vinyl Sulfides by Copper-Catalyzed Decarboxylative C―S Cross-Coupling

Chapter 2: Decarboxylative C―S Cross-Coupling 21

2.1 Introduction

The utility of vinyl sulfides has enormously increased over the past several years.

Vinyl sulfides can be used as complementary building blocks to carbonyl compounds80 and Michael acceptors81 for synthesis of many polymeric materials,82 natural products,83 and synthetic reagents.84 Conventional approaches to the synthesis of vinyl sulfides include the addition of thiols to alkynes under free radical85 or metal-catalyzed conditions,86 Wittig olefination,87 and direct nucleophilic substitution through use of vinyl halides.88 Despite their usefulness, these approaches either require harsh reaction conditions, costly starting materials and solvents or lack of stereocontrol at the double bond geometry.

Numerous methods have been developed for the stereoselective synthesis of (E)- vinyl sulfides.89 In contrast, it has been challenging to prepare Z-isomers.90 In 2005,

Kondoh et al.91 reported the synthesis of (Z)-1-alkenylsufides via a cesium-catalyzed hydrothiolation of alkynes in the presence of 2,2,6,6-tetramethylpiperidine-N-oxyl

(TEMPO) as a radical inhibitor. However, this synthetic strategy is only applicable to alkylthiols. More recently, Wang et al.92 have reported the synthesis of (Z)-1- alkenylsufides via a copper-catalyzed hydrothiolation of alkynes with diaryl disulfides, but the need of large amounts of rongalite (4 equiv) as the radical initiator can cause environmental concerns.

Chapter 2: Decarboxylative C―S Cross-Coupling 22

Recently, coupling reactions initiated by the decarboxylation of carboxylic acids have shown great promise in the field of synthetic chemistry.93,94 In particular, we have shown that a broad range of aryl sulfides can be prepared through decarboxylative C―S cross-coupling.95 Herein, we demonstrate a novel copper-catalyzed decarboxylative thiolation of arylpropiolic acids, resulting in stereoselective formation of (Z)-vinyl sulfides under mild reaction conditions.

2.2 Results and Discussion

Phenylpropiolic acid (1a) and 4-methoxybenzenethiol (2a) were used as the substrates to screen and optimize reaction conditions. Copper(I) complexes generally gave significantly higher yields of the product than copper (II) source (Table 2.1). The amount of CuI can be decreased down to 4.0 mol%. Different bases were screened, and the combination of cesium carbonate with CuI afforded the best conversion efficiency

(Table 2.1, entry 13, Fig. 2.1 for GC/MS). In contrast to previously reported synthesis of aryl sulfides that requires a binary Pd/Cu catalyst and a high temperature (160 oC) treatment,95 this approach offers relatively mild reaction conditions without the need of the Pd catalyst. Further, the concentration of thiol was optimized using 4.0 mol% CuI with cesium carbonate in NMP at 90 oC over 24 h (Table 2.2). It was found that 0.75 mmol of 4-methoxybenzenethiol with 0.5 mmol phenylpropiolic acid afforded the best conversion to the desired cross-coupling product in 99% yield (Table 2.2, entry 5).

Chapter 2: Decarboxylative C―S Cross-Coupling 23

Table 2.1: Decarboxylative C―S coupling under different conditions.a

a All the reactions were carried out with phenylpropiolic acid 1a (0.5 mmol) and 4- methoxybenzenethiol 2a (0.75 mmol) in the presence of a metal catalyst, NMP (3 mL), and base (1.2 equiv) at 90 oC for 24 h under air atmosphere. b GC yield. Isolated yield is in parenthesis.

Chapter 2: Decarboxylative C―S Cross-Coupling 24

Figure 2.1: (a) GC analysis of decarboxylative C―S Cross-Couplings of phenylpropiolic acid with 4-methoxybenzenethiol. (b) Corresponding mass spectra of the peaks shown in GC spectrum at 14.58 minute, confirming the high stereoselective formation of (Z)-(4-Methoxyphenyl)(styryl)sulfane with excellent yield.

Chapter 2: Decarboxylative C―S Cross-Coupling 25

Table 2.2: Decarboxylative C―S cross-couplings of phenylpropiolic acid with different concentrated 4-methoxybenzenethiol.

a GC/MS yields.

Chapter 2: Decarboxylative C―S Cross-Coupling 26

Under the optimal reaction conditions, a wide range of thiols including aromatic, benzylic and aliphatic thiols were examined to react with phenylpropiolic acid via decarboxylative cross-coupling reactions. The results are summarized in Table 2.3. We observed that in the presence of the phenylpropiolic acid all thiols afforded anti-

Markovnikov coupling products in good to excellent yields with high stereoselectivity for

Z-isomers. The arylthiols with electron-rich and electron-deficient aromatic moieties were effectively converted to the corresponding vinyl sulfides. Importantly, the decarboxylative coupling reactions are tolerant to a broad range of functional groups including ethers, amines, alcohols, halides, and nitrogen-containing heterocycles. The functional group tolerance should enable further derivatization of the as-synthesized vinyl sulfides (3k, 3o, 3p-3s) through cross-coupling reactions such as Suzuki-Miyaura,

Sonogashira, and Heck reactions.

To expand the scope of the general reaction conditions further, we carried out decarboxylative C―S cross-coupling via different aryl-substituted alkynyl carboxylic acids (Table 2.4). All alkynyl carboxylic acids were converted into the corresponding alkenyl sulfides in excellent yields. However, alkynyl carboxylic acids with electron- withdrawing substituents in the para-position led to low stereoselectivity (Table 2.4, entries 1,2 and 4-7). In stark contrast, introduction of electron-donating group in the ortho-position resulted in the quantitative formation of the corresponding Z-isomer

(Table 2.4, entry 3).

Chapter 2: Decarboxylative C―S Cross-Coupling 27

Table 2.3: Decarboxylative coupling of phenylpropiolic acid with thiols.a

Chapter 2: Decarboxylative C―S Cross-Coupling 28

Table 2.3: Decarboxylative coupling of phenylpropiolic acid with thiolsa (cont.).

a All the reactions were carried out with phenylpropiolic acid (0.5 mmol) and thiols (0.75 mmol) in the presence of CuI (4.0 mol%), and Cs2CO3 (1.2 equiv) in 3 mL of NMP at 90 ºC under air atmosphere. b Yields of isolated products are the average of at least two experiments. c The Z/E ratio was based on the analysis of 1H NMR spectra.

Chapter 2: Decarboxylative C―S Cross-Coupling 29

Table 2.4: Decarboxylative coupling of substituted phenylpropiolic acids with thiols.a

aAll the reactions were carried out with acids (0.5 mmol) and thiols (0.75 mmol) in the presence b of CuI (4.0 mol%) and Cs2CO3 (1.2 equiv) in 3 mL of NMP at 90 ºC under air atmosphere. Yields of isolated products are the average of at least two experiments. c The Z/E ratio was based on the analysis of 1H NMR spectra.

Chapter 2: Decarboxylative C―S Cross-Coupling 30

2.3 Mechanistic consideration

Scince Z-isomers were isolated as major product in presence of CuI and base, mechanism of the present reaction might be different from those of radical induced hydrothiolation reaction.114 In the base mediated113 or radical induced hydrothiolation reaction, a radical inhibitor or radical initiator was added for obtaining the high Z- selectivity, whereas the present reaction does not required any of these two. Therefore, decarboxylation of acid group plays a significant role in the present reaction mechanism.

Thus, we have formulated a working mechanism as outlined in the Scheme 2.1. The

alkynyl carboxylic acid initially reacts with a cuprous ion in presence of base Cs2CO3 to form the corresponding copper complex A. At the low reaction temperature (90 oC) and in presence of base, it is expected that the nucleophilic addition is faster than the decarboxylation of acids. Therefore, nucleophilic addition of thiolate anion is occurred first to the complex A to generate an intermediate B and it was followed by the decarboxylation of B to yield the corresponding alkenyl anion C. It should be noted that the necleophilic addition of the thiolate happens in the same side with phenyl ring since other side is occupied by Cu through co-ordination with carboxylic acid. Now, the intermediate C undergoes protonation to give the product with regeneration of initial cuprous ion. Like this cyclic manner the Z-vinyl sulfides are formed in the reaction mixture. The lower stereoselectivity resulting from use of aryl-substituted alkynyl carboxylic acids with electron-withdrawing groups (Table 2.4, entries 1, 2 and 4-7) can

Chapter 2: Decarboxylative C―S Cross-Coupling 31

Scheme 2.1: Proposed mechanism.

Chapter 2: Decarboxylative C―S Cross-Coupling 32 be attributed to the reversible addition of the thiolate to the Z-isomer. The electron- withdrawing groups may stabilize the benzylic anion D, leading to the formation of the

E-isomer.

2.4 Conclusion

In summary, we have disclosed a copper-based decarboxylative cross-coupling method for the synthesis of vinyl sulfides with high stereoselectivity for Z-isomers. This method is important not only for expanding our understanding of the decarboxylative reaction, but also for providing a convenient synthetic pathway for facile synthesis of biologically or pharmaceutically relevant vinyl sulfide compounds. A number of thiols

(aromatic, alkyl, benzylic and heterocycles) stereoselectively underwent the reaction with propiolic acids to afford the corresponding (Z)-1-alkenyl sulfides in good to excellent yields without the need for a halocarbon precursor. Moreover, this synthetic methodology dose not need any air sensitive additives and can be conducted in air with cheapest copper-catalyst, thereby making this method more attractive for industrial application.

Chapter 2: Decarboxylative C―S Cross-Coupling 33

2.5 Experimental Section

General Methods. Unless otherwise stated, all reactions were carried out without taking precautions to exclude air and moisture. All solvents were used as received. All the chemicals were purchased from commercial sources and used as received unless stated otherwise. Reactions were conducted in 20 mL vials equipped with a conventional screw cap. All reaction temperatures refer to bath temperatures. Column chromatography was carried out on silica gel (230-400 mesh). The yields of the coupling product listed in

Tables 3.3 and 3.4 refer to isolated yields (average of two runs).

Physical Measurements. 1H NMR and 13C NMR spectra were recorded on a

Bruker ACF 300 (or 500) FT-NMR spectrometer and referenced to residual peaks of the solvent. Coupling reactions of phenylpropiolic acid with 4-methoxybenzenethiol shown in Table 3.1 and 3.2 were examined by using a Hewlett- Packard Series 6890 GC (Santa

Clara, CA, USA) coupled to a Hewlett Packard 5973 MS detector. High-resolution mass spectra were obtained using a Finnigan MAT95XL-T mass spectrometer.

A General procedure for decarboxylative C―S coupling. To a solution of N- methyl-2-pyrrolidone (NMP) (3 mL) charged with phenylpropiolic acid (0.5 mmol) and

thiol (0.75 mmol) was added CuI (3.8 mg, 0.02 mmol) and Cs2CO3 (391 mg, 1.2 mmol).

The resulting mixture was stirred at 90 °C. Upon completion of the reaction (approx. 24 hr), the mixture was cooled to room temperature, poured into a solution of HCl in water

(1 N, 15 mL), and extracted several times with 15 mL of ethyl acetate. The combined

Chapter 2: Decarboxylative C―S Cross-Coupling 34

organic layers were washed with water and brine, dried over Na2SO4, and filtered. The solvent was removed in vacuo and the residue was purified by column chromatography

(silica gel, eluent: hexane/ethyl acetate) to afford the coupling product.

Spectral data

(Z)-(4-Methoxyphenyl)(styryl)sulfane (3a, Z/E = 100:0).96 Obtained as a white

1 solid in 95% yield. H NMR (300 MHz, CDCl3) δ 7.51 (d, 2H), 7.41 (q, 4H), 7.25 (t, 1H),

13 6.89 (d, 2H), 6.49 (d, 1H), 6.40 (d, 1H), 3.82 (s, 3H); C NMR (125 MHz, CDCl3) δ

159.5, 136.6, 132.9, 128.7, 128.33, 128.3, 126.9, 126.8, 125.8, 114.8, 55.4; HR EIMS:

242.0763 m/z (calcd. for C15H14OS: 242.0765).

Dodecyl(styryl)sulfane (3b, Z/E = 83:17).97 Obtained as a yellow liquid in 78%

1 yield. H NMR (300 MHz, CDCl3) δ 7.49 (d, 2H), 7.39-7.28 (m, 2H), 7.20 (t, 1H), 6.72 (d,

0.17  1H), 6.46 (d, 0.17  1H), 6.43 (d, 0.83  1H), 6.25 (d, 0.83  1H), 2.82-2.75 (m,

13 2H), 1.69 (quint, 2H), 1.43-1.26 (m, 18H), 0.88 (t, 3H); C NMR (75 MHz, CDCl3) δ

137.1, 128.6, 128.2, 127.7, 126.5, 125.2, 35.9, 31.9, 30.2, 29.6, 29.5, 29.4, 29.3, 29.2,

28.8, 28.6, 22.6, 14.1; HR EIMS: 304.2227 m/z (calcd. for C20H32S: 304.2225).

Chapter 2: Decarboxylative C―S Cross-Coupling 35

Octyl(styryl)sulfane (3c, Z/E = 88:12). Obtained as a yellow liquid in 95% yield.

1 H NMR (300 MHz, CDCl3) δ 7.5 (d, 2H), 7.39-7.29 (m, 2H), 7.21 (t, 1H), 6.74 (d, 0.12

 1H), 6.47 (d, 0.12  1H), 6.45 (d, 0.88  1H), 6.26 (d, 0.88  1H), 2.83-2.77 (m, 2H),

13 1.71 (quint, 2H), 1.45-1.29 (m, 10H), 0.90 (t, 3H); C NMR (75 MHz, CDCl3) δ 137.1,

128.6, 128.2, 127.7, 126.5, 125.2, 35.9, 32.6, 31.8, 30.2, 29.2, 28.6, 22.6, 14.1; HR EIMS:

248.1595 m/z (calcd. for C16H24S: 248.1599).

Butyl(styryl)sulfane (3d, Z/E = 88:12).97 Obtained as a light yellow liquid in

1 93% yield. H NMR (300 MHz, CDCl3) δ 7.48 (d, 2H), 7.39-7.28 (m, 2H), 7.20 (t, 1H),

6.73 (d, 0.12  1H), 6.46 (d, 0.12  1H), 6.43 (d, 0.88  1H), 6.25 (d, 0.88  1H), 2.83-

2.77 (m, 2H), 1.67 (quint, 2H), 1.51-1.39 (m, 2H), 0.93 (t, 3H); 13C NMR (75 MHz,

CDCl3) δ 137.1, 128.6, 128.2, 127.7, 126.5, 125.3, 35.6, 32.3, 21.7, 13.6; HR EIMS:

192.0973 m/z (calcd. for C12H16S: 192.0972).

Chapter 2: Decarboxylative C―S Cross-Coupling 36

Phenethyl(styryl)sulfane (3e, Z/E = 79:21).98 Obtained as a yellow liquid in 90%

1 yield. H NMR (300 MHz, CDCl3) δ 7.50 (d, 2H), 7.40-7.20 (m, 8H), 6.72 (d, 0.21 

1H), 6.54-6.45 (m, 1H), 6.26 (d, 0.79  1H) 3.07-2.98 (m, 4H); 13C NMR (75 MHz,

CDCl3) δ 139.9, 136.9, 128.6, 128.5, 128.2, 127.0, 126.7, 126.5, 125.9, 125.5, 124.7, 37.1,

36.8, 35.9, 34.0; HR EIMS: 240.0976 m/z (calcd. for C16H16S: 240.0973).

Cyclohexyl(styryl)sulfane (3f, Z/E = 90:10).99 Obtained as a light yellow liquid

1 in 80% yield. H NMR (300 MHz, CDCl3) δ 7.49 (d, 2H), 7.37-7.28 (m, 2H), 7.19 (t, 1H),

6.76 (d, 0.1  1H), 6.57 (d, 0.1  1H), 6.43 (d, 0.9  1H), 6.33 (d, 0.9  1H), 2.90-2.84 (m,

1H), 2.08-2.05 (m, 2H), 1.83-1.79 (m, 2H), 1.66-1.62 (m, 1H), 1.56-1.25 (m, 5H); 13C

NMR (75 MHz, CDCl3) δ 137.2, 128.6, 128.5, 128.2, 126.9, 126.5, 125.9, 125.6, 125.0,

47.8, 33.7. 26.0, 25.6; HR EIMS: 218.1127 m/z (calcd. for C14H18S: 218.1129).

Benzyl(styryl)sulfane (3g, Z/E = 90:10).99 Obtained as a yellow liquid in 89%

1 yield. H NMR (300 MHz, CDCl3) δ 7.48-7.18 (m, 10H), 6.72 (d, 0.1  1H), 6.53 (d, 0.1

Chapter 2: Decarboxylative C―S Cross-Coupling 37

 1H), 6.43 (d, 0.9  1H), 6.26 (d, 0.9  1H), 4.02-4.00 (m, 2H); 13C NMR (75 MHz,

CDCl3) δ 137.4, 136.9, 129.0, 128.8, 128.7, 128.6, 128.2, 127.9, 127.4, 127.3, 127.0,

126.7, 126.0, 125.9, 125.6, 124.3, 39.5; HR EIMS: 226.0817 m/z (calcd. for C15H14S:

226.0816).

(4-Methylbenzyl)(styryl)sulfane (3h, Z/E = 90:10). Obtained as a yellow liquid

1 in 90% yield. H NMR (300 MHz, CDCl3) δ 7.44 (d, 2H), 7.35-7.12 (m, 7H), 6.72 (d,

0.10  1H), 6.51 (d, 0.10  1H), 6.40 (d, 0.90  1H), 6.24 (d, 0.90  1H), 3.98-3.96 (m,

13 2H), 2.33 (s, 3H); C NMR (75 MHz, CDCl3) δ 137.1, 136.9, 134.3, 130.3, 129.4, 128.9,

128.7, 128.6, 128.4, 128.2, 126.9, 126.7, 126.1, 125.7, 125.6, 124.6, 39.3, 21.1; HR

EIMS: 240.0970 m/z (calcd. for C16H16S: 240.0973).

(4-tert-butylbenzyl)(styryl)sulfane (3i, Z/E = 90:10). Obtained as a yellow

1 liquid in 90% yield. H NMR (300 MHz, CDCl3) δ 7.47 (d, 2H), 7.39-7.19 (m, 7H), 6.76

(d, 0.10  1H), 6.54 (d, 0.10  1H), 6.44 (d, 0.90  1H), 6.30 (d, 0.90  1H), 4.01-3.99 (m,

13 2H), 1.33 (s, 9H); C NMR (75 MHz, CDCl3) δ 150.3, 136.9, 134.2, 128.65, 128.61,

Chapter 2: Decarboxylative C―S Cross-Coupling 38

128.5, 128.2, 127.6, 126.9, 126.6, 126.3, 125.63, 125.6, 124.7, 39.2, 37.0, 34.5, 31.3; HR

EIMS: 282.1444 m/z (calcd. for C19H22S: 282.1442).

(4-Methoxybenzyl)(styryl)sulfane (3j, Z/E = 80:20).98 Obtained as a yellow

1 solid in 95% yield. H NMR (300 MHz, CDCl3) δ 7.46 (d, 2H), 7.37-7.18 (m, 5H), 6.87

(d, 2H), 6.72 (d, 0.20  1H), 6.53 (d, 0.20  1H), 6.42 (d, 0.80  1H), 6.26 (d, 0.80  1H),

13 3.97 (m, 2H), 3.8 (s, 3H); C NMR (75 MHz, CDCl3) δ 158.9, 136.9, 130.1, 129.9, 129.3,

128.6, 128.5, 128.2, 127.8, 126.9, 126.7, 126.1, 125.7, 125.6, 124.5, 114.1, 55.3, 39.0,

36.8; HR EIMS: 256.0916 m/z (calcd. for C16H16OS: 256.0922).

(4-Chlorobenzyl)(styryl)sulfane (3k, Z/E = 85:15). Obtained as a yellow liquid

1 in 75% yield. H NMR (300 MHz, CDCl3) δ 7.44-7.18 (m, 9H), 6.67 (d, 0.15  1H), 6.52

(d, 0.15  1H), 6.44 (d, 0.85  1H), 6.19 (d, 0.85  1H), 3.97-3.95 (m, 2H); 13C NMR (75

MHz, CDCl3) δ 136.7, 136.0, 133.3, 130.3, 130.1, 128.8, 128.7, 128.6, 128.2, 127.2,

126.9, 126.4, 125.7, 125.4, 123.7, 38.8, 36.8; HR EIMS: 260.0419 m/z (calcd. for

C15H13ClS: 260.0418).

Chapter 2: Decarboxylative C―S Cross-Coupling 39

2-(Styrylthiomethyl)furan (3l, Z/E = 84:16).97 Obtained as a red liquid in 87%

1 yield. H NMR (300 MHz, CDCl3) δ 7.48-7.20 (m, 6H), 6.75 (d, 0.16  1H), 6.58 (d,

0.16  1H), 6.48 (d, 0.84  1H), 6.35-6.30 (m, 3H), 4.01-3.98 (m, 2H); 13C NMR (75

MHz, CDCl3) δ 150.8, 142.6, 142.3, 136.7, 128.8, 128.6, 128.5, 128.2, 127.1, 126.8,

126.1, 125.7, 125.5, 123.8, 110.5, 110.5, 108.1, 107.8, 31.5, 29.7; HR EIMS: 216.0616

m/z (calcd. for C13H12OS: 216.0609).

Phenyl(styryl)sulfane (3m, Z/E = 90:10).99 Obtained as a light yellow liquid in

1 90% yield. H NMR (500 MHz, CDCl3) δ 7.6 (d, 2H), 7.52 (d, 2H), 7.49-7.28 (m, 6H),

6.94 (d, 0.1  1H), 6.79 (d, 0.1  1H), 6.65 (d, 0.9  1H), 6.56 (d, 0.9  1H); 13C NMR

(125 MHz, CDCl3) δ 136.5, 136.2, 135.2, 131.8, 130.1, 129.8, 129.1, 128.74, 128.66,

128.3, 127.6, 127.3, 127.2, 127.1, 126.9, 126.0, 123.4; HR EIMS: 212.0654 m/z (calcd.

for C14H12S: 212.0660).

Chapter 2: Decarboxylative C―S Cross-Coupling 40

Styryl(p-tolyl)sulfane (3n, Z/E = 90:10).100 Obtained as a light yellow liquid in

1 95% yield. H NMR (300 MHz, CDCl3) δ 7.53 (d, 2H), 7.42-7.23 (m, 5H), 7.16 (d, 2H),

6.86 (d, 0.1  1H), 6.65 (d, 0.1  1H), 6.55 (d, 0.9  1H), 6.46 (d, 0.9  1H), 2.35 (s, 3H);

13 C NMR (125 MHz, CDCl3) δ 137.4, 136.6, 132.7, 130.6, 130.5, 130.0, 128.7, 128.6,

128.3, 127.3, 127.1, 127.0, 126.5, 125.9, 124.5, 21.1; HR EIMS: 226.0818 m/z (calcd. for

C15H14S: 226.0816).

4-Clorophenyl(styryl)sulfane (3o, Z/E = 93:7).96 Obtained as a yellow solid in

1 82% yield. H NMR (300 MHz, CDCl3) δ 7.51 (d, 2H), 7.41-7.24 (m, 7H), 6.82 (d, 0.07

 1H), 6.73 (d, 0.07  1H), 6.62(d, 0.93  1H), 6.41 (d, 0.93  1H); 13C NMR (125 MHz,

CDCl3) δ 136.2, 134.7, 133.3, 131.2, 129.3, 128.8, 128.3, 128.1, 127.3, 125.1; HR EIMS:

246.0266 m/z (calcd. for C14H11ClS: 246.0270).

(Z)-(4-Bromophenyl)(styryl)sulfane (3p, Z/E = 100:0).101 Obtained as a white

1 solid in 88% Yield. H NMR (300 MHz, CDCl3) δ 7.54-7.26 (m, 9H), 6.64 (d, 1H), 6.43

Chapter 2: Decarboxylative C―S Cross-Coupling 41

13 (d, 1H); C NMR (125 MHz, CDCl3) δ 136.2, 135.4, 132.2, 131.4, 128.7, 128.3, 128.2,

127.3, 124.8, 121.2; HR EIMS: 289.9765 m/z (calcd. for C14H11BrS: 289.9765).

2-(Styrylthio)aniline (3q, Z/E = 92:08).101 Obtained as a brown solid in 81%

1 yield. H NMR (500 MHz, CDCl3) δ 7.55 (d, 2H), 7.44-7.38 (m, 3H), 7.28-7.24 (m, 1H),

7.19-7.15 (m, 1H), 6.76-6.71 (m, 2H), 6.67 (d, 0.08  1H), 6.52 (d, 0.92  1H), 6.18 (d,

13 0.92  1H), 4.24 (br. s, 2H); C NMR (125 MHz, CDCl3) δ 147.7, 136.6, 135.2, 130.4,

128.8, 128.6, 128.3, 127.7, 127.0, 126.7, 118.7, 117.8, 116.2, 115.3; HR EIMS: 227.0764

m/z (calcd. for C14H13NS: 227.0769).

4-(Styrylthio)aniline (3r, Z/E = 94:06). Obtained as a yellow solid in 94% yield.

1 H NMR (300 MHz, CDCl3) δ 7.50 (d, 2H), 7.37 (t, 2H), 7.29-7.20 (m, 3H), 6.64-6.60 (m,

13 2H), 6.40 (q, 2H), 3.62 (br. s, 2H); C NMR (75 MHz, CDCl3) δ 146.5, 136.8, 134.1,

133.3, 129.4, 128.6, 128.2, 126.7, 125.7, 125.0, 123.7, 115.6; HR EIMS: 227.0766 m/z

(calcd. for C14H13NS: 227.0769).

Chapter 2: Decarboxylative C―S Cross-Coupling 42

S

HO

2-(Styrylthio)phenol (3s, Z/E = 85:15).102 Obtained as a yellow solid in 80%

1 yield. H NMR (300 MHz, CDCl3) δ 7.51- 7.16 (m, 7H), 7.02-6.84 (m, 2H), 6.57-6.49 (m,

13 1H), 6.28(d, 0.15  1H), 6.17 (br s, 1H), 6.02 (d, 0.85  1H); C NMR (75 MHz, CDCl3)

δ 156.2, 136.0, 135.1, 131.6, 128.8, 128.4, 128.1, 127.4, 126.4, 125.9, 122.9, 121.1, 119.3,

115.6; HR EIMS: 228.0609 m/z (calcd. for C14H12OS: 228.0609).

Naphthalen-2-yl(styryl)sulfane (3t, Z/E = 90:10).103 Obtained as a brown solid

1 in 92% yield. H NMR (300 MHz, CDCl3) δ 7.99-7.26 (m, 12H), 6.99 (d, 0.1  1H), 6.81

13 (d, 0.1  1H), 6.68 (d, 0.9  1H), 6.62 (d, 0.9  1H); C NMR (75 MHz, CDCl3) δ 136.5,

133.7, 133.5, 132.3, 132.2, 128.8, 128.5, 128.3, 127.8, 127.7, 127.4, 127.2, 126.8, 126.2,

126.1, 125.7, 123.2; HR EIMS: 262.0814 m/z (calcd. for C18H14S: 262.0816).

2-(Styrylthio)pyridine (3u, Z/E = 94:6).104 Obtained as a yellow liquid in 81%

1 Yield. H NMR (300 MHz, CDCl3) δ 8.53 (d, 1H), 7.58-7.52 (m, 3H), 7.43-7.38 (m, 3H),

7.30-7.24 (m, 2H), 7.08-7.05 (m, 1H), 6.89 (d, 0.06  1H), 6.76 (d, 0.94  1H); 13C NMR

Chapter 2: Decarboxylative C―S Cross-Coupling 43

(75 MHz, CDCl3) δ 156.5, 149.7, 136.7, 136.5, 131.9, 128.7, 128.3, 127.4, 127.1, 122.8,

120.5, 120.1; HR EIMS: 213.0536 m/z (calcd. for C13H10NS: 213.0534).

(4-Bromostyryl)(phenyl)sulfane (3aa, Z/E = 30:70). Obtained as a yellow solid

1 in 90% yield. H NMR (300 MHz, CDCl3) δ 7.51-7.16 (m, 9H), 6.88 (d, 0.70  1H),

13 6.63-6.47 (m, 1.3H); C NMR (75 MHz, CDCl3) δ 135.8, 135.5, 135.4, 134.6, 131.8,

131.4, 130.2, 130.1, 129.6, 129.2, 127.4, 127.3, 127.2, 125.9, 124.9, 121.2, 120.9; HR

EIMS: 289.9767 m/z (calcd. for C14H11BrS: 289.9759).

(4-Chlorostyryl)(phenyl)sulfane (3ab, Z/E = 44:56).105 Obtained as a yellow

1 solid in 93% yield. H NMR (300 MHz, CDCl3) δ 7.48-7.22 (m, 9H), 6.86 (d, 0.56  1H),

13 6.62 (d, 0.56  1H), 6.52 (s, 0.44  2H); C NMR (75 MHz, CDCl3) δ 135.8, 135.1,

134.9, 134.7, 133.1, 130.2, 130.2, 130.1, 129.9, 129.7, 129.2, 128.8, 128.5, 127.4, 127.2,

127.1, 126.9, 125.9, 124.7; HR EIMS: 246.0269 m/z (calcd. for C14H11ClS: 246.0265).

Chapter 2: Decarboxylative C―S Cross-Coupling 44

(Z)-(2-Methylstyryl)(4-methoxybenzyl)sulfane (3ac, Z/E = 100:0). Obtained as

1 a yellow liquid in 95% yield. H NMR (300 MHz, CDCl3) δ 7.54 (d, 1H), 7.38 (d, 2H),

7.26-7.11 (m, 3H), 6.86 (d, 2H), 6.60 (d, 1H), 6.44 (d, 1H), 3.79 (s, 3H), 2.32 (s, 3H); 13C

NMR (75 MHz, CDCl3) δ 159.3, 136.0, 135.3, 132.7, 130.0, 128.6, 128.3, 127.3, 126.8,

125.5, 124.6, 114.7, 55.3, 19.9; HR EIMS: 256.0917 m/z (calcd. for C16H16OS:

256.0922).

(4-Bromostyryl)(octyl)sulfane (3ad, Z/E = 68:32). Obtained as a light yellow

1 liquid in 94% yield. H NMR (500 MHz, CDCl3) δ 7.50-7.13 (m, 4H), 6.73 (d, 0.32 

1H), 6.42-6.26 (m, 1.68H), 2.79 (t, 2H), 1.69 (quint, 2H), 1.41-1.28 (m, 10H), 0.89 (t,

13 3H); C NMR (125 MHz, CDCl3) δ 136.1, 136.0, 131.6, 131.3, 130.1, 129.8, 128.8,

128.3, 126.9. 126.5, 124.0, 120.2, 35.9, 32.6, 31.8, 30.2, 29.4, 29.1, 28.7, 28.5, 22.6, 14.0;

HR EIMS: 326.0699 m/z (calcd. for C16H23BrS: 326.0704).

Chapter 2: Decarboxylative C―S Cross-Coupling 45

(4-Chlorostyryl)(octyl)sulfane (3ae, Z/E = 51:49). Obtained as a yellow liquid

1 in 95% yield. H NMR (300 MHz, CDCl3) δ 7.44-7.17 (m, 4H), 6.71(d, 0.49  1H),

6.42-6.36 (m, 1H), 6.27 (d, 0.51  1H), 2.79 (t, 2H), 1.69(quint, 2H), 1.41-1.28 (m, 10H),

13 0.89 (t, 3H); C NMR (75 MHz, CDCl3) δ 135.7, 135.5, 132.2, 132.0, 129.8, 128.7,

128.6, 128.3, 126.6, 126.4, 125.1, 124.0, 35.9, 32.6, 31.8, 30.2, 29.4, 29.1, 28.8, 28.5,

22.6, 14.1; HR EIMS: 282.1210 m/z (calcd. for C16H23ClS: 282.1209).

(4-Bromostyryl)(4-methoxybenzyl)sulfane (3af, Z/E = 70:30). Obtained as a

1 yellow solid in 92% yield. H NMR (300 MHz, CDCl3) δ 7.47-7.26 (m, 5H), 7.10 (d,

1H), 6.87 (d, 2H), 6.72 (d, 0.30  1H), 6.43 (d, 0.30  1H), 6.36-6.26 (m, 0.70  2H),

13 3.96 (m, 2H), 3.80 (s, 3H); C NMR (75 MHz, CDCl3) δ 159.0, 158.9, 135.9, 135.8,

131.7, 131.3, 130.1, 130.0, 129.9, 129.0, 128.9, 127.1, 127.0, 126.2, 125.7, 124.5, 120.5,

120.3, 114.2, 114.1, 55.3, 39.0, 36.7; HR EIMS: 334.0020 m/z (calcd. for C16H15OBrS:

334.0021).

Chapter 2: Decarboxylative C―S Cross-Coupling 46

O

S Cl

(4-Chlorostyryl)(4-methoxybenzyl)sulfane (3ag, Z/E = 58:42). Obtained as a

1 yellow solid in 94% yield. H NMR (300 MHz, CDCl3) δ 7.40-7.15 (m, 6H), 6.88 (d,

2H), 6.71 (d, 0.42  1H), 6.45 (d, 0.42  1H), 6.36 (d, 0.58  1H), 6.28 (d, 0.58  1H),

13 3.98-3.96 (m, 2H), 3.81 (s, 3H); C NMR (75 MHz, CDCl3) δ 159.0, 158.9, 135.5, 135.4,

132.4, 132.2, 130.1, 129.9, 129.8, 129.1, 128.9, 128.7, 128.3, 126.9, 126.7, 126.2, 125.5,

124.4, 114.1, 114.0, 55.3, 38.9, 36.7; HR EIMS: 290.0528 m/z (calcd. for C16H15OClS:

290.0527).

Chapter 3: Cu-catalysed C―H Activation/C―S Cross-Coupling 47

CHAPTER 3

Copper-Catalyzed C―H Activation/C―S Cross-Coupling of Heterocycles with Thiols

Chapter 3: Cu-catalysed C―H Activation/C―S Cross-Coupling 48

3.1 Introduction

The formation of C―S bonds, fundamental to the art of organic synthesis, represents a key step to the synthesis of a broad range of biologically important molecules and functional materials.106 In particular, 2-thio-substituted-1,3-benzothiazoles are essential building blocks found in a large number of pharmaceutically active molecules. These molecules include Cathepsin-D inhibitor (A), potent heat shock protein-

90 inhibitor (B), avarol-3’-thiobenzothizole (C), 2-(thiocyanatomethylthio)-1,3- benzothiazole (TCMBT; D), and dual antagonist for the human CCR1 and CCR3 receptors (E) (Figure 3.1).106 Additionally, 2-thio-substituted-1,3-benzothiazoles have also been found in advanced materials used as corrosion inhibitors, vulcanization catalysts in the rubber industry as well as reagents for metal-catalyzed cross-coupling reactions.107

The most straightforward method for the synthesis of 2-(arylthio)benzothiazoles involves either cross-coupling of mercapto-benzothiazole with aryl halides (route a,

Scheme 3.1) or a nucleophilic attack of arylthiols by preformed 2-halobenzothiazoles

(route b, Scheme 3.1).108,109 Alternatively, the 2-(arylthio)-benzothiazole can be prepared through intramolecular S-arylation of a dithiocarbamate.110,111 Despite the promise of these methods, there are significant limitations typically associated with the need of mercapto-benzothiazole or organohalide precursors and multi-step procedures. Therefore, a new synthetic method that allows direct thiolation of benzothiazole and its analogues with alkyl or aryl thiols via C―H bond activation would be highly desirable due to the simplified one-step procedure and the elimination of halocarbon precursors.

Over the past decades, extensive efforts have been undertaken to develop Chapter 3: Cu-catalysed C―H Activation/C―S Cross-Coupling 49

Figure 3.1: Examples of biologically active molecules containing the 2-thio-1,3- benzothiazole scaffold.

Scheme 3.1: Classical routes for the synthesis of 2-arylthiobenzothiazoles

Chapter 3: Cu-catalysed C―H Activation/C―S Cross-Coupling 50 the synthetic strategies which directly functionalize C―H grou C―C or C―N/O bonds by using Rh-, Ru-, and (more extensively) Pd based noble metal catalysts.112,113 Few instances of copper-catalyzed C―H bond arylation have also been reported in the literature.114 However, an important challenge in C―H activation lies in the direct installation of sulfur moiety on aryl, alkyl or heterocycle C―H bonds. This is partly due to the propensity of thiols toward oxidative dimerization and their affinity for metals, resulting in reduced catalytic efficiency. As part of our longstanding interest in developing novel C–S cross-coupling reactions, we recently developed a convenient strategy for the synthesis of aryl-substituted benzothiazoles and benzoxazoles through use of arylboronic acids by metal-catalyzed direct arylation reactions.115 Herein, we report a new preparation of 2-thio-substituted-1,3-benzothiazoles by direct C–H bond functionalization with alky or aryl thiols in the presence of copper catalysts. We also present mechanistic investigations that suggest a stepwise reaction mechanism involving a hydrogen atom abstraction pathway.

3.2 Results and Discussion

3.2.1 Development of direct thiolation of benzothiazole: The coupling of benzothiazole (1a) with electron-rich 4-methoxythiophenol (2a) was chosen as a model system to determine the optimum reaction conditions and the selected results are summarized in the Table 3.1. In the absence of a metal catalyst or ligand, only trace amounts of desired products (3a) were obtained after 24 h (Table 3.1, entries 1 and 2).

However, to our surprise, on adding a combination of CuI (20 mol%) and 2,2′-bipyridine

o ligand (L1) in presence of K3PO4 in DMSO at 100 C, the desired product 3a was Chapter 3: Cu-catalysed C―H Activation/C―S Cross-Coupling 51

Table 3.1: Optimization of the C―S cross-coupling of benzothiazole with 4- methoxythiophenol.a

a Conditions: benzothiazole (1.0 mmol), 4-Methoxythiophenol (1.5 mmol), solvent (3 mL), base (2.5 equiv), 140 oC, 24 h. b GC yield. c The entry has been done with out ligand, d Isolated yield is in parenthesis. Bipy = 2,2′-bipyridine.

Chapter 3: Cu-catalysed C―H Activation/C―S Cross-Coupling 52 obtained in 15% yield (Table 3.1, entry 3). The yield of 3a could be improved with an increased amount of CuI/L1 (Table 3.1, entries 4 and 5) or at an increased reaction temperature (Table 3.1, entries 6 and 7). Further experimentations revealed that this C–S cross-coupling reaction was effective in a range of polar aprotic solvents such as DMSO,

DMF, and NMP (Table 3.1, entries 8 and 9). In stark contrast, the coupling reaction proceeded less efficiently in polar protic solvents (PEG, EG) or nonpolar solvent

(dioxane). In all cases studied, the conversion is less than 10% (Table 3.1, entries 10-12).

Notably, the reactions through use of strong bases, including NaOtBu, KOtBu, KOH and

Cs2CO3, occurred with low reaction conversions (Table 3.1, entries 13-16). The reaction with K2CO3 or Na2CO3 as the base resulted in the formation of 3a in 54% and 99% yield, respectively (Table 3.1, entries 17 and 18). From subsequent examinations of various copper sources (Table 3.1, entries 19-22), CuI proved to be the best catalyst (Table 3.1, entry 18).

Ligand influence on the thiolation of benzothiazole: To investigate the ligand effect on the C–S cross-coupling, a series of Cu(I)-catalyzed reactions between 1a and arylthiol 2a or alkylthiol (1-octanethiol; 2e) in presence of different ligands were carried out under the standard reaction conditions. The structures of the ligands and the summery of the results are shown in Figure 3.2. Nitrogen-based bidentate or tridentate ligands (L1 to L6) and oxygen-based bidentate ligand (L7) that stabilize the Cu(I) species in solutions are well studied for C–S cross-coupling reactions.111a,116 In our studies, the reaction with added L1 gave high reaction yields for both aryl and alkyl thiol substrates.

By comparison, 1,10-phenanthroline (L2), DMEDA (L3) and TMEDA (L4) were much Chapter 3: Cu-catalysed C―H Activation/C―S Cross-Coupling 53

Figure 3.2: Effect of ligand on the cross-coupling of benzothiazoles with thiols. Reaction conditions: 1a (1.0 mmol), 2a (1.5 mmol), CuI/ligand (1.0 equiv/1.0 o equiv), Na2CO3 (2.5 equiv) in DMF (3 mL) at 100 C for 24 h.

Chapter 3: Cu-catalysed C―H Activation/C―S Cross-Coupling 54 less effective for the alkythiol substrate. In the case of using N1-(2-

(dimethylamino)ethyl)-N1,N2,N2-trimethylethane-1,2-diamine (L5), ethane-1,2-diamine

(L6) and pentane-2,4-dione (L7), satisfactory results were not obtained for both aryl and alky thiol substrates.

3.2.2 Scope of the reaction: In a further set of experiments, we examined the scope and generality of the approach for the direct thiolation of benzothiazole 1a with a series of alky and aryl thiols (2b–o) under the optimum reaction conditions. Our results showed that both alkyl and aryl thiols can be efficiently converted to the corresponding cross-coupling products (Table 3.2). Importantly, good chemoselectivity was observed in the coupling of 1a with 4-bromothiophenol 2m or 4-chlorothiophenol 2n. In both cases, the benzothiazole underwent direct thiolation with the halogenated arylthiol substrates to give the desired bromo- or chloro-substituted 2-(arylthio)benzothiazoles (3m and 3n) in relatively high yield (Table 3.2, entries 12 and 13). Functional group tolerance was also tested in the reaction of benzothiazole and 4-aminothiolphenol 2o. We found that the amine substituent had no marked effect on the reaction yield (Table 3.2, entry 3o). The

GC/MS analysis of the reaction mixture revealed that no C―N coupling product is formed. Importantly, the amine-substituted benzothiazole 3o enables direct derivatization by reacting with 3,5-dichloro-2-hydroxybenzoic acid in presence of O-(7- azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) to give the Cathepsin-D inhibitor analogue (3p), demonstrating a potential utility of our simplified strategy for accessing a broad range of biologically important molecules

(Figure 3.3).

Chapter 3: Cu-catalysed C―H Activation/C―S Cross-Coupling 55

Table 3.2: CuI/Bipy-catalyzed direct thiolation of benzothiazole with thiols.a

Chapter 3: Cu-catalysed C―H Activation/C―S Cross-Coupling 56

Table 3.2: CuI/Bipy-catalyzed direct thiolation of benzothiazole with thiolsa (cont.).

a Conditions: benzothiazole (1.0 mmol), thiols (1.5 mmol), DMF (3 mL), CuI (1.0 equiv), o b 2,2′-bipyridine (1.0 equiv), Na2CO3 (2.5 equiv), 140 C, 24 h. Isolated yield.

Figure 3.3: Synthesis of cathepsin-D analogues.

Chapter 3: Cu-catalysed C―H Activation/C―S Cross-Coupling 57

In addition to the benzothiazole substrate 1a, other substituted heterocycles can react with arylthiols to furnish the corresponding aryl sulfides. For example, under the standard reaction conditions 1,3-thiazole is selectively monothiolated at the 2-position by

4-methoxythiophenol 2a to generate the cross-coupling product (3q) in 79% yield (Table

3.3). Similarly, 4,5-dimethylthiazole and 1-methylbenzimidazole can be directly thiolated by 2a to afford the cross-coupling thiazole and imidazole products (3r and 3s) in 86% and 96% yields, respectively (Table 3.3). Interestingly, indole and its methylated derivatives can also be selectively monothiolated at the 2-position in good yields (3t–v) by reacting with phenylthiol 2i (Table 3.3).

Chapter 3: Cu-catalysed C―H Activation/C―S Cross-Coupling 58

Table 3.3: Scope of heteroarene coupling partners.a

a Conditions: benzothiazole (1.0 mmol), thiols (1.5 mmol), DMF (3 mL), CuI (1.0 equiv), 2,2′- o b bipyridyl (1.0 equiv), Na2CO3 (2.5 equiv), 140 C, 24 h. Isolated yield.

Chapter 3: Cu-catalysed C―H Activation/C―S Cross-Coupling 59

3.3 Mechanistic studies

3.3.1: First reactive intermediate: In an effort to gain a better understanding of the reaction mechanism, we carried out density functional theory (DFT) studies and concurrently conducted control experiments to verify our hypothesis. The first active intermediate formed may be either the C–H activated Cu-benzothiazole complex (Ia)117-

120 or Cu-thiolate complex (Ib) (Scheme 3.2). Results from our modeling suggested that the formation of the Cu-thiolate complex Ib is thermodynamically more favored than the

Cu-benzothiazolate complex Ia by 19.8 kcal/mol (Figure 3.5). Further experimental evidence was delineated from two parallel experiments. The reaction of benzothiazole with CuI, 2,2′-bipyridine and Na2CO3 dissolved in deuterated dimethylformamide showed no formation of the perceived C–H activated product Ia upon heating at 110 °C for 4 h based on in situ 1H NMR analysis (Scheme 3.3, path A and Figure 3.5). In sharp contrast, the second control experiment involving a two-step procedure and the formation of a Cu-thiolate complex gave rise to the cross-coupling product, 3e, in 57 % yield

(Scheme 3.3, path B). These data provide strong support that the reaction between the benzothiazole and thiol substrates under our standard reaction conditions may operate via the formation of the Cu-thiolate complex intermediate.

3.3.2 β-hydride elimination (BHE) Vs. Hydrogen atom abstraction (HAA):

Mechanistic scenarios into Cu-catalyzed Ullmann-type coupling reactions have been proposed and explored.121 Single electron transfer (SET), hydrogen atom transfer (HAT),

σ-bond metathesis and oxidative addition/reductive elimination (OA/RE) pathways were evaluated in order to search for the most plausible pathway (Scheme 3.4). The SET and

HAT pathways were first ruled out due to significantly increased energies of Chapter 3: Cu-catalysed C―H Activation/C―S Cross-Coupling 60

Scheme 3.2: Working Hypothesis.

Chapter 3: Cu-catalysed C―H Activation/C―S Cross-Coupling 61

Scheme 3.3: Control experiments supporting the formation of thio-substituted benzothiazole via path B.

Figure 3.5: 1H NMR characterizations in deteurated DMF confirming the failed attempt to the synthesis of the Cu-benzothiazole complex. (a) Room-temperature (~23 oC) 1H NMR spectrum of a solution containing the benzothiazole compound. (b) Room-temperature 1H NMR spectrum of a solution containing benzothiazole, o 2,2′-bipyridine, CuI, and Na2CO3. (c) 1H NMR spectrum, obtained at 110 C, of a solution in the presence of benzothiazole, 2,2′-bipyridine, CuI, and Na2CO3.

Chapter 3: Cu-catalysed C―H Activation/C―S Cross-Coupling 62

Scheme 3.4: Plausible Ullmann type reaction pathways: single electron transfer (SET), hydrogen atom transfer (HAT), and σ-bond metathesis, and oxidative addition/reductive elimination (OA/RE).

Chapter 3: Cu-catalysed C―H Activation/C―S Cross-Coupling 63 intermediates relative to I by 136.0 and 88.4 kcal/mol, respectively. The other two pathways were also excluded as the OA/RE CuIII intermediate optimization failed with the thiazolate breaking off and non-convergence for the σ-bond metathesis transition state structures. It was observed that the formation of the proposed cuprous hydride species resulting from all above-mentioned processes is unlikely (+39.5 kcal/mol relative to I), suggesting that the preceding TS minima, even if located, would be of considerably higher energy and unattainable under our reaction conditions. Alternative pathways, independent of the Ullmann type, were therefore proposed and examined (Scheme 3.5).

Starting from Cu-thiolate intermediate I, a benzothiazole-coordinated intermediate II was proposed and located. The phenylthiolate group was then found to migrate onto the electrophilic sp2 carbon of the benzothiazole moiety to form the Cu- mercaptobenzothiazole complex IV via transition state TS-III. The occurrence of β- hydride elimination process from IV via transition state TS-Vb to CuI-hydrido intermediate VIb and the product was ruled out due to the high overall transition state energy of 57.5 kcal/mol (Figures 3.5 and 3.6). These observations urged us to consider the involvement of oxygen in these processes (Scheme 3.5).

Reports on C–H bond activation/functionalization by CuII-superoxo complexes in biological enzymes such as dopamine hydroxylase and peptidylglycine α-hydroxylating monooxygenases prompted us to construct models for probing the reactivity of V(3), which is believed to form through dioxygen binding to IV.122 The geometry of the optimized triplet state intermediate V(3) shows characteristic superoxo O–O bond length of 1.26 Å and Cu–O–O bond angle of 119.0° (Figure 3.6).123 The distance of 2.23 Å between the terminal O and the C2 hydrogen suggests that it is well positioned for the Chapter 3: Cu-catalysed C―H Activation/C―S Cross-Coupling 64

Scheme 3.5: Proposed reaction Mechanism.

Figure 3.5: Schematic representation (energy vs reaction coordinate) of the Cu(I) mediated C–S cross-coupling reaction. Inset: selected energies of intermediates and transition state comparing with the energy of the optimized mininum energy crossing point (MECP) structure. Chapter 3: Cu-catalysed C―H Activation/C―S Cross-Coupling 65 subsequent hydrogen abstraction step. Through transition state TS-VI(3), the hydroperoxo complex VII(3) is located but at +18.0 kcal/mol relative to the singlet hydroperoxo complex VII(1). By computing the potential energy surfaces of V for both singlet and triplet states in the abstraction of the C2 hydrogen, it was observed that the two profiles intersect before TS-VI(3) at the hypothetical point termed as the minimum crossing energy point (MECP) (Figure 3.5),124-127 which serves to rationalize the transitioning of triplet energy surface to single energy surface. Utilizing a code developed by Harvey and co-workers,128 the MECP geometry and its corresponding energy was estimated to be 2.0 kcal/mol lower than TS-VI(3) (Figure 3.6). It is portrayed that the bond length of the dioxygen elongates as it reaches to abstract the hydrogen, beginning with O–O bond length of 1.26 Å to 1.33 Å of MECP and finally to the hydroperoxo VII(1) O–O bond length of 1.49 Å.129 Complex VII(1) will dissociate to the desired product and CuI- hydroperoxo complex. We believe that the CuI-hydroperoxo complex will be subsequently oxidized to CuII species and no longer participate in the reaction.130

To elucidate the critical role of molecular oxygen in mediating the coupling reaction, we also conducted a series of experiments by varying the concentration of oxygen. As summarized in Table 3.4, the reaction between benzothiazole 1a and 1- octanethiol (1e) conducted under N2 did not proceed (entry 1). Intriguingly, the yield of coupling product 3e increases with higher oxygen concentration and reaches 72% in air

(entries 2-4). However, the reaction yield decreased significantly to 30% when the reaction was conducted under a pure oxygen atmosphere. The suppressed production is likely due to the facile formation of disulfide by-products generated by oxidation of 1- octanethiol at elevated oxygen concentrations (Figure 3.7). Chapter 3: Cu-catalysed C―H Activation/C―S Cross-Coupling 66

Figure 3.6: Optimized geometries of selected transition states and intermediates showing key bond lengths.

Chapter 3: Cu-catalysed C―H Activation/C―S Cross-Coupling 67

Table 3.4: Effect of atmosphere on the cross-coupling reactions.a

a Conditions: benzothiazole (1.0 mmol), thiols (1.5 mmol), DMF (3 mL), CuI (1.0 equiv), 2,2′- o b bipyridine (1.0 equiv), Na2CO3 (2.5 equiv), 140 C, 24 h. GC yields.

Figure 3.7: Comparative control experiments showing the yield of the disulfide product for octanethiol oxidation reaction as a function of reaction time under pure oxygen and aerobic condition, respectively. The results show that the oxidation of octanethiol to disulfide product is facilitated by oxygen in the presence of copper. Chapter 3: Cu-catalysed C―H Activation/C―S Cross-Coupling 68

3.4 Conclusion

We have reported the first example of copper mediated C–S cross-coupling through direct functionalization of a heterocycle C–H bond. By using this synthetic strategy, various substituted 2-mercaptobenzothiazoles, imidazoles and indoles were conveniently synthesized in good yields. The copper-mediated protocol is palladium free, tolerates a variety of functional groups, and eliminates the need for an organohalide species. Mechanistic investigations of this organic transformation revealed that the generation of the first reactive intermediate as Cu-thiol complex occurs instead of the generally accepted Cu-thiazole complex, as corroborated by DFT calculations. We postulated that molecular oxygen participates in the reaction by abstracting the hydrogen from the C2 carbon of the thiazole to form the Cu-hydroperoxo compound. Further work is underway to expand the scope of this direct C–S bond functionalization reaction.

Chapter 3: Cu-catalysed C―H Activation/C―S Cross-Coupling 69

3.5 Experimental Section

General Methods: Unless otherwise stated, all reactions were carried out without taking precautions to exclude air and moisture. All solvents were used as received. All the chemicals were purchased from commercial sources and used as received unless stated otherwise. Reactions were conducted in 20 mL vials equipped with a conventional crew cap. All reaction temperatures refer to oil-bath temperatures. Column chromatography was carried out on silica gel (230-400 mesh). The yields of the coupling product listed in Tables 3.2 and 3.3 refer to isolated yields (average of two runs).

Physical Measurements: 1H NMR and 13C NMR spectra were recorded on a

Bruker ACF 300 and 75 MHz FT-NMR spectrometers as well as Bruker Avance 500 and

125 MHz FT-NMR spectrometers and referenced to solvent peaks. Coupling reactions of benzothiazole with 4-methoxybenzenethiol shown in Table 3.1 and in Figure 3.2 were determined by using Hewlett- Packard Series 6890 GC (Santa Clara, CA, USA) coupled to a Hewlett Packard 5973 MS detector. High-resolution mass spectra were obtained using a Finnigan MAT95XL-T mass spectrometer.

A General procedure for C―S cross-coupling: To a solution of N,N- dimethylformamide (DMF) (3 mL) charged with benzothizole (1a, 0.5 mmol) and 4- methoxybenzenethiol (2a, 0.75 mmol) was added CuI (95.2 mg, 0.5 mmol), 2,2′- bipyridyl (78 mg, 0.5 mmol), Na2CO3 (2.5 equiv.). The resulting mixture was stirred at

140 °C and monitored by TLC. Upon completion of the reaction (approx. 24 h), the mixture was cooled to room temperature and admixed with water (15 mL). The product was extracted with ethylacetate (3 x 15 mL), organic layer dried over anhydrous Na2SO4, concentrated under reduced pressure, and purified over column of silica gel (EtOAc: Chapter 3: Cu-catalysed C―H Activation/C―S Cross-Coupling 70

Hexane as eluents) to give the corresponding product. The identity and purity of the products were confirmed by spectroscopic analysis.

Synthesis of CuSPh complex. The copper-Complex is prepared according to the

114j previously reported method. To an ice-cold mixture of 25 mL conc. aq. NH3 and 100 mL H2O was added CuSO4.5H2O (6.26 g, 25.1 mmol) forming a royal blue-colored solution. Then, solid NH2OH.HCl (3.89 g, 56.0 mmol) was added to the mixture which

o was stirring overnight at 25 C under N2 purge to produce a colorless solution of

+ [Cu(NH3)2] . A solution of PhSH (2.84 g, 25.8 mmol) in 125 mL of EtOH was added drop wise. A pale yellow solid formed immediately. The solid product was collected via filtration and was washed several times with H2O, EtOH, and ether in succession and

1 vacuum-dried. Yellowish solid; H NMR (500 MHz, D6-DMSO): δ 7.51 (d, J = 10 Hz,

2H), 7.37 (t, J = 10 Hz, 2H), 7.28 (t, J = 5 Hz, 1H).

Spectral data

S S O N

2-(4-methoxyphenylthio)benzo[d]thiazole (3a).111b Obtained as a white solid in

1 95% yield. H NMR (500 MHz, CDCl3): δ 7.86-7.85 (d, 1H), 7.68-7.62 (m, 3H), 7.4-7.37

13 (t, 1H), 7.26-7.22 (t, 1H), 7.02-6.99 (d, 2H), 3.88 (s, 3H); C NMR (125 MHz, CDCl3): δ

171.8, 161.7, 154.2, 137.5, 135.4, 126, 124, 121.8, 120.7, 120.2, 115.5, 55.4; HR EIMS:

273.0264 m/z (calcd. for C14H11ONS2: 273.0282).

Chapter 3: Cu-catalysed C―H Activation/C―S Cross-Coupling 71

S S (CH2)2CH3 N

2-(propylthio)benzo[d]thiazole (3b).131 Obtained as a yellow liquid in 85%

1 yield. H NMR (300 MHz, CDCl3): δ 7.88-7.85 (d, 1H), 7.76-7.73 (d, 1H), 7.43-7.38 (t,

1H), 7.31-7.26 (t, 1H), 3.35-3.31 (t, 2H), 1.92-1.80 (m, 2H), 1.11-1.06 (t, 3H); 13C NMR

(125 MHz, CDCl3): δ 167.4, 153.2, 135.1, 126, 124.1, 121.4, 120.9, 35.5, 22.7, 13.4; HR

EIMS: 209.0329 m/z (calcd. for C10H11NS2: 209.0333).

S S (CH2)3CH3 N

2-(butylthio)benzo[d]thiazole (3c). Obtained as a yellow liquid in 93% yield. 1H

NMR (500 MHz, CDCl3): δ 7.87-7.86 (d, 1H), 7.75-7.74 (d, 1H), 7.42-7.39 (t, 1H), 7.30-

7.27 (t, 1H), 3.36-3.34 (t, 2H), 1.84-1.78 (m, 2H), 1.5-1.47 (m, 2H), 0.98-0.95 (t, 3H);

13 C NMR (125 MHz, CDCl3) δ 167.4, 153.4, 135.1, 126, 124.1, 121.4, 120.9, 33.3, 31.2,

21.9, 13.6; HR EIMS: 223.0489 m/z (calcd. for C11H13NS2: 223.0489).

S S (CH2)5CH3 N

2-(hexylthio)benzo[d]thiazole (3d). Obtained as a yellow liquid in 80% yield.

1 H NMR (300 MHz, CDCl3): δ 7.92-7.89 (d, 1H), 7.80-7.77 (d, 1H), 7.47-7.42 (t, 1H),

7.35-7.30 (t, 1H), 3.41-3.36 (t, 2H), 1.91-1.81 (quint, 2H), 1.57-1.47 (quint, 2H), 1.41-

13 1.29 (m, 4H), 0.96-0.91 (t, 3H); C NMR (125 MHz, CDCl3): δ 167.4, 153.4, 135.1, 126,

124.1, 121.4, 120.8, 33.6, 31.2, 29.1, 28.4, 22.4, 14; HR EIMS: 251.0791 m/z (calcd. for

C13H17NS2: 251.0802). Chapter 3: Cu-catalysed C―H Activation/C―S Cross-Coupling 72

S S (CH2)7CH3 N 2-(octylthio)benzo[d]thiazole (3e). Obtained as a yellow liquid in 66% yield. 1H

NMR (500 MHz, CDCl3): δ 7.87-7.85 (d, 1H), 7.75-7.74 (d, 1H), 7.42-7.39 (t, 1H), 7.30-

7.25 (t, 1H), 3.35-3.34 (t, 2H), 1.85-1.79 (quint, 2H), 1.5-1.45 (quint, 2H), 1.35-1.26 (m,

13 8H), 0.90-0.87 (t, 3H); C NMR (125 MHz, CDCl3): δ 167.4, 153.3, 135.1, 126, 124.1,

121.4, 120.8, 33.7, 31.7, 29.2, 29.1, 29, 28.7, 22.6, 14; HR EIMS: 279.1112 m/z (calcd. for C15H21NS2: 279.1115).

S S (CH2)11CH3 N

2-(dodecylthio)benzo[d]thiazole (3f).132 Obtained as a yellow liquid in 75%

1 yield. H NMR (500 MHz, CDCl3): δ 7.87-7.86 (d, 1H), 7.75-7.74 (d, 1H), 7.42-7.39 (t,

1H), 7.30-7.27 (t, 1H), 3.36-3.33 (t, 2H), 1.85-1.80 (quint, 2H), 1.50-1.45 (m, 2H), 1.35-

13 1.26 (m, 16H), 0.89-0.87 (t, 3H); C NMR (125 MHz, CDCl3): δ 167.4, 153.3, 135.1,

125.9, 124.1, 121.4, 120.9, 33.6, 31.9, 29.63, 29.61, 29.5, 29.4, 29.3, 29.2, 29, 28.7, 22.6,

14.1; HR EIMS: 335.1741 m/z (calcd. for C19H29NS2: 335.1741).

S S N

2-(phenethylthio)benzo[d]thiazole (3g).131 Obtained as a light yellow liquid in

1 62% yield. H NMR (500 MHz, CDCl3): δ 7.89-7.88 (d, 1H), 7.76-7.74 (d, 1H), 7.43-

7.40 (t, 1H), 7.34-7.22 (m, 6H), 3.61-3.57 (t, 2H), 3.15-3.12 (t, 2H); 13C NMR (125 MHz, Chapter 3: Cu-catalysed C―H Activation/C―S Cross-Coupling 73

CDCl3): δ 166.6, 153.3, 139.7, 135.3, 128.7, 128.6, 126.7, 126, 124.2, 121.5, 121, 35.6,

34.8; HR EIMS: 271.0484 m/z (calcd. for C15H13NS2: 271.0489).

S S N

2-(cyclohexylthio)benzo[d]thiazole (3h). Obtained as a yellow liquid in 93%

1 yield. H NMR (500 MHz, CDCl3): δ 7.88-7.87 (d, 1H), 7.75-7.74 (d, 1H), 7.42-7.39 (t,

1H), 7.30-7.27 (t, 1H), 3.93-3.87 (m, 1H), 2.22-2.18 (m, 2H), 1.82-1.78 (m, 2H), 1.67-

13 1.29 (m, 6H); C NMR (125 MHz, CDCl3): δ 166.4, 153.4, 135.3, 125.9, 124.1, 121.6,

120.8, 47.3, 33.3, 25.8, 25.6; HR EIMS: 249.0636 m/z (calcd. for C13H15NS2: 249.0646).

S S N

2-(phenylthio)benzo[d]thiazole (3i).111b Obtained as a light yellow liquid in

1 90% yield. H NMR (300 MHz, CDCl3): δ 7.89-7.86 (d, 1H), 7.75-7.72 (d, 2H), 7.66-

13 7.63 (d, 1H), 7.51-7.37 (m, 4H), 7.28-7.23 (t, 1H); C NMR (75 MHz, CDCl3): δ 169.6,

153.9, 135.5, 135.3, 130.4, 129.94, 129.9, 126.1, 124.3, 121.9, 120.7; HR EIMS:

243.0157 m/z (calcd. for C13H9NS2: 243.0176).

S S N

2-(p-tolylthio)benzo[d]thiazole (3j).111b Obtained as a white solid in 80% yield.

1 H NMR (300 MHz, CDCl3): δ 7.87-7.84 (d, 1H), 7.63-7.6 (d, 3H), 7.4-7.35 (t, 1H), 7.29-

13 7.21 (m, 3H), 2.42 (s, 3H); C NMR (75 MHz, CDCl3): δ 170.7, 154, 141.1, 135.5, 135.4, Chapter 3: Cu-catalysed C―H Activation/C―S Cross-Coupling 74

130.7, 126.2, 126, 124.1, 121.8, 120.7, 21.4; HR EIMS: 257.0314 m/z (calcd. for

C14H11NS2: 257.0333).

S S N

2-(3,5-dimethylphenylthio)benzo[d]thiazole (3k). Obtained as a light yellow

1 liquid in 95% yield. H NMR (500 MHz, CDCl3): δ 7.88-7.87 (d, 1H), 7.65-7.64 (d, 1H),

7.41-7.38 (t, 1H), 7.35 (s, 2H), 7.27-7.24 (t, 1H), 7.13 (s, 1H), 2.35 (s, 6H); 13C NMR

(125 MHz, CDCl3): δ 170.5, 153.8, 139.7, 135.5, 132.9, 132.2, 129.2, 126.1, 124.2, 121.8,

120.7, 21.2; HR EIMS: 271.0472 m/z (calcd. for C15H13NS2: 271.0489).

S S N

2-(naphthalen-2-ylthio)benzo[d]thiazole (3l). Obtained as a brown solid in 68%

1 yield. H NMR (500 MHz, CDCl3): δ 8.27 (s, 1H), 7.93-7.86 (m, 4H), 7.73-7.71 (dd, 1H),

13 7.62-7.55 (m, 3H), 7.41-7.38 (t, 1H), 7.27-7.23 (t, 1H); C NMR (125 MHz, CDCl3): δ

169.7, 153.7, 135.5, 135.4, 133.8, 133.7, 131.1, 129.7, 128.1, 127.9, 127.7, 127, 126.2,

124.4, 121.9, 120.8; HR EIMS: 293.0315 m/z (calcd. for C17H11NS2: 293.0333).

S S Br N

2-(4-bromophenylthio)benzo[d]thiazole (3m). Obtained as a yellowish white

1 solid in 56% yield. H NMR (300 MHz, CDCl3): δ 7.9-7.87 (d, 1H), 7.7-7.67 (d, 1H),

13 7.63-7.57 (m, 4H), 7.45-7.39 (t, 1H), 7.32-7.26 (t, 1H); C NMR (125 MHz, CDCl3): δ Chapter 3: Cu-catalysed C―H Activation/C―S Cross-Coupling 75

168.1, 153.7, 136.5, 135.5, 133.1, 129, 126.3, 125.1, 124.6, 122.1, 120.9; HR EIMS:

320.9265 m/z (calcd. for C13H8BrNS2: 320.9282).

S S Cl N

2-(4-chlorophenylthio)benzo[d]thiazole (3n). Obtained as a yellow liquid in

1 66% yield. H NMR (300 MHz, CDCl3): δ 7.9-7.89 (d, 1H), 7.69-7.65 (m, 3H), 7.47-7.39

13 (m, 3H), 7.32-7.27 (t, 1H); C NMR (125 MHz, CDCl3): δ 168.4, 153.7, 137, 136.4,

135.5, 130.1, 128.4, 126.3, 124.6, 122, 120.8; HR EIMS: 276.9780 m/z (calcd. for

C13H8ClNS2: 276.9787).

S S NH2 N

4-(benzo[d]thiazol-2-ylthio)aniline (3o). Obtained as a brown solid in 74%

1 yield. H NMR (500 MHz, CDCl3): δ 7.85-7.83 (d, 1H), 7.63–7.62 (d, 1H), 7.52-7.49 (d,

13 2H), 7.39-7.36 (t, 1H), 7.24-7.21 (t, 1H), 6.77-6.74 (d, 2H); C NMR (125 MHz, CDCl3):

δ 173.3, 154.3, 148.8, 137.6, 135.4, 126, 123.9, 121.6, 120.7, 116.8, 115.9; HR EIMS:

258.0274 m/z (calcd. for C13H10N2S2: 258.0285).

N S O OH S Cl N H

Cl

N-(4-(benzo[d]thiazol-2-ylthio)phenyl)-3,5-dichloro-2-hydroxybenzamide

1 (3p). Obtained as an off-white solid in 75% yield. H NMR (500 MHz, [D6] DMSO): δ Chapter 3: Cu-catalysed C―H Activation/C―S Cross-Coupling 76

12.25 (br s, 1H), 10.86 (br s, 1H), 8.07 (s, 1H), 8.06-7.82 (m, 7H), 7.47-7.44 (t, 1H),

13 7.36-7.32 (t, 1H); C NMR (125 MHz, [D6] DMSO): δ 169.5, 166.4, 154.1, 153.4, 140.1,

136.1, 134.7, 132.9, 126.6, 126.4, 124.4, 123.7, 122.6, 122.45, 122.4, 121.7, 121.3, 119.7;

HR EIMS: 445.9725 m/z (calcd. for C20H12Cl2N2O2S2: 445.9717).

S S O N

2-(4-methoxyphenylthio)thiazole (3q). Obtained as a yellow liquid in 79% yield.

1 H NMR (500 MHz, CDCl3): δ 7.65-7.64 (d, 1H), 7.62-7.59 (d, 2H), 7.14-7.13 (d, 1H),

13 6.97-6.94 (d, 2H), 3.85 (s, 3H); C NMR (125 MHz, CDCl3): δ 169, 161.2, 143.2, 136.7,

121.6, 119.3, 115.4, 55.4; HR EIMS: 223.0117 m/z (calcd. for C10H9NOS2: 223.0120).

S S O N

2-(4-methoxyphenylthio)-4,5-dimethylthiazole (3r). Obtained as a red liquid in

1 86% yield. H NMR (500 MHz, CDCl3): δ 7.57-7.54 (d, 2H), 6.93-6.90 (d, 2H), 3.83 (s,

13 3H), 2.26 (s, 3H), 2.21 (s, 3H); C NMR (125 MHz, CDCl3): δ 162.6, 160.9, 148.8,

136.2, 127.4, 122.5, 115.1, 55.3, 14.6, 11.2; HR EIMS: 251.0433 m/z (calcd. for

C12H13ONS2: 251.0439).

N S O N

2-(4-methoxyphenylthio)-1-methyl-1H-benzo[d]imidazole (3s). Obtained as a

1 brown solid in 96% yield. H NMR (500 MHz, CDCl3): δ 7.71-7.69 (d, 1H), 7.44-7.41 (d, Chapter 3: Cu-catalysed C―H Activation/C―S Cross-Coupling 77

2H), 7.25-7.19 (m, 3H), 6.87-6.84 (d, 2H), 3.76 (s, 3H), 3.71 (s, 3H); 13C NMR (125

MHz, CDCl3): δ 159.9, 149.6, 143, 136.5, 133.9, 122.7, 122.1, 121.1, 119.5, 115.1, 109,

55.3, 30.6; HR EIMS: 270.0817 m/z (calcd. for C15H14N2OS: 270.0827).

H N S

2-(phenylthio)-1H-indole (3t). Obtained as a white solid in 80% yield. 1H NMR

(300 MHz, CDCl3): δ 8.41 (br s, 1H), 7.64-7.61 (d, 1H), 7.49-7.43 (m, 2H), 7.3-7.03 (m,

13 7H); C NMR (125 MHz, CDCl3): δ 139.2, 136.5, 130.6, 129.1, 128.7, 126, 125.9, 124.8,

123, 120.9, 119.7, 111.5; HR EIMS: 225.0607 m/z (calcd. for C14H11NS: 225.0612).

H N S

5-methyl-2-(phenylthio)-1H-indole (3u). Obtained as a white solid in 82% yield.

1 H NMR (300 MHz, CDCl3): δ 8.31 (br s, 1H), 7.44-7.43 (m, 2H), 7.34-7.31 (d, 1H),

13 7.26-7.04 (m, 6H), 2.43 (s, 3H); C NMR (125 MHz, CDCl3): δ 139.5, 134.8, 130.8,

130.4, 129.4, 128.7, 125.7, 124.7, 124.6, 119.2, 111.2, 102.1, 21.4; HR EIMS: 239.0767 m/z (calcd. for C15H13NS: 239.0769).

H N S

7-methyl-2-(phenylthio)-1H-indole (3v). Obtained as a brown colored gel in

1 85% yield. H NMR (300 MHz, CDCl3): δ 8.35 (br s, 1H), 7.50-7.46 (m, 2H), 7.20-7.03 Chapter 3: Cu-catalysed C―H Activation/C―S Cross-Coupling 78

13 (m, 7H), 2.53 (s, 3H); C NMR (125 MHz, CDCl3): δ 139.3, 136.1, 130.3, 128.8, 128.7,

125.9, 124.8, 123.6, 121.1, 120.7, 117.4, 103.4, 16.4; HR EIMS: 239.0769 m/z (calcd. for

C15H13NS: 239.0766).

4.6 Computational Details

All density functional theory (DFT) gas-phase calculations were performed with

Gaussian 09 computational suite.133 Becke’s three-parameter hybrid exchange functional and the nonlocal correlation functional of Lee, Yang and Parr (B3LYP) was applied for optimizations of all compounds and frequency analyses were done to verify minimum structures showing positive eigenvalues of the Hessian matrix or transition state structures exhibiting only a single negative eigenvalue at both restrained (RB3LYP for singlet states) and unrestrained (UB3LYP for triplet states) level of theory.134,135

LANL2DZ effective core potential of Hay and Wadt was applied for I and Ag atoms,136-

138 and the all electron split-valence Pople basis set 6-31++G(d,p) containing diffuse and polarization functions on both heavy atoms and hydrogens was used for the rest of atoms.139-141 Minimum Crossing Energy Point (MECP) was determined and optimized with the code designed by Harvey and co-workers at the same level of theory.128,142 This

Fortan-based code together with shell scripts extract calculated Gaussian output energies and gradients of two input structures with different spin states to generate an effective gradient towards the MECP. All energies reported are sum of electronic energy with ZPE corrections except for the estimation of MECP energy.

Chapter 3: Cu-catalysed C―H Activation/C―S Cross-Coupling 79

Cartesian coordinates and geometries of intermediates and transition states

Thiophenol C 3.053921 -1.01731 -0.40453 C 4.451921 -1.01491 -0.39312 C 5.15281 0.19456 -0.38669 C 4.451949 1.404034 -0.39459 C 3.053948 1.40645 -0.406 C 2.350594 0.194585 -0.39898 H 2.50608 -1.9543 -0.41748 H 4.990919 -1.95816 -0.39332 H 6.239039 0.194552 -0.3804 H 4.990968 2.347272 -0.39595 H 2.506128 2.343445 -0.42008 S 0.54509 0.194569 -0.46691 H 0.32827 0.195213 0.866149

Benzothiazole C -1.01864 -0.51788 0.110239 C 0.362061 -0.25829 0.214725 C 0.859549 1.039764 0.117647 C -0.05363 2.080542 -0.08738 C -1.44524 1.831136 -0.19441 C -1.92611 0.515912 -0.0935 H -1.37677 -1.53987 0.190038 H 1.051953 -1.08184 0.37369 H 1.924444 1.233472 0.1991 H -2.99245 0.332112 -0.17605 N -2.23528 2.956349 -0.39731 C -1.5049 4.021645 -0.44578 H -1.90234 5.019417 -0.59596 S 0.235885 3.80112 -0.25171

(Bipyridyl)copper iodide complex H 1.962359 -4.57703 0 C 2.083033 -3.49901 0 C 2.27006 -0.74658 0 C 0.962683 -2.66767 0 C 3.345439 -2.90526 0 C 3.442246 -1.5144 0 H -0.04503 -3.07321 0 H 4.244699 -3.5138 0 Chapter 3: Cu-catalysed C―H Activation/C―S Cross-Coupling 80

H 4.417969 -1.04313 0 C 2.270051 0.74678 0 C 2.083033 3.499213 0 C 3.44224 1.514602 0 C 3.345441 2.90546 0 C 0.962683 2.667883 0 H 4.417957 1.043319 0 H 4.244699 3.514001 0 H -0.04503 3.073423 0 H 1.962363 4.577229 0 N 1.053568 -1.33132 0 N 1.053559 1.331518 0 Cu -0.60011 0.000087 0 I -3.08959 -0.00021 0

Complex I H 0.759867 3.646628 -1.67817 C 0.198338 2.720301 -1.73584 C -1.1595 0.322734 -1.79108 C 0.481288 1.675173 -0.85444 C -0.81538 2.5375 -2.67658 C -1.5053 1.325787 -2.70701 H 1.258834 1.762476 -0.10097 H -1.06996 3.326322 -3.37814 H -2.29913 1.1764 -3.4294 C -1.83285 -1.00765 -1.74081 C -2.98262 -3.50792 -1.51102 C -2.81939 -1.40064 -2.65577 C -3.39974 -2.66196 -2.53953 C -1.99534 -3.05031 -0.64043 H -3.13016 -0.73696 -3.45366 H -4.16407 -2.97781 -3.24307 H -1.63387 -3.66818 0.175665 H -3.40604 -4.49815 -1.38192 N -0.18003 0.510706 -0.88386 N -1.43365 -1.83591 -0.74797 Cu 0.070672 -1.14998 0.507244 S 1.408551 -1.38377 2.245162 C 2.332279 0.147436 2.098175 C 3.821279 2.554579 1.917149 C 1.981428 1.279438 2.860134 C 3.459921 0.244397 1.25859 C 4.190791 1.432438 1.166298 Chapter 3: Cu-catalysed C―H Activation/C―S Cross-Coupling 81

C 2.713709 2.466893 2.768262 H 1.124843 1.217371 3.524936 H 3.756379 -0.6244 0.678208 H 5.0569 1.478422 0.509995 H 2.41977 3.324805 3.368682 H 4.393579 3.475816 1.849782

(Bipyridyl)copper thiazolate Ia complex H -0.33502 2.942383 -3.50694 C -0.90943 2.675078 -2.6261 C -2.29429 1.924943 -0.36593 C -0.44884 1.679963 -1.75891 C -2.11715 3.306803 -2.32751 C -2.82475 2.931987 -1.18383 H 0.482147 1.138825 -1.91918 H -2.50894 4.084725 -2.97623 H -3.76384 3.419137 -0.94786 C -2.95155 1.432869 0.882044 C -4.05087 0.421744 3.207447 C -4.1667 1.946528 1.354269 C -4.7215 1.437383 2.526543 C -2.84629 -0.0406 2.680569 H -4.67708 2.735735 0.815506 H -5.66268 1.829287 2.900195 H -2.2852 -0.82861 3.172375 H -4.44365 -0.00614 4.123377 N -1.13034 1.325275 -0.66543 N -2.30587 0.446077 1.551263 Cu -0.5243 -0.24693 0.804292 C 1.143016 -1.11424 0.390067 C 3.019557 -1.53346 -0.80599 C 3.267145 -2.48 0.222087 N 1.842983 -0.804 -0.67649 S 1.945755 -2.41092 1.364784 C 4.418127 -3.27769 0.207356 H 4.604445 -4.00094 0.996046 C 5.324564 -3.12611 -0.84215 H 6.222309 -3.73785 -0.86755 C 5.088069 -2.18998 -1.86699 H 5.806886 -2.08793 -2.67553 C 3.944597 -1.39566 -1.85464 H 3.752194 -0.67086 -2.64041

Chapter 3: Cu-catalysed C―H Activation/C―S Cross-Coupling 82

Complex II H 2.844327 1.820911 -4.13219 C 2.81372 1.191389 -3.24909 C 2.619691 -0.37444 -0.99071 C 1.620308 1.024976 -2.54838 C 3.957146 0.544629 -2.77415 C 3.862179 -0.24338 -1.62934 H 0.70847 1.529032 -2.85607 H 4.911465 0.662803 -3.27857 H 4.746603 -0.72552 -1.22858 C 2.425131 -1.17864 0.245821 C 1.928677 -2.56369 2.578468 C 3.366515 -2.11149 0.706638 C 3.115787 -2.81053 1.884898 C 1.039017 -1.62904 2.052905 H 4.274814 -2.30152 0.14638 H 3.833627 -3.53715 2.253385 H 0.104243 -1.39854 2.555972 H 1.693976 -3.07947 3.503617 N 1.518999 0.256221 -1.45455 N 1.272698 -0.95332 0.917276 Cu -0.11916 0.383633 -0.01677 S -1.06189 2.428005 0.417743 C -3.03817 -0.35423 -0.01166 C -2.09911 -1.9708 -1.21541 C -3.44043 -2.4171 -1.27748 H -3.10122 0.561012 0.571222 S -4.46106 -1.30278 -0.38786 N -1.91153 -0.79918 -0.48601 C -0.05102 3.354945 1.545569 C -0.46955 4.643333 1.943128 C 1.167168 2.87791 2.071211 C 0.293555 5.413516 2.821668 H -1.4044 5.034659 1.551642 C 1.930139 3.65192 2.949166 H 1.511181 1.88879 1.782951 C 1.502224 4.926726 3.333966 H -0.05878 6.402208 3.107181 H 2.866146 3.253367 3.335222 H 2.09604 5.527717 4.017043 C -3.78876 -3.58044 -1.97346 H -4.81866 -3.91998 -2.01974 C -2.7736 -4.29175 -2.60964 Chapter 3: Cu-catalysed C―H Activation/C―S Cross-Coupling 83

H -3.01986 -5.1968 -3.15689 C -1.43628 -3.85248 -2.55667 H -0.66661 -4.4247 -3.06595 C -1.08933 -2.6971 -1.86484 H -0.06536 -2.34159 -1.82147

TS-III Imaginary frequency = -91.36 cm-1 H 4.743615 -4.01604 -1.17079 C 4.472966 -3.03427 -0.79749 C 3.667186 -0.55962 0.122119 C 3.137739 -2.63278 -0.78376 C 5.433402 -2.1437 -0.31714 C 5.027774 -0.89446 0.149069 H 2.349823 -3.28934 -1.14063 H 6.484225 -2.41662 -0.30123 H 5.762552 -0.19911 0.537 C 3.141168 0.754985 0.59183 C 1.994712 3.121414 1.414224 C 3.967276 1.83177 0.933983 C 3.38355 3.027891 1.353661 C 1.23647 2.006519 1.050355 H 5.045737 1.753448 0.862839 H 4.009102 3.874639 1.619852 H 0.151469 2.035318 1.064761 H 1.496806 4.033647 1.723317 N 2.743557 -1.43115 -0.33907 N 1.796216 0.853974 0.657785 Cu 0.730621 -0.8221 -0.10103 C -1.68832 -1.33932 -1.51772 C -2.02454 -1.56442 0.743074 C -3.36347 -1.77614 0.326552 H -1.17479 -1.81912 -2.34651 S -3.44379 -1.8015 -1.43731 N -1.10588 -1.4212 -0.2784 S -1.33848 0.597806 -2.51987 C -1.63425 1.920556 -1.37869 C -1.00785 3.164744 -1.61329 C -2.47629 1.809027 -0.25392 C -1.22821 4.253374 -0.76795 H -0.35402 3.271634 -2.47427 C -2.67591 2.89735 0.600746 H -2.98932 0.877515 -0.04964 Chapter 3: Cu-catalysed C―H Activation/C―S Cross-Coupling 84

C -2.05877 4.128073 0.352516 H -0.74731 5.204011 -0.98726 H -3.33264 2.780233 1.459155 H -2.23315 4.97567 1.009579 C -1.74424 -1.5387 2.119902 H -0.72287 -1.38229 2.456869 C -2.78023 -1.7183 3.039808 H -2.55555 -1.70214 4.102993 C -4.1017 -1.90993 2.61346 H -4.89727 -2.04307 3.340342 C -4.39931 -1.93235 1.243989 H -5.42039 -2.08013 0.90417

Complex IV H -5.34226 -3.55937 -0.27156 C -5.02857 -2.52121 -0.25081 C -4.11616 0.081478 -0.21382 C -3.67514 -2.19638 -0.33737 C -5.95148 -1.48085 -0.13384 C -5.49202 -0.16503 -0.11319 H -2.91511 -2.96744 -0.42497 H -7.01422 -1.68877 -0.05452 H -6.19564 0.652041 -0.00477 C -3.52795 1.450581 -0.20156 C -2.26317 3.89897 -0.17444 C -4.29377 2.617274 -0.31817 C -3.65164 3.855301 -0.30152 C -1.56502 2.694832 -0.07228 H -5.36988 2.567305 -0.43661 H -4.22957 4.76995 -0.3941 H -0.48063 2.661537 0.015149 H -1.72366 4.839959 -0.16024 N -3.22918 -0.93204 -0.32236 N -2.18345 1.503803 -0.0809 Cu -1.18227 -0.34181 -0.15854 S 2.029346 1.309801 -0.11864 C 1.571218 -0.53273 0.68735 C 1.051161 -2.12478 -0.89509 C 2.377593 -2.5473 -0.621 H 1.289083 -0.22231 1.691718 S 3.028782 -1.64045 0.750568 N 0.566822 -1.12408 -0.07653 C 3.181441 1.932267 1.089427 Chapter 3: Cu-catalysed C―H Activation/C―S Cross-Coupling 85

C 5.022762 2.885221 3.001466 C 2.735084 2.541322 2.277693 C 4.566807 1.803321 0.878854 C 5.477264 2.280016 1.825451 C 3.647752 3.012115 3.225 H 1.667909 2.650378 2.449901 H 4.918284 1.328229 -0.03123 H 6.543838 2.174899 1.644606 H 3.284827 3.480911 4.136184 H 5.732545 3.254552 3.736507 C 0.35177 -2.7585 -1.93693 H -0.65567 -2.43134 -2.18235 C 0.962934 -3.78539 -2.66303 H 0.413657 -4.26632 -3.46842 C 2.273905 -4.18831 -2.38083 H 2.740008 -4.98183 -2.95718 C 2.991792 -3.55687 -1.35388 H 4.011272 -3.85828 -1.13008

Complex V3 H -5.10452 -3.79176 -0.12545 C -4.85624 -2.73656 -0.16465 C -4.10631 -0.08399 -0.26367 C -3.52245 -2.3306 -0.20119 C -5.8455 -1.7527 -0.17574 C -5.46865 -0.41175 -0.22435 H -2.71342 -3.05539 -0.19167 H -6.89662 -2.02277 -0.14071 H -6.22662 0.362535 -0.21399 C -3.60914 1.321486 -0.30683 C -2.52245 3.855849 -0.3447 C -4.44705 2.424017 -0.52055 C -3.89575 3.704523 -0.53675 C -1.74973 2.710654 -0.14985 H -5.51001 2.291786 -0.68433 H -4.53141 4.569102 -0.70274 H -0.67271 2.76352 -0.01069 H -2.05236 4.833391 -0.35053 N -3.15594 -1.04292 -0.25249 N -2.27998 1.479245 -0.13057 S 2.038285 1.464934 -0.18159 C 1.70821 -0.36675 0.379588 C 1.043866 -1.89517 -1.24006 Chapter 3: Cu-catalysed C―H Activation/C―S Cross-Coupling 86

C 2.3856 -2.34244 -1.09297 H 1.460828 -0.25826 1.443108 S 3.190129 -1.46535 0.208776 N 0.650589 -0.88896 -0.39518 Cu -1.14071 -0.29723 0.00465 O -1.22355 -0.49603 2.232911 O -0.20913 -0.18801 2.910645 C 3.151947 2.030098 1.098877 C 4.920561 2.945879 3.081349 C 2.688413 2.288495 2.400783 C 4.510002 2.231183 0.801999 C 5.38598 2.695429 1.787007 C 3.571641 2.735709 3.386418 H 1.639338 2.136883 2.636514 H 4.870296 2.019951 -0.19979 H 6.433503 2.852306 1.544261 H 3.20361 2.926436 4.390936 H 5.603825 3.301337 3.847618 C 2.906382 -3.35618 -1.89102 H 3.935074 -3.68173 -1.76607 C 0.236595 -2.50386 -2.22146 H -0.78231 -2.15424 -2.36386 C 2.083763 -3.95888 -2.85355 H 2.479413 -4.75317 -3.47929 C 0.758148 -3.52952 -3.01115 H 0.129542 -3.99167 -3.76769

MECP H -4.42739 -2.25226 -3.77002 C -4.28831 -1.94411 -2.73932 C -3.82487 -1.13203 -0.14483 C -3.10017 -1.3278 -2.34738 C -5.27321 -2.16035 -1.77395 C -5.03959 -1.75523 -0.46022 H -2.28166 -1.15182 -3.0403 H -6.20733 -2.64838 -2.03602 H -5.78291 -1.94128 0.306318 C -3.46797 -0.6719 1.227275 C -2.60591 0.20151 3.695694 C -4.39607 -0.54646 2.270023 C -3.95548 -0.1072 3.51859 C -1.74821 0.065669 2.603731 H -5.44538 -0.76806 2.111861 Chapter 3: Cu-catalysed C―H Activation/C―S Cross-Coupling 87

H -4.6595 -8.8E-05 4.338692 H -0.69135 0.311124 2.66687 H -2.22343 0.547685 4.650217 N -2.88226 -0.92571 -1.08831 N -2.16804 -0.365 1.409185 S 2.260184 -0.55224 1.330055 C 1.768968 0.532028 -0.08965 C 0.344827 2.342422 -0.2211 C 1.542999 3.016884 -0.57762 S 2.914444 1.923696 -0.50165 N 0.475858 1.011706 0.116167 Cu -0.96632 -0.26663 -0.43012 O -0.07063 -0.97799 -2.04882 O 1.259003 -1.0344 -2.08845 H 1.735905 -0.1991 -1.05354 C 3.724917 -1.4001 0.732114 C 6.030927 -2.79061 -0.04502 C 3.676286 -2.28625 -0.35577 C 4.928638 -1.21687 1.429148 C 6.075072 -1.91964 1.046507 C 4.832945 -2.96541 -0.74611 H 2.746391 -2.42607 -0.89829 H 4.962626 -0.52448 2.264632 H 7.002208 -1.77486 1.594246 H 4.792882 -3.64001 -1.59672 H 6.924263 -3.32934 -0.34896 C 1.535459 4.37092 -0.91825 H 2.455649 4.874356 -1.19844 C -0.86456 3.063588 -0.19847 H -1.78405 2.555497 0.076791 C 0.323802 5.068691 -0.8933 H 0.306705 6.123983 -1.14977 C -0.86686 4.415024 -0.535 H -1.80219 4.967413 -0.52245

TS-VI3 Imaginary frequency = -52.03 cm-1 H -4.4498 0.674726 -3.96749 C -4.26565 0.26554 -2.97998 C -3.68151 -0.73841 -0.47803 C -3.02612 0.447869 -2.36791 C -5.24376 -0.45471 -2.2936 C -4.94877 -0.96571 -1.03062 Chapter 3: Cu-catalysed C―H Activation/C―S Cross-Coupling 88

H -2.22638 0.991302 -2.86074 H -6.21993 -0.62636 -2.73697 H -5.68896 -1.54996 -0.49667 C -3.26732 -1.26588 0.852254 C -2.32112 -2.22674 3.255907 C -4.17095 -1.8051 1.777869 C -3.68991 -2.29143 2.992645 C -1.48639 -1.66226 2.291246 H -5.23356 -1.83274 1.566332 H -4.37623 -2.70983 3.722704 H -0.41391 -1.57757 2.442249 H -1.90426 -2.59622 4.186786 N -2.74332 -0.03304 -1.14808 N -1.9461 -1.19477 1.122458 S 2.188205 -0.79029 1.243864 C 1.914959 0.734224 0.281354 C 0.566126 2.6003 0.458358 C 1.821205 3.266823 0.541571 S 3.128211 2.091277 0.513376 N 0.621501 1.233626 0.381183 Cu -0.82979 0.007452 -0.26817 O 0.152401 -0.52871 -2.06059 O 1.343271 0.030792 -2.32083 H 1.750514 0.24824 -1.38494 C -0.61372 3.374275 0.463468 H -1.57739 2.876661 0.399997 C -0.52639 4.762011 0.553972 H -1.43743 5.354424 0.55813 C 0.719086 5.405702 0.637125 H 0.768982 6.488254 0.705667 C 1.901931 4.655495 0.629933 H 2.867256 5.149177 0.692788 C 3.195406 -1.82946 0.189341 C 4.808461 -3.5852 -1.30195 C 4.113243 -1.3261 -0.74408 C 3.096086 -3.21774 0.374611 C 3.903062 -4.08707 -0.36167 C 4.903801 -2.204 -1.4908 H 4.214851 -0.25622 -0.89252 H 2.380681 -3.61628 1.088846 H 3.812834 -5.15923 -0.2087 H 5.603657 -1.79994 -2.21721 H 5.42984 -4.26218 -1.88091 Chapter 3: Cu-catalysed C―H Activation/C―S Cross-Coupling 89

Complex VII (1) H -1.54196 -4.40951 1.691235 C -2.02357 -3.48325 1.395441 C -3.17164 -1.12442 0.541161 C -1.52437 -2.74722 0.324157 C -3.14832 -2.99643 2.067627 C -3.7255 -1.80541 1.635902 H -0.65237 -3.08519 -0.22841 H -3.5654 -3.53225 2.915024 H -4.58723 -1.40178 2.15525 C -3.73808 0.141304 0.006804 C -4.65739 2.470285 -1.14195 C -5.021 0.605274 0.332871 C -5.48105 1.78809 -0.24294 C -3.39875 1.940237 -1.42463 H -5.6617 0.044876 1.004414 H -6.47239 2.16198 -0.00436 H -2.72768 2.403015 -2.14172 H -4.98225 3.387726 -1.62195 N -2.07441 -1.59696 -0.09898 N -2.94475 0.813468 -0.85531 S 0.077797 0.863564 1.407587 C 1.169342 0.671641 0.027638 C 1.756815 0.205848 -2.07354 C 3.029556 0.571632 -1.58042 S 2.907992 1.016337 0.116023 N 0.728113 0.26669 -1.1261 Cu -1.33511 -0.36546 -1.65196 O -1.43133 -0.50024 -3.60949 O -1.62632 0.910809 -4.05511 H -2.18522 0.757164 -4.82967 C 1.183968 1.47086 2.690278 C 2.782276 2.424704 4.776191 C 1.807022 0.568469 3.563609 C 1.348803 2.85132 2.870988 C 2.151409 3.32468 3.911857 C 2.608704 1.048283 4.602381 H 1.665044 -0.49879 3.425502 H 0.853099 3.544364 2.198508 H 2.281091 4.394485 4.047377 H 3.094511 0.34739 5.275066 H 3.404253 2.795167 5.586006 Chapter 3: Cu-catalysed C―H Activation/C―S Cross-Coupling 90

C 4.161019 0.559127 -2.40118 H 5.137605 0.840461 -2.01964 C 1.594751 -0.16747 -3.41591 H 0.590365 -0.41469 -3.77202 C 2.725758 -0.1797 -4.22903 H 2.62359 -0.46296 -5.27267 C 3.993353 0.175263 -3.73212 H 4.856186 0.157576 -4.3921

Complex VII (3) H 0.13196 -4.09453 2.510912 C 0.13331 -3.14602 3.035892 C 0.225907 -0.69279 4.376731 C 1.329017 -2.51502 3.332549 C -1.07352 -2.51345 3.434463 C -1.02644 -1.30407 4.094616 H 2.296541 -2.92745 3.061852 H -2.03215 -2.97759 3.220455 H -1.94544 -0.81551 4.399764 C 0.412859 0.555617 5.046433 C 1.007627 2.96462 6.33739 C -0.63382 1.382834 5.536162 C -0.35124 2.570575 6.172391 C 1.989339 2.128526 5.845407 H -1.66452 1.070719 5.406008 H -1.15591 3.197727 6.544365 H 3.039025 2.387998 5.94944 H 1.276897 3.889809 6.834333 N 1.385225 -1.33647 3.981594 N 1.736775 0.960244 5.21421 S 4.928089 -0.94937 7.175058 C 5.550961 0.243175 6.029555 C 5.477365 1.693516 4.323257 C 6.787301 1.972563 4.776598 S 7.148674 0.973754 6.171317 N 4.819591 0.706113 5.050646 Cu 3.064893 -0.36198 4.46074 O 4.22852 -1.70635 3.678569 O 4.526986 -1.15165 2.362003 H 5.460683 -0.90653 2.457948 C 6.197943 -2.2288 7.082428 C 8.068421 -4.29102 7.000013 C 6.355924 -2.96683 5.900439 Chapter 3: Cu-catalysed C―H Activation/C―S Cross-Coupling 91

C 6.953879 -2.52247 8.223381 C 7.888926 -3.56134 8.178307 C 7.304798 -3.99149 5.866171 H 5.741115 -2.73756 5.031257 H 6.813963 -1.94578 9.132585 H 8.476839 -3.79414 9.061441 H 7.435973 -4.5656 4.953388 H 8.797482 -5.09561 6.966591 C 7.591103 2.919881 4.133278 H 8.597541 3.130857 4.480079 C 4.954883 2.373311 3.212328 H 3.952349 2.150566 2.862442 C 7.057856 3.590356 3.034073 H 7.660564 4.333985 2.521572 C 5.75327 3.318936 2.578473 H 5.365721 3.8541 1.717309

(Bipyridyl)copper(I) hydroperoxo + product complex H -0.95384 -4.11599 1.331345 C -0.77466 -3.23721 1.94214 C -0.22173 -1.0464 3.519387 C 0.413655 -3.11195 2.666109 C -1.71068 -2.20494 2.023208 C -1.43527 -1.09203 2.818094 H 1.195202 -3.86729 2.649622 H -2.64377 -2.25948 1.470071 H -2.14971 -0.27861 2.872865 C 0.185023 0.093147 4.392356 C 1.079611 2.149062 6.001046 C -0.68609 1.136744 4.728078 C -0.23688 2.174337 5.543018 C 1.893811 1.078481 5.633327 H -1.70812 1.136253 4.368408 H -0.90611 2.985611 5.813511 H 2.927834 1.033388 5.960269 H 1.480483 2.933907 6.633234 N 0.672173 -2.04695 3.43248 N 1.460494 0.069667 4.85493 S 5.482681 -0.49096 7.577485 C 5.997254 0.770566 6.456915 C 5.875639 2.703949 5.381192 C 7.131213 2.278716 4.88089 S 7.537735 0.715456 5.567805 Chapter 3: Cu-catalysed C―H Activation/C―S Cross-Coupling 92

N 5.262586 1.823604 6.262105 Cu 2.581271 -1.56674 4.485055 O 3.982793 -2.81539 4.463951 O 3.443493 -4.01178 3.755941 H 3.633673 -4.6935 4.4166 C 6.721397 -1.77234 7.322392 C 8.600942 -3.80905 7.022996 C 6.544737 -2.72591 6.309563 C 7.817451 -1.84244 8.194892 C 8.758663 -2.86299 8.041195 C 7.499517 -3.7383 6.164976 H 5.678357 -2.694 5.645796 H 7.930172 -1.10251 8.981445 H 9.610262 -2.91729 8.713485 H 7.3729 -4.47412 5.375887 H 9.333833 -4.60237 6.902796 C 7.859347 3.058659 3.978154 H 8.819254 2.725203 3.596136 C 5.350006 3.937997 4.969055 H 4.390718 4.266856 5.35602 C 7.320116 4.282286 3.579086 H 7.870146 4.905006 2.879787 C 6.076769 4.717321 4.072339 H 5.678722 5.674678 3.748782

TS-Vb Imaginary frequency = -718.28 cm-1 H -4.70759 3.442683 -0.53752 C -4.4799 2.395205 -0.37148 C -3.77955 -0.24439 0.036243 C -3.18806 1.919541 -0.58301 C -5.45766 1.491594 0.050691 C -5.10407 0.160439 0.25758 H -2.3933 2.578726 -0.91807 H -6.47952 1.817587 0.219393 H -5.85285 -0.54854 0.590238 C -3.30658 -1.63854 0.256219 C -2.2492 -4.1569 0.649868 C -4.14102 -2.67262 0.70655 C -3.60618 -3.94341 0.904244 C -1.48441 -3.08336 0.19806 H -5.19119 -2.49449 0.905133 H -4.23954 -4.75334 1.253455 Chapter 3: Cu-catalysed C―H Activation/C―S Cross-Coupling 93

H -0.42541 -3.18939 -0.02087 H -1.7909 -5.12944 0.794915 N -2.84355 0.636144 -0.39003 N -1.99754 -1.85964 0.002269 Cu -0.96389 -0.18379 -0.77526 S 1.954774 -1.37722 -1.18758 C 1.311529 0.281854 -0.80831 C 0.884637 1.920126 0.683044 C 1.583765 2.716482 -0.26518 H 0.071857 0.023121 -1.98943 S 2.203905 1.686572 -1.55189 N 0.828637 0.565051 0.415482 C 3.47311 -1.44983 -0.21801 C 5.852118 -1.72533 1.237717 C 3.469078 -1.27214 1.174084 C 4.669039 -1.76947 -0.87594 C 5.852785 -1.9169 -0.14643 C 4.660134 -1.3966 1.892756 H 2.540849 -1.02258 1.676827 H 4.671597 -1.8919 -1.95501 H 6.775471 -2.16677 -0.6631 H 4.654747 -1.24462 2.968762 H 6.774148 -1.82893 1.802988 H 2.267768 4.688806 -0.82602 C 1.727741 4.092798 -0.09607 H 1.274946 5.765699 1.184921 C 1.168683 4.694809 1.038389 H 0.048521 4.400942 2.858792 C 0.476497 3.921223 1.982607 H -0.20428 1.939794 2.542478 C 0.328327 2.543317 1.813532

(Bipyridyl)copper(I) hydride H 0 1.194101 -4.4396 C 0 1.147242 -3.35567 C 0 0.907257 -0.60996 C 0 -0.08768 -2.70459 C 0 2.303693 -2.57534 C 0 2.185352 -1.18595 H 0 -1.02178 -3.25929 H 0 3.285807 -3.03877 H 0 3.076524 -0.56918 C 0 0.670381 0.863599 Chapter 3: Cu-catalysed C―H Activation/C―S Cross-Coupling 94

C 0 0.037204 3.546153 C 0 1.703295 1.811443 C 0 1.380003 3.167914 C 0 -0.9312 2.540608 H 0 2.74312 1.505745 H 0 2.167293 3.915895 H 0 -1.99211 2.774494 H 0 -0.25828 4.590092 N 0 -0.20507 -1.37162 N 0 -0.62464 1.238029 Cu 0 -2.14068 -0.34458 H 0 -3.64571 -0.58574

Product trithiazole S 1.250859 1.722756 -0.83947 C 0.192311 0.315565 -1.02487 C -0.69554 -1.4269 -2.05729 C -1.41968 -1.53258 -0.84383 S -0.93164 -0.24231 0.244295 N 0.203158 -0.37159 -2.11971 C 0.845441 2.301604 0.814172 C 0.305198 3.301661 3.368496 C 1.59711 1.860249 1.912253 C -0.16605 3.255976 0.992999 C -0.43682 3.749906 2.271453 C 1.322097 2.359239 3.187979 H 2.388078 1.131757 1.764363 H -0.73392 3.604756 0.136195 H -1.2235 4.486174 2.408265 H 1.903572 2.013616 4.03775 H 0.094972 3.689849 4.360969 C -0.9212 -2.3577 -3.08243 H -0.36441 -2.27303 -4.01004 C -1.85728 -3.3686 -2.88051 H -2.04042 -4.09476 -3.66699 C -2.5704 -3.46366 -1.67155 H -3.29566 -4.26047 -1.5356 C -2.3595 -2.54698 -0.64063 H -2.91192 -2.62368 0.290757

Cartesian coordinates and geometries of alternate pathways

(Bipyridyl)copper(II) thiolate Ib Chapter 3: Cu-catalysed C―H Activation/C―S Cross-Coupling 95

H -1.18227 4.416194 -2.99791 C -1.3047 3.351646 -2.8323 C -1.57498 0.652195 -2.30352 C -0.90348 2.780961 -1.62563 C -1.86242 2.519985 -3.80253 C -1.99921 1.157143 -3.53727 H -0.46556 3.384107 -0.83667 H -2.18929 2.923448 -4.7557 H -2.43315 0.506205 -4.2861 C -1.68361 -0.78666 -1.92528 C -1.81722 -3.40682 -1.0553 C -2.21192 -1.76651 -2.77242 C -2.27875 -3.08862 -2.33186 C -1.30218 -2.38053 -0.26521 H -2.56943 -1.51263 -3.76257 H -2.68743 -3.85726 -2.98019 H -0.93136 -2.5745 0.736245 H -1.85307 -4.42121 -0.67398 N -1.03395 1.469983 -1.36928 N -1.23595 -1.10852 -0.68827 Cu -0.51089 0.502625 0.37388 S 0.2199 0.973325 2.396824 C 1.95731 0.851309 2.47991 C 4.745324 0.699594 2.760602 C 2.570465 1.127257 3.728968 C 2.770642 0.497202 1.375099 C 4.149751 0.423564 1.519089 C 3.952137 1.050278 3.861539 H 1.949745 1.398465 4.576964 H 2.310027 0.283883 0.415127 H 4.768358 0.152179 0.669281 H 4.41444 1.262878 4.820245 H 5.824134 0.640822 2.866876

Benzothiazole radical anion S 1.517909 -0.91215 -1.03383 C 0.563362 0.097513 0.063041 C -0.836 -0.2202 -0.11061 N -1.13557 -1.16423 -1.02308 C 0.996367 1.061503 0.961105 H 2.056587 1.285898 1.060833 C 0.04617 1.761753 1.748164 H 0.375265 2.518732 2.45582 Chapter 3: Cu-catalysed C―H Activation/C―S Cross-Coupling 96

C -1.31948 1.45728 1.606098 H -2.04864 1.988347 2.218135 C -1.76929 0.491018 0.706481 H -2.8278 0.262575 0.609913 C -0.03617 -1.76904 -1.52915 H -0.04752 -2.20639 -2.52673

(Bipyridyl)copper(II)-hydrido-thiolate E = -1321.763475 H -1.48022 -2.92188 2.306709 C -0.64829 -2.29287 2.009838 C 1.382708 -0.6087 1.213608 C -0.8893 -1.03957 1.445933 C 0.673912 -2.70682 2.164545 C 1.703489 -1.85643 1.762835 H -1.89779 -0.67469 1.28379 H 0.905166 -3.67819 2.591263 H 2.735514 -2.16553 1.878738 C 2.407209 0.382496 0.783185 C 4.143144 2.356743 -0.05692 C 3.788735 0.174968 0.897778 C 4.662793 1.172759 0.469093 C 2.757374 2.494487 -0.12915 H 4.181904 -0.74473 1.314455 H 5.735824 1.026748 0.549188 H 2.285179 3.394747 -0.5115 H 4.789871 3.15712 -0.4 N 0.09757 -0.22208 1.056677 N 1.919072 1.532105 0.273937 Cu -0.20632 1.729525 0.183989 S -2.29729 1.715925 -0.81981 C -2.70005 0.021774 -1.1945 C -3.43439 -2.64028 -1.84291 C -3.92002 -0.52909 -0.74627 C -1.86202 -0.79555 -1.98204 C -2.22152 -2.10791 -2.29588 C -4.2835 -1.83838 -1.0718 H -4.58299 0.087731 -0.14603 H -0.92996 -0.3832 -2.3579 H -1.55739 -2.71362 -2.9081 H -5.23433 -2.23308 -0.72137 H -3.71766 -3.65821 -2.0958 H -0.23449 3.293238 0.202574 Chapter 3: Cu-catalysed C―H Activation/C―S Cross-Coupling 97

Benzothiazole radical S 1.47486 -0.94976 -1.1274 C 0.574272 0.076271 0.011938 C -0.8104 -0.19758 -0.10765 N -1.10933 -1.18106 -1.06741 C 1.048248 1.026753 0.918401 H 2.108837 1.238472 1.011806 C 0.113747 1.701664 1.706333 H 0.458352 2.44549 2.418559 C -1.26201 1.434239 1.592169 H -1.96484 1.975376 2.218357 C -1.73594 0.485692 0.687662 H -2.7946 0.269468 0.589205 C -0.07718 -1.61726 -1.62545

Chapter 4: Direct Arylation of Benzothiazoles and Benzoxazoles 98

CHAPTER 4

Direct Arylation of Benzothiazoles and Benzoxazoles with Arylboronic Acids

Chapter 4: Direct Arylation of Benzothiazoles and Benzoxazoles 99

4.1 Introduction

Aryl-substituted benzothiazoles and benzoxazoles are an important class of heterocyclic compounds that have shown a wide spectrum of biological activities, such as antitumor and antiviral, and antimicrobial activities.143-145 Some representative examples are incorporated in Figure 4.1. In addition, these chemicals have become essential building blocks for the synthesis of conjugated functional materials as industrial dyes and plant growth regulators.146

The conventional methods for the synthesis of these chemicals typically involve either the metal-catalyzed intramolecular cyclization of thioformanilides or cross- coupling of carboxylic acids and 2-aminophenol (or 2-aminothiophenol) in the presence of Lawesson’s reagent.147,148 However, these reactions are dependent on preactivation of two aromatic carbon fragments with halides and electropositive groups such as boronic acids or stannanes. This preactivation of both the (hetero)aryl coupling partners is wasteful as it necessitates the functionalization and subsequent disposal of the activating groups. Alternatively, Aryl-substituted benzothiazoles and benzoxazoles can be prepared by direct arylation of heterocycles via metal-catalyzed C―H bond activation with aryl halides.149,150

We have recently demonstrated that benzothiazole compounds can be obtained by a decarboxylative C―S cross-coupling of 2-nitrobenzoic acid with benzyl thiol under relatively harsh conditions.151 More recently, we have shown that the cross-coupling of nitro-substituted aryl halides with benzyl thiol can also afford aryl-substituted benzothiazole derivatives in moderate yield.152 As a part of our ongoing effort devoted to the synthesis of aryl-substituted benzothiazoles and benzoxazoles, we describe herein a Chapter 4: Direct Arylation of Benzothiazoles and Benzoxazoles 100

Figure 4.1: Representative examples of aryl-substituted benzothiazoles and benzoxazoles in medicinal chemistry.

Chapter 4: Direct Arylation of Benzothiazoles and Benzoxazoles 101 novel synthetic pathway that involve direct C―H bond functionalization of benzothiazole and benzoxazole precursors by using arylboronic acids and transition- metal catalysts under aerobic conditions. It should be noted that You et al. have recently reported the direct arylation of azoles via metal-catalyzed C―H bond functionalization with arylboronic acids.153

4.2 Results and Discussion

The reaction of benzothiazole (1a) with phenylboronic acid (2a) was selected as a prototype reaction. The selected results from our experiments were summarized in Table

4.1. We observed that the reactions involving monometallic systems such as 10 mol%

Pd(OAc)2 or 50 mol% Cu(OAc)2 resulted in low conversions (Table 4.1, entries 1 and 2).

Encouragingly, the reaction performed in dimethyl sulfoxide (DMSO) at 100 oC in the presence of a Pd/Cu cocatalyst (10/20 mol%) and 2,2'-bipyridine (30 mol%) as the ligand afforded phenyl benzothiazole (3a) in 45% yield (Table 4.1, entry 3). After a screening of reaction conditions and bases, the optimum conditions for the direct arylation reaction were identified as a combination of a Pd/Cu cocatalyst (5/10 mol%) and phenanthroline ligand (30 mol%) with inexpensive K3PO4 as the base (Table 4.1, entry 13). Under the optimum reaction condition, the desired cross-coupling product 3a was obtained in 89% yield along with small amount of biphenyl (8%) and phenol (3%) as the by-products

(Figure 4.2). The reaction also proceeds at lower loadings of the Pd/Cu cocatalyst or the ligand, but with a substantial decrease in the reaction yields (Table 4.1, entries 14-16).

Chapter 4: Direct Arylation of Benzothiazoles and Benzoxazoles 102

Table 4.1: Reaction condition screening for the direct arylation of benzothiazole with phenylboronic acid.a

a Reaction conditions: 1a (0.5 mmol), 2a (1 mmol), base (1.5 mmol), solvent (3 mL), 100 oC, 24 h. b GC yield. Isolated yield is in parenthesis. Bipy: 2,2'-bipyridine; Phenanthr: 1,10-phenanthroline.

Chapter 4: Direct Arylation of Benzothiazoles and Benzoxazoles 103

Figure 4.2: (a) GC Analysis of the cross-coupling reaction of benzothiazole with phenylboronic acid in the presence PdII/CuII catalyst under aerobic conditions. (b) The corresponding mass spectrum of the peak shown in GC spectrum at 13.56 min, confirming the formation of 2-phenylbenzothiazole in high yield.

The effect of the copper catalyst was also studied as demonstrated in Table 4.2.

In absence of copper salt or in presence of metallic copper powder, the reaction occurred Chapter 4: Direct Arylation of Benzothiazoles and Benzoxazoles 104 with <10% reaction conversion (Table 4.2, entries 1 and 2). However, of the Cu(I) and

Cu(II) salts are used as the catalyst in the reaction, Cu(OAc)2 provided best reaction conversion to the desired cross-coupling product in 89% yield (Table 4.2, entry 6).

Ligand effect on cross-coupling reaction of benzothiazole and phenylboronic acid: The Suzuki-type reaction is generally carried out in the presence of phosphine ligands, which stabilize the active Pd(0) species and accelerate the reaction rate.154 In our reaction protocol, we found that palladium catalyst was quite easily precipitated and the coupling reaction was retarded in the absence of any ligand. To stabilize and minimize the precipitation of palladium catalysts, we surveyed a series of ligands for these reactions. The structures of these ligands and the summery of the results of this study are shown in Figure 4.3. Each reaction was conducted at 100 oC for 24 h with 30 mol% of ligand, 5 mol% of Pd(OAc)2 and 10 mol% of Cu(OAc)2 and the conversion to the desired cross-coupling product was measured by GC. During this study, we found that the most suitable ligands for cross-couplings was the bidentate 1,10-phenanthroline (1), which have been known to facilitate the efficient reoxidation of Pd(0) by molecular oxygen and remain stable upon exposure to air and moisture.155 The reactions with 2,2′-bipyridyl (2), ethane-1,2-diamine (3), and DMEDA (4) and were afforded the cross-coupling product in low yields. However, in the case of phosphine ligands such as PPh3 (8) and dppe (9), the yields dramatically reduced. Similarly, pentane-2,4-dione (7), TMEDA (5) and N1-(2-

(dimethylamino)ethyl)- N1,N2,N2-trimethylethane-1,2-diamine (6) were observed to be incompatible with our coupling system.

Chapter 4: Direct Arylation of Benzothiazoles and Benzoxazoles 105

Table 4.2: Optimization of the reaction conditions with respect to the [Cu] source.a

a Conditions: benzothiazole (0.5 mmol), phenylboronic acid (1.0 mmol), DMSO (3 mL), o Pd(OAc)2 (5 mol%), [Cu] (10 mol%), 1,10-phenanthroline (30 mol%), K3PO4 (1.5 mmol), 100 C, 24 h. b GC yield.

Chapter 4: Direct Arylation of Benzothiazoles and Benzoxazoles 106

Figure 4.3: Optimization of the reaction conditions with respect to the ligand.

4.2.1: Mechanistic study: Chapter 4: Direct Arylation of Benzothiazoles and Benzoxazoles 107

To gain a better understanding of the reaction mechanism, we carried out a series of reactions under the same reaction conditions, but in different atmospheres.

Interestingly, the reaction resulted in a much lower yield of product 3a in a nitrogen atmosphere in comparison to under aerobic conditions (Table 4.3, entries 1 and 2).

However, the reaction performed in a pure oxygen atmosphere only afforded 3a in 17%

(Table 4.3, entry 3). The predominant by-products are biphenyl (16%) and phenol (48%) as determined by gas chromatography analysis (Figure 4.4). These results indicate that oxygen accelerates the cross-coupling reactions; however with high concentrations of oxygen the oxidative hydroxylation of phenylboronic acid dominates the reaction.156

Chapter 4: Direct Arylation of Benzothiazoles and Benzoxazoles 108

Table 4.3: Influence of atmosphere on the yield of 3a.a

a Reaction conditions: 1a (0.5 mmol), 2a (1 mmol), base (1.5 mmol), solvent (3 mL), 100 oC, 24 h. b GC yield.

Chapter 4: Direct Arylation of Benzothiazoles and Benzoxazoles 109

Figure 4.4: (a) GC Analysis of the cross-coupling reaction of benzothiazole with phenylboronic acid in the presence PdII/CuII catalyst under aerobic conditions. (b) The corresponding mass spectrum of the peak shown in GC spectrum at 13.56 min, confirming the formation of 2-phenylbenzothiazole in high yield.

On the basis of these experimental data, a plausible catalytic mechanism was proposed as shown in Scheme 4.1 for the oxygen-promoted direct arylation of Chapter 4: Direct Arylation of Benzothiazoles and Benzoxazoles 110 benzothiazole. The reaction first proceeds by deprotonation of the benzothiazole, followed by transmetalation with an organometallic copper complex E to give the corresponding heteroaryl copper intermediate D.157,150h Subsequently, the heteroaryl copper intermediate D reacts with a palladium species B to form the corresponding diarylpalladium intermediate C.157 Upon reductive elimination, the desired cross- coupling product of 3a is formed. Trace molecular oxygen in the presence of CuII oxidizes the resulting Pd0 to a peroxopalladium complex A,158 which reacts with arylboronic acid to regenerate the palladium species B. At high oxygen concentration, the oxidative hydroxylation of arylboronic acid competes with the transmetalation between the species B and D, resulting in increased reaction by-products.

Chapter 4: Direct Arylation of Benzothiazoles and Benzoxazoles 111

Scheme 4.1: Proposed mechanism for the arylation of benzothiazole via C―H activation.

Chapter 4: Direct Arylation of Benzothiazoles and Benzoxazoles 112

4.2.2 Scope of the synthetic method:

Further experimentation has shown that various substituted arylboronic acids allow the direct arylation of benzothiazole 1a under the optimum reaction conditions

(Table 4.4). Both electron-rich and electron-deficient arylboronic acids were successfully converted to the corresponding cross-coupling products in moderate to good yields. The treatment of heteroaryl boronic acid with 1a also furnished the corresponding product (3k) in moderate yield (Table 4.4, entry 10). Remarkably, chloro-substituted arylboronic acid readily underwent a direct arylation with 1a to generate the desired chloro-substituted benzothiazole (3i) in 62% yield (Table 4.4, entry 8). The functional group tolerance should allow further derivatization of the 3i through cross-coupling reactions such as

Suzuki-Miyaura and Heck reactions.

In a further set of experiments, we have carried out the direct arylation of benzoxazole (1b) with various substituted arylboronic acids (Table 4.5). In similar reaction patterns to the arylation of benzothiazole 1a, various substituted arylboronic acids successfully reacted with 1b to afford the corresponding aryl-substituted benzoxazoles under the optimum reaction conditions. Although the groups of Daugulis and Miura have reported the direct arylation of benzothiazoles with aryl halides,159 our method reported herein eliminate the use of aryl halide precursors and proceeds under milder conditions. More recently, Itami’s group160 has also reported an interesting nickel- catalyzed direct arylation of azole compounds with aryl halides and triflates, but the reactions with benzoxazole resulted in substantial loss in yield. In our cases, benzoxazole can be efficiently arylated at the 2-position with a broad range of electronically and structurally diverse boronic acids with good selectivity. Chapter 4: Direct Arylation of Benzothiazoles and Benzoxazoles 113

Table 4.4: Direct arylation of benzothiazole 1a with various arylboronic acids 2b- 2k.a

a Reaction conditions: 1a (0.5 mmol), 2b-k (1 mmol), Pd(OAc)2 (5.0 mol%), Cu(OAc)2 (10 o mol%), 1,10-phenanthroline (30 mol%) and K3PO4 (1.5 mmol) in DMSO at 100 C (oil bath temperature) under aerobic conditions. b Yields of isolated products are the average of at least two experiments. c The reactions were conducted at 80 oC (oil bath temperature). Chapter 4: Direct Arylation of Benzothiazoles and Benzoxazoles 114

Table 4.5: Direct arylation of benzoxazole 1b with various arylboronic acids 2a- 2k.a

a Reaction conditions: 1a (0.5 mmol), 2 (1 mmol), Pd(OAc)2 (5.0 mol%), Cu(OAc)2 (10 mol%), o 1,10-phenanthroline (30 mol%) and K3PO4 (1.5 mmol) in DMSO at 100 C (oil bath temperature) under aerobic conditions. b Yields of isolated products are the average of at least two experiments. c The reactions were conducted at 80 oC (oil bath temperature). Chapter 4: Direct Arylation of Benzothiazoles and Benzoxazoles 115

To evaluate the suitability of the reaction for further scale-up, we prepared the phenyl benzothiazole in 15 mL of DMSO by treating benzothiazole 1a (5.0 mmol) with phenyl boronic acid 2a (10.0 mmol) in the presence of a Pd/Cu cocatalyst (0.25/0.5 mmol), 1,10-phenanthroline (1.5 mmol) and a large excess of K3PO4 (15.0 equiv) for 32 h at 100 oC under aerobic conditions (Scheme 4.2). The resulting mixture was isolated and purified to obtain the desired product 3a in 80% yield.

4.3 Conclusion

In summary, we have presented a new transition metal-catalyzed C―C bond- forming reaction between benzothiazoles (or benzoxazoles) and arylboronic acids. This organic transformation represents a simple way to carry out the arylation of benzothiazole

(or benzoxazole) compounds, a task that otherwise requires several synthetic steps or harsh reaction conditions. Various arylboronic acids showed good reactivity in this transformation. Importantly, this new method obviates the use of organohalide precursors need in previously reported methods.

Chapter 4: Direct Arylation of Benzothiazoles and Benzoxazoles 116

Scheme 4.2: Scaled-up phenylation of benzothiazole 1a (5 mmol) in the presence of 2a (10 mmol), Pd(OAc)2 (5 mol%), Cu(OAc)2 (10 mol%), 1,10- o phenanthroline (30 mol%) and K3PO4 (15 equiv) in DMSO at 100 C under aerobic conditions. Product 3a was isolated in 80% yield.

Chapter 4: Direct Arylation of Benzothiazoles and Benzoxazoles 117

4.4 Experimental Section

General Methods: Unless otherwise stated, all reactions were carried out without taking precautions to exclude air and moisture. All solvents were used as received. All the chemicals were purchased from commercial sources and used as received unless stated otherwise. Reactions were conducted in 20 mL vials equipped with a conventional crew cap. All reaction temperatures refer to oil-bath temperatures. Column chromatography was carried out on silica gel (230-400 mesh). The yields of the coupling product listed in Tables 4.4 and 4.5 refer to isolated yields (average of two runs).

Physical Measurements: 1H NMR and 13C NMR spectra were recorded on a Bruker

ACF 300 and 75 MHz FT-NMR spectrometers as well as Bruker Avance 500 and 125

MHz FT-NMR spectrometers and referenced to solvent peaks. Coupling reactions of benzothiazole with phenylboronic acid shown in Table 4.1, 4.2 and 4.3, and in Figure 4.3 were determined by using Hewlett- Packard Series 6890 GC (Santa Clara, CA, USA) coupled to a Hewlett Packard 5973 MS detector. High-resolution mass spectra were obtained using a Finnigan MAT95XL-T mass spectrometer.

A General procedure for C―C cross-coupling: Pd(OAc)2 (5.6 mg, 0.025 mmol),

Cu(OAc)2 (9.0 mg, 0.05 mmol), 1,10-phenanthroline (27 mg, 0.15 mmol) and K3PO4

(318.3 mg, 1.5 mmol) were added to a solution of DMSO (3 mL) charged with arylboronic acid (1.0 mmol) and heteroarene (0.5 mmol). The reaction was stirred at 100 oC under aerobic conditions for 24 h. The resulting mixture was then cooled to room temperature and diluted with ethyl acetate. The organic layer was collected, washed with water and brine, dried over magnesium sulfate, and filtered. The solvent was removed in Chapter 4: Direct Arylation of Benzothiazoles and Benzoxazoles 118 vacuo, and the remaining residue was purified by silica-gel column chromatography

(eluent: hexane/ethyl acetate) to yield the corresponding coupling product.

Spectral data

S

N

2-phenylbenzo[d]thiazole (3a).151a Obtained as a white solid in 85% yield. 1H

NMR (300 MHz, CDCl3) δ 8.12-8.07 (m, 3H), 7.91 (d, J = 9 Hz, 1H), 7.52-7.47 (m, 4H),

13 7.42-7.39 (m, 1H); C NMR (75 MHz, CDCl3) δ 168.1, 154.1, 135.1, 133.6, 131.0, 129.0,

127.6, 126.3, 125.2, 123.2, 121.6; HR EIMS: 211.0453 m/z (calcd. for C13H9NS:

211.0456).

S O N

2-(4-methoxyphenyl)benzo[d]thiazole (3b).160 Obtained as a brown solid in 72%

1 yield. H NMR (500 MHz, CDCl3) δ 8.08-8.05 (m, 3H), 7.87 (d, J = 5 Hz, 1H), 7.48 (t, J

= 8 Hz, 1H), 7.37 (t, J = 8 Hz, 1H), 7.01 (d, J = 10 Hz, 2H), 3.9 (s, 3H); 13C NMR (125

MHz, CDCl3) δ 168.1, 162.2, 153.4, 134.4, 129.3, 126.4, 125.9, 125, 122.6, 121.5, 114.4,

55.5; HR EIMS: 241.0555 m/z (calcd. for C14H11NOS: 241.0561).

S

N

2-(4-isopropylphenyl)benzo[d]thiazole (3c). Obtained as a white solid in 88%

1 yield. H NMR (500 MHz, CDCl3) δ 8.07 (d, J = 10 Hz, 1H), 8.03 (d, J = 10 Hz, 2H), Chapter 4: Direct Arylation of Benzothiazoles and Benzoxazoles 119

7.89 (d, J = 8 Hz, 1H), 7.49 (t, J = 8 Hz, 1H), 7.39-7.35 (m, 3H), 2.98 (sept, J = 7 Hz,

13 1H), 1.30 (d, J = 7 Hz, 6H); C NMR (125 MHz, CDCl3) δ 168.3, 154, 152.4, 134.8,

131.2, 127.6, 127.1, 126.2, 125, 123, 121.5, 34.1, 23.7; HR EIMS: 253.0923 m/z (calcd. for C16H15NS: 253.0925).

S

N

2-p-tolylbenzo[d]thiazole (3d).151b Obtained as a white solid in 86% yield. 1H

NMR (500 MHz, CDCl3) δ 8.07 (d, J = 8 Hz, 1H), 7.99 (d, J = 8 Hz, 2H), 7.88 (d, J = 8

Hz, 1H), 7.48 (t, J = 7 Hz, 1H), 7.37 (t, J = 7 Hz, 1H), 7.29 (d, J = 8 Hz, 2H) 2.43 (s, 3H);

13 C NMR (125 MHz, CDCl3) δ 168.3, 154, 141.5, 134.8, 130.8, 129.7, 127.5, 126.3, 125,

123, 121.5, 21.5; HR EIMS: 225.0612 m/z (calcd. for C14H11NS: 225.0612).

S

N

2-(4-tert-butylphenyl)benzo[d]thiazole (3e).161 Obtained as a brown solid in

1 80% yield. H NMR (500 MHz, CDCl3) δ 8.07 (d, J = 8 Hz, 1H), 8.03 (d, J = 8 Hz, 2H),

7.90 (d, J = 7.5 Hz, 1H), 7.53-7.47 (m, 3H) 7.38 (t, J = 8 Hz, 1H), 1.37 (s, 9H); 13C NMR

(125 MHz, CDCl3) δ 168.2, 154.6, 154.1, 134.9, 130.8, 127.4, 126.2, 125.9, 125, 123,

121.5, 35, 31.2; HR EIMS: 267.0184 m/z (calcd. for C17H17NS: 267.1082).

Chapter 4: Direct Arylation of Benzothiazoles and Benzoxazoles 120

S

N

2-o-tolylbenzo[d]thiazole (3f).160 Obtained as a white solid in 57% yield. 1H

NMR (500 MHz, CDCl3) δ 8.11 (d, J = 8 Hz, 1H), 7.94 (d, J = 7.5 Hz, 1H), 7.76 (d, J = 7

Hz, 1H), 7.51 (t, J = 8 Hz, 1H), 7.43-7.30 (m, 4H), 2.66 (s, 3H); 13C NMR (125 MHz,

CDCl3) δ 168, 153.7, 137.2, 135.6, 133, 131.5, 130.5, 130, 126.14, 126.10, 125.1, 123.4,

121.3, 21.3; HR EIMS: 225.0605 m/z (calcd. for C14H11NS: 225.0612).

S

N

2-(biphenyl-4-yl)benzo[d]thiazole (3g).162 Obtained as a white solid in 55%

1 yield. H NMR (500 MHz, CDCl3) δ 8.19 (d, J = 9 Hz, 2H), 8.11 (d, J = 8 Hz, 1H), 7.93

(d, J = 8 Hz, 1H), 7.74 (d, J = 8 Hz, 2H), 7.67 (d, J = 7.5 Hz, 2H), 7.53-7.47 (m, 3H),

13 7.42-7.39 (m, 2H); C NMR (125 MHz, CDCl3) δ167.6, 154.2, 143.7, 140, 135, 132.5,

128.9, 127.96, 127.90, 127.6, 127.1, 126.3, 125.1, 123.2, 121.6; HR EIMS 287.0771 m/z

(calcd. for C19H13NS: 287.0769).

S

N

2-(naphthalen-1-yl)benzo[d]thiazole (3h).160 Obtained as a yellowish-white

1 solid in 60% yield. H NMR (500 MHz, CDCl3) δ 8.57 (s, 1H), 8.22 (dd, J = 8.5 Hz, 1H),

8.13 (d, J = 8 Hz, 1H), 7.98-7.87 (m, 4H), 7.56-7.50 (m, 3H), 7.42-7.39 (m, 1H); 13C

NMR (75 MHz, CDCl3) δ 168.1, 154.2, 135.1, 134.4, 133.2, 131, 128.8, 127.9, 127.6, Chapter 4: Direct Arylation of Benzothiazoles and Benzoxazoles 121

127.4, 126.9, 126.4, 125.2, 124.4, 123.2, 121.6; HR EIMS 261.0612 m/z (calcd. for

C17H11NS: 261.0612).

S Cl N

2-(4-chlorophenyl)benzo[d]thiazole (3i).160 Obtained as a grey solid in 62%

1 yield. H NMR (500 MHz, CDCl3) δ 8.07-8.02 (m, 3H), 7.91 (d, J = 7.5 Hz, 1H), 7.52-

13 7.46 (m, 3H), 7.40 (t, J = 8 Hz, 1H); C NMR (125 MHz, CDCl3) δ 166.6, 154, 137.1,

135, 132.1, 129.3, 128.7, 126.5, 125.4, 123.3, 121.6; HR EIMS 245.0068 m/z (calcd. for

C13H8ClNS: 245.0066).

S NO2 N

2-(4-nitrophenyl)benzo[d]thiazole (3j).161 Obtained as a yellowish-white solid in

1 58% yield. H NMR (300 MHz, CDCl3) δ 8.32 (quart, J = 9 Hz, 4H), 8.14 (d, J = 8 Hz,

1H), 7.96 (d, J = 8 Hz, 1H), 7.56 (t, J = 8 Hz, 1H), 7.47 (t, J = 8 Hz, 1H); 13C NMR (125

MHz, CDCl3) δ 164.8, 154.1, 149, 139.2, 135.5, 128.2, 126.9, 126.2, 124.3, 123.9, 121.8;

HR EIMS: 256.0306 m/z (calcd. for C13H8N2O2S: 256.0306).

S N N

2-(pyridin-4-yl)benzo[d]thiazole (3k).163 Obtained as a light yellow solid in 59%

1 yield. H NMR (500 MHz, CDCl3) δ 8.79 (s, 2H), 8.15 (d, J = 8 Hz, 1H), 8.02 (d, J = 5.5

Hz, 2H), 7.97 (d, J = 8 Hz, 1H), 7.57 (t, J = 7.5 Hz, 1H), 7.48 (t, J = 8 Hz, 1H); 13C NMR Chapter 4: Direct Arylation of Benzothiazoles and Benzoxazoles 122

(125 MHz, CDCl3) δ 165, 154, 150.6, 140.6, 135.2, 126.8, 126.2, 123.9, 121.9, 121.3;

HR EIMS 212.0409 m/z (calcd. for C12H8N2S: 212.0408).

O

N 2-phenylbenzo[d]oxazole (3l).160 Obtained as a white solid in 90% yield. 1H

NMR (500 MHz, CDCl3) δ 8.3-8.2 (m, 2H), 7.81-7.75 (m, 1H), 7.61-7.49 (m, 4H), 7.37-

13 7.34 (m, 2H); C NMR (125 MHz, CDCl3) δ 163, 150.8, 142, 131.5, 128.9, 127.6, 127.1,

125.1, 124.6, 120, 110.6; HR EIMS: 195.0688 m/z (calcd. for C13H9NO: 195.0684).

O O N

2-(4-methoxyphenyl)benzo[d]oxazole (3m).159a Obtained as a brown solid in

1 88% yield. H NMR (500 MHz, CDCl3) δ 8.20 (d, J = 9 Hz, 2H), 7.75-7.73 (m, 1H),

7.57-7.54 (m, 1H), 7.35-7.26 (m, 2H), 7.03 (d, J = 9 Hz, 2H), 3.90 (s, 3H) ppm; 13C

NMR (125 MHz, CDCl3) δ 163.2, 162.3, 150.7, 142.3, 129.4, 124.6, 124.4, 119.7, 119.6,

114.4, 110.4, 55.4 ppm; HR EIMS 225.0790 m/z (calcd. for C14H11NO2: 225.0790).

O

N

2-p-tolylbenzo[d]oxazole (3n).164 Obtained as a white solid in 85% yield. 1H

NMR (500 MHz, CDCl3) δ 8.15 (d, J = 8 Hz, 2H), 7.78-7.74 (m, 1H), 7.59-7.56 (m, 1H),

13 7.36-7.33 (m, 4H), 2.44 (s, 3H); C NMR (125 MHz, CDCl3) δ 163.3, 150.7, 142.1, 142,

129.6, 127.6, 124.8, 124.5, 124.5, 119.8, 110.5, 21.6; HR EIMS 209.0847 m/z (calcd. for

C14H11NO: 209.0841). Chapter 4: Direct Arylation of Benzothiazoles and Benzoxazoles 123

O

N

2-(4-tert-butylphenyl)benzo[d]oxazole (3o).165 Obtained as a brown solid in

1 67% yield. H NMR (500 MHz, CDCl3) δ 8.19 (d, J = 8 Hz, 2H), 7.78-7.76 (m, 1H),

13 7.56-7.54 (m, 3H), 7.36-7.32 (m, 2H), 1.38 (s, 9H); C NMR (125 MHz, CDCl3) δ 163.2,

155.1, 150.7, 142.2, 127.5, 125.9, 124.8, 124.4, 124.3, 119.8, 110.5, 35, 31.1; HR EIMS

251.1315 m/z (calcd. for C17H17NO: 251.1310).

O

N

2-o-tolylbenzo[d]oxazole (3p).159a Obtained as a white solid in 65% yield. 1H

NMR (500 MHz, CDCl3) δ 8.18 (d, J = 8 Hz, 1H), 7.83-7.79 (m, 1H), 7.61-7.58 (m, 1H),

13 7.43-7.40 (t, 1H), 7.38-7.33 (m, 4H), 2.82 (s, 3H); C NMR (75 MHz, CDCl3) δ 163.4,

150.3, 142.1, 138.8, 131.8, 130.9, 129.9, 126.2, 126, 125, 124.2, 120.1, 110.5, 22.2; HR

EIMS 209.0840 m/z (calcd. for C14H11NO: 209.0841).

O

N 2-(biphenyl-4-yl)benzo[d]oxazole (3q).150k Obtained as a white solid in 75%

1 yield. H NMR (500 MHz, CDCl3) δ 8.34 (d, J = 8 Hz, 2H), 7.80-7.76 (m, 3H), 7.67 (d, J

= 7 Hz, 2H), 7.62-7.59 (m, 1H), 7.49 (t, J = 7.5 Hz, 2H), 7.42-7.35(m, 3H); 13C NMR

(125 MHz, CDCl3) δ 162.9, 150.8, 144.2, 142.2, 140, 128.9, 128.1, 128, 127.5, 127.1, Chapter 4: Direct Arylation of Benzothiazoles and Benzoxazoles 124

125.9, 125.1, 124.6, 120, 110.6; HR EIMS 271.1003 m/z (calcd. for C19H13NO:

271.0997).

O

N

2-(naphthalen-1-yl)benzo[d]oxazole (3r).150a Obtained as a white solid in 80%

1 yield. H NMR (500 MHz, CDCl3) δ 8.80 (s, 1H), 8.33 (dd, J = 8.5 Hz, 1H), 8.01-7.98

(m, 2H), 7.91-7.90 (d, 1H), 7.83-7.81 (m, 1H), 7.65-7.55 (m, 3H), 7.39-7.37 (m, 2H); 13C

NMR (125 MHz, CDCl3) δ 163.2, 150.9, 142.1, 134.8, 133, 129, 128.8, 128.2, 127.9,

127.8, 126.9, 125.2, 124.7, 124.4, 124, 120, 110.6; HR EIMS 245.0839 m/z (calcd. for

C17H11NO: 245.0841).

O Cl N

2-(4-chlorophenyl)benzo[d]oxazole (3s).166 Obtained as a white solid in 68%

1 yield. H NMR (500 MHz, CDCl3) δ 8.19 (d, J = 9 Hz, 2H), 7.78-7.76 (m, 1H), 7.59-7.57

13 (m, 1H), 7.51 (d, J = 9 Hz, 2H), 7.38-7.36 (m, 2H); C NMR (125 MHz, CDCl3) δ 162,

150.7, 142, 137.7, 129.3, 128.8, 125.7, 125.3, 124.7, 120.1, 110.6; HR EIMS: 229.0299 m/z (calcd. for C13H8ClNO: 229.0294).

O NO2 N

2-(4-nitrophenyl)benzo[d]oxazole (3t).166 Obtained as a white solid in 62% yield.

1 H NMR (500 MHz, CDCl3) δ 8.45-8.38 (m, 4H), 7.84-7.82 (d, 1H), 7.65-7.63 (d, 1H), Chapter 4: Direct Arylation of Benzothiazoles and Benzoxazoles 125

13 7.46-7.40 (m, 2H); C NMR (125 MHz, CDCl3) δ 160.6, 151, 149.4, 141.9, 132.8, 128.4,

126.3, 125.2, 124.2, 120.7, 110.9; HR EIMS 240.0539 m/z (calcd. for C13H8N2O3:

240.0535).

O N N

2-(pyridin-4-yl)benzo[d]oxazole (3u).163 Obtained as a white solid in 60% yield.

1 H NMR (500 MHz, CDCl3) δ 8.82 (d, J = 5.5 Hz, 2H), 8.10-8.09 (m, 2H), 7.84-7.82 (m,

13 1H), 7.64-7.62 (m, 1H), 7.45-7.39 (m, 2H); C NMR (125 MHz, CDCl3) δ 160.6, 150.9,

150.6, 141.7, 134.4, 126.3, 125.1, 121, 120.7, 110.9; HR EIMS 196.0636 m/z (calcd. for

C12H8N2O: 196.0637). Chapter 5: Nanocontact-induced catalytic activation 126

CHAPTER 5

Nanocontact-induced catalytic activation in palladium nanoparticles

Chapter 5: Nanocontact-induced catalytic activation 127

5.1 Introduction

In the field of catalysis, most catalysts are traditionally divided into

‘homogeneous’, ‘heterogeneous’, and ‘enzymatic’ subsections. Each one has its own methods and applications. Homogeneous catalysts are molecularly dispersed with the reactants in the same phase, which provides easy access to the catalytic site but can make the separation of the catalyst and products difficult. Heterogeneous catalysts (usually solids) are in a different phase from the reactants, which reduces separation problems but provides more limited access to the catalytic site due to diffusion resistance. In this regard, the question is what will happen in an intermediate case, i.e. nanocatalysts, which have a much higher mobility with respect to the heterogeneous case, but a lower mobility with respect to the homogeneous case? Metal nanoclusters are attractive as catalysts because:

1) They show unique catalytic properties and can catalyze new types of reactions not accessible to traditional homogeneous and heterogeneous catalysts.

2) Due to the presence of a large number of co-ordinatively unsaturated surface atoms, they can lead to high catalytic activity either via leached species or surface reaction.

3) Synthetically, they can be prepared by simple and straightforward methods as opposed to that of metal complexes.

4) They can be easily isolated from the reaction mixtures and re-dispersed in various solvents and are stable up to 150 ºC compared the metal complexes; consequently they retain their catalytic activity for recycling.

Chapter 5: Nanocontact-induced catalytic activation 128

In the past ten years, the filed of metal-nanocluster-based organic transformations has undergone an exponential growth. Two types of studies have been reported in the literatures; one is catalysis in solution where nanoclusters are directly dispersed in solvents and other one is catalysis by nanoclusters supported on a substrate. The use of supported nanoclusters in heterogeneous catalysis accounts for the majority of the publications, while the catalysis by cluster suspension accounts for only about 15-20% of the work. The use of various polymer stabilised clusters as catalysts in liquid phase has been reviewed.167 The use of monometallic and bimetallic clusters stabilised by solvent and surfactants as catalysts has been surveyed.168 Bimetallic catalysts in colloidal dispersions that are stabilized with PVP as potential catalysts are also discussed in great detail.169

The high catalytic efficiency and recyclability reported for metal-nanoclusters170-

177 encouraged us to investigate further cluster catalysts for the C―C cross-coupling reactions. We anticipated that the introduction of nanocontacts178-181 between nanoparticles should significantly impact material reactivity for organic synthesis, as metallic nanocontacts are known to exhibit different characteristics in electronic, optoelectronic, electrical and magnetic properties from individual non-interacting nanoparticles. In this chapter, we report the synthesis of novel palladium (Pd) nanostructures composed of a network of nanoparticles with high-density point contacts between the particles. We present experimental evidence for significant nanocontact- induced catalytic activation of the nanomaterials for C―C cross-coupling reactions in water-based solvents and at ambient conditions.

Chapter 5: Nanocontact-induced catalytic activation 129

5.2 Results and Discussion

5.2.1 Synthesis of Pd-nanowires

The novel method for the synthesis of Pd-nanowires has been developed by Dr.

Changlong Jiang. We first synthesised the Pd nanomaterials with high-density nanocontacts by a low-temperature solution reaction using poly(N-vinylpyrrolidone)

(PVP) as a stabilizing ligand. From the previous reports, it has been shown that PVP one of the most polymeric capping reagent for the shape-controlled formation of metal nanoparticles and nanowires.182-185 In fact; from our studies, we found that the shape of the as-prepared nanomaterials depends on the concentration of PVP employed in the synthetic process. For example, only dispersed small particles (~ 5 nm in average diameter) were formed in the presence of 0.0025 mmol PVP (Fig. 5.1). As the concentration of PVP increased, the rate of particle aggregation became predominant, resulting in the formation of uniformly interconnected particle nanowires (Fig. 5.1). It should be noted that trace amount of copper powder was used as a reducing agent to control the slow rate of particle growth and subsequently the formation of high density nanocontacts at the particle–particle interface. Although detailed mechanistic picture is not confirm yet, a plausible mechanism for the nanocontact formation is shown in

Scheme 5.1. We suggested that Pd ions were first reduced by the copper metal to form Pd nanoparticles, which were subsequently assembled into one-dimensional nanostructures via the PVP template. Upon annealing at 50 oC without stirring for 24 h, Pd nanowires comprising a network of nanocontacts were formed in nearly quantitative yield. The resulted black solid residue was collected by filtration and washed thoroughly with ethanol and distilled water several times to remove the copper and excess PVP and finally

Chapter 5: Nanocontact-induced catalytic activation 130

Figure 5.1: Control experiments for the synthesis of Pd nanowires as a function of PVP concentration. (a) SEM image of the Pd nanoparticles synthesized with 0.0025-mmol PVP. (Inset) TEM image of the as-synthesized particles. (b) SEM image of the reaction product obtained with 0.005-mmol PVP. (c) SEM image of the nanowires formed with optimum PVP concentration (0.01 mmol).

Chapter 5: Nanocontact-induced catalytic activation 131

Scheme 5.1: A schematic illustration of formation of Pd nanocontacts and nanowire growth.

Chapter 5: Nanocontact-induced catalytic activation 132 dried in oven at 50 oC to furnish the title compound as a free flowing powder.

5.2.2 Characterization of Pd-nanowires

Transmission electron microscopy (TEM), scanning electron microscopy (SEM) and X-ray powder diffraction (XRD) were used to determine the surface morphology and crystal structure of the as-synthesized palladium nanowires after the synthesis. In addition, the elemental composition of the as-prepared nanowires was determined by XPS. The results are summarized in Figure 5.2. As evident from SEM, these nanowires have a uniform morphology with an averaged diameter of 100 nm (Figure 5.2a). High- magnification SEM shows that each individual nanowire consists of corn-like elongated particle assemblies (Figure 5.2b). The XRD pattern of Pd nanowires was shown in Figure

5.2c. All peaks can be indexed to face-centered cubic Pd (Joint Committee on Powder

Diffraction Standards Card No. 05-0681). We attribute the peak sharpening to the particle aggregation resulting from the formation of high density nanocontacts. In agreement with

SEM studies, TEM shows densified nanoparticles arrays along the long axis direction of the nanowire (Figure 5.2d). A three-dimensional web of interconnected (~5-nm in diameter) particles can be visually traced from the outer edge of the nanowire by high- resolution TEM (Figure 5.2e). Lattice fringe analysis exhibits high-density nanocontacts between the nanoparticles, indicating the polycrystalline nature of the nanowire. The fringe distance of 0.22 nm corresponds to the {111} planes of the Pd (Figure 5.2e). The porous network structure has a pore size distribution centered at 5 nm and a surface area

2 -1 of 45 m g (Figure 5.3). The figure 5.2f shows the XPS spectra where the Pd (3d5/2) and

Pd (3d3/2) peaks were observed at 335.48 and 340.67 eV respectively. Both the peacks are the characteristic values for Pd metal.

Chapter 5: Nanocontact-induced catalytic activation 133

Figure 5.2: Characterization of Pd nanowires. (a) SEM image of the as synthesized nanowire. (b) High-magnification SEM image showing surface morphology of the nanowire. (c) X-ray powder diffraction pattern of the nanowire. (d) TEM image of a single Pd nanowire. (e) High-magnification TEM image of the nanowire shown in Fig. 1D. The space between neighboring particles is indicated by arrows. (f) XPS spectrum of the nanowire.

Chapter 5: Nanocontact-induced catalytic activation 134

Figure 5.3: Pore-size distribution of the palladium nanowires measuremed by Barrett-Joyner-Halenda analysis.

Chapter 5: Nanocontact-induced catalytic activation 135

5.2.3 Catalytic activity of the Pd-nanowires

The Pd nanowires were examined for catalytic activity during Suzuki cross- coupling reactions under very mild conditions. For example, addition of phenylboronic acid to a mixture of iodobenzene, sodium t-butoxide and the Pd nanowires in water provided biphenyl product in an almost quantitative conversion after 24 hours (eq. 1).

It is worth noting that the insoluble biphenyl product formed at water-air interface can be easily separated from the catalyst precipitated to the bottom of the solution (Figure 5.4).

After the reaction, the Pd nanowires were isolated from the reaction mixture by centrifugation and washed with ethanol and water several times and dried in oven at 50 oC for further use. The figure 5.4c and 5.4d display the TEM images of the recovered catalytic nanowires from the above Suzuki reactions. Both the images proved that the size and morfolozy of the Pd nanowires remains intact after reactions.

In the further set of experiments, we studied the substrate scopes of the novel method. Several phenyl halides were examined for their ability to react with phenylboronic acid in the presence of the nanowires at room temperature (~ 23 oC)

(Table 5.1). In comparison, the PVP-stabilized dispersed Pd nanoparticles (~ 5 nm) only afforded a relatively low yield of product (50%) for numerous tries under these conditions (Table 5.1, entry 4). Indeed, early reports of the Suzuki reaction using dispersed Pd nanoparticles as the catalysts were typically carried out under reflux conditions (78 ~ 120 oC).186-194 Our experimental results also reveal that the use of ethanol as a solvent generally shortens the time (~ 4 h) needed to complete the

Chapter 5: Nanocontact-induced catalytic activation 136

Figure 5.4: (a) Optical image of the reaction set-up for the room-temperature palladium nanowires-catalyzed Suzuki coupling between iodobenzene and phenylboronic acid in water. (b) Optical image of the reaction after 24 h. (c) TEM image of a recovered catalytic nanowire from the Suzuki reaction. (d) High- magnification TEM image of the nanowire shown in Figure 5.4c.

Chapter 5: Nanocontact-induced catalytic activation 137

Table 5.1: Palladium nanowire-catalyzed Suzuki coupling of aryl halides and a phenylboronic acids at room temperature.

a Reaction conditions: aryl halide (1 mmol), phenylboronic acid (1.2 mmol), NaOtBu (2 mmol), Pd nanowire catalyst (6.5 mol %), total solvent volume (10 mL). b GC/MS yields. c Values in parenthesis are isolated yields. d E/W refers to a solvent mixture of ethanol and water (2:3; v:v). e The entry relates to an analogous reaction using Pd nanoparticles as catalysts. f The reaction is carried out at 50 oC. g PEG refers to polyethylene glycol. h The reaction is carried out at 80 oC.

Chapter 5: Nanocontact-induced catalytic activation 138 conversions (Table 5.1, entries 3, 5, 8, and 15). The enhanced activity can be largely attributed to improved solubility of the organic substrates in ethanol. Nonetheless, a binary combination of solvents in ethanol/water (2:3; v:v) offers comparably efficient conversions for a variety of substrates listed in Table 5.1 (entries 2, 9, 10, 12, 13, 16, 17, and 19). Importantly, the catalyst was also active towards arylchlorides with electron withdrawing groups (Table 5.1, entries 20 and 21), indicating that it is active enough to initiate the oxidative addition step of the strong C―Cl bond.

The catalytic activity of Pd nanowires is not limited to Suzuki reactions. It can be readily extended to other coupling reactions such as Heck reactions. Selected results for nanowire-catalyzed Heck reactions are summarized in Table 5.2. For instance, the chemical reaction of an iodobenzene with a styrene in the presence of the nanowire catalyst exhibits stereoselectivity with a high conversion (85%) for trans-coupling (Table

5.2, entry 1) at room temperature, albeit with the need of a polar aprotic solvent (DMF, dimethylformamide). Alternatively, the trans-coupling product can be favored in aqueous solvents at elevated temperatures (Table 5.2, entry 3), while its dispersed Pd nanoparticle counterpart gives rise to a low yield of product (Table 5.2, entry 4) under these conditions.

The scope of the Pd catalyst was further examined by recycling it from the reaction of iodobenzene with phenylboronic acid. It was observed that the catalyst exhibits consistent catalytic activity (~99%) over six recycles (Table 5.3). It should be noted that the nanowire catalyst exhibits considerable thermal stability and mechanical robustness even after repeated ultrasonic treatment at elevated temperatures.

Chapter 5: Nanocontact-induced catalytic activation 139

Table 5.2: Palladium nanowire-catalyzed Heck coupling of aryl halides and alkenes.a

a Reaction conditions: aryl halide (1 mmol), alkene (1.2 mmol), triethylamine (TEA) (2 mmol), Pd nanowire catalyst (6.5 mol %), total solvent volume (10 mL). b GC/MS yields. c The entry relates to an analogous reaction using Pd nanoparticles as catalysts. d E/W refers to a solvent mixture of ethanol and water (1:1; v:v).

Table 5.3: Recycling test of the Pd nanowires for room-temperature Suzuki- coupling.a

a Reaction conditions: phenyl halide (1mmol), phenylboronic acid (1.2 mmol), NaOtBu (2 mmol), Pd catalyst (6.5 mol %), ethanol/water (2:3; v:v; total volume 10 mL). b After each run the catalyst was isolated by centrifugation, washed with EtOH three times and air-dried at room temperature for seven consecutive reactions. c GC yields.

Chapter 5: Nanocontact-induced catalytic activation 140

5.2.4 Mechanistic Studies:

To benchmark the method, we further compared the activity of our Pd nanomaterials with bulk metal, dispersed nanoparticle counterparts, and palladium(II) acetate [Pd(OAc)2] as well as commercially available Pd catalyst (10% Pd/C) for coupling reactions by UV-vis spectroscopy. The formation of the biphenyl product for two different batch catalysts was monitored by quantitative absorption analysis of aliquot samples taken from the reaction at different time intervals as shown in Fig. 5.5a. The bulk metal (Pd foil, 1.6 mg), dispersed nanoparticles (~5 nm; 1 mg), 10% Pd/C catalyst (10 mg), and nanowires (1 mg) exhibit markedly different kinetic profiles for the coupling reaction between the phenylboronic acid and iodobenzene substrates at room temperature.

For the substrates we studied, the reaction profile fit well to a first-order rate equation

(Fig. 5.5b). The bulk metal did not show any catalytic activity toward the coupling reaction, while the nanoparticles and the Pd/C catalyst exhibited moderate catalytic activities. In contract, the Pd nanowires exhibit a rate constant that is about 200 and 34 times greater than that of the 5-nm nanoparticles and Pd/C catalyst, respectively (Fig.

6.5b). It is worth noting that the Pd(OAc)2 catalyst shows a reactivity pattern similar to that of the Pd nanowires, but poses a substantial recycling challenge.

The coupling reaction is considered to proceed via the proposed mechanism shown in Scheme 5.2. Our current hypothesis is that several factors may contribute to the dramatically enhanced catalytic activity of the Pd nanowires. The particle aggregation may change the local binding geometry (structural effect) or it may directly modify the reactivity of the Pd surface atoms, especially those located at grain boundaries (electronic effect). In particular, the high density surface electrons within the pores may contribute to

Chapter 5: Nanocontact-induced catalytic activation 141

Figure 5.5: (a) Formation of biphenyl product in ethanol as a function of time at room temperature by different catalysts including Pd nanowires, Pd nanoparticles, Pd foil, commercial Pd/C particles, and Pd(OAc)2. The data points (average of two runs) were derived by acquiring the biphenyl absorption band (centered at 247 nm) for aliquot samples taken from the reaction at different time intervals. (b) Linear regression plot for the determination of the observed rate constants kobs. The values were determined from a ln plot of the change in iodobenzene concentration versus time for respective reactions.

Chapter 5: Nanocontact-induced catalytic activation 142

Scheme 5.2: Proposed catalytic cycle for the coupling reaction between aryl halides and phenylboronic acids in the presence of Pd MPNs. The dotted cycles shown in the scheme indicate grain boundaries that are possible active sites for the catalytic reaction.

Chapter 5: Nanocontact-induced catalytic activation 143 facile oxidative addition of the phenyl halide and stabilization of the resulting intermediate. Alternatively, high interfacial energy and relatively weak bonding in the grain boundaries make them feasible as preferred active sites for molecular absorption of the reactants, thus dominating kinetics of the catalytic reaction. In addition, the three- dimensional network of high-density nanopores will also contribute to enhanced materials activity due to the higher local concentration of the reactants in the pores by capillary condensation as compared to that in the bulk solution.

5.3 Conclusion

We have reported the synthesis and catalytic studies of novel Pd nanostructures via a combination of the PVP-templated method and a slow particle crystallization process. These one-dimensional nanomaterials made of high density nanocontacts of ~1 nm in contact length at the particle–particle interface. The palladium nanowires display extremely high catalytic reactivity towards carbon―carbon cross-couplings under mild conditions. We suggested that the presence of nanocontacts triggers electron transfer and localized charge redistribution in the contact region. The charge redistribution causes the nanocontacts to become highly attractive to charged organic molecules, resulting in the facilitation of organic transformations.

These studies are important not only because they provide a potential platform to study the underlying principle that governs the catalytic reactivity of nanomaterials, but also because they shed insight into designing highly reactive and recyclable catalytic systems for organic transformations. Further investigations into the mechanism will be the subject of future research in our laboratory.

Chapter 5: Nanocontact-induced catalytic activation 144

5.4 Experimental Sections

General Methods: All chemicals were purchased from Sigma-Aldrich and used as starting materials without further purification. Unless otherwise stated, all reactions were carried out without taking precautions to exclude air and moisture. All solvents were used as received. Reactions were conducted in 20 mL vials equipped with a conventional crew cap. All reaction temperatures refer to oil-bath temperatures. Column chromatography was carried out on silica gel (230-400 mesh).

Physical Measurements: 1H NMR and 13C NMR spectra were recorded on a Bruker

ACF 300 and 75 MHz FT-NMR spectrometers as well as Bruker Avance 500 and 125

MHz FT-NMR spectrometers and referenced to solvent peaks. All the coupling reactions shown in Table 5.1, 5.2 and 5.3 were determined by using Hewlett- Packard Series 6890

GC (Santa Clara, CA, USA) coupled to a Hewlett Packard 5973 MS detector.

Synthesis of the palladium nanowires: In a typical experiment, palladium acetate

(122 mg; 0.538 mmol) and poly(N-vinyl pyrrolidone) (Mw = 40,000; 400 mg; 0.01 mmol) were dissolved in methanol (15 mL), followed by addition of copper powder (25 mg;

0.39 mmol). The resulted mixture was heated at 50 oC for 24 h to give a black precipitate which was collected, washed with ethanol and distilled water several times, and dried in air for further characterization and organic reactions.

Characterization: The sample morphology and crystal structure were investigated by field-emission scanning electron microcopy (JEOL 6701) and transmission electron microscopy (JEOL 3010). XPS spectra were recorded using an Omicron ESCA probe operated in vacuum at around 4.8  10-10 Torr with a monochromated AlKα radiation

(1486.6 eV, 300 W). Binding energies of XPS spectra were corrected by referencing the

Chapter 5: Nanocontact-induced catalytic activation 145

C1s signal of adventitious hydrocarbon to 284.8 eV. The electron pass energy in the analyzer was set at 50 eV. The crystallographic phase of the sample was determined by powder XRD on a Siemens D5005 X-ray diffractometer with Cu Kα radiation (λ =

1.5406 Å) at a scan rate of 0.01 o/s. The porosity of the sample was measured by a pore size analyzer (Micromeritics Tristar). The sample was degassed under a N2 flow at 300 oC for 4 h prior to the measurement. The Barrett-Joyner-Jalenda method was used to obtain the pore size distribution.

Catalytic reactions: In a typical Suzuki cross-coupling reaction, a mixture of phenylboronic acid (1.2 mmol), aryl halides (1 mmol), Pd nanowire catalyst (6.5 mol%), and NaOtBu (2 mmol) was stirred in water (10 mL) or water/ethanol (3:2; v:v) at room temperature. Reaction progress was monitored by GC-MS (Hewlett-Parkard). After complete consumption of starting materials, the resulting reaction mixture was then centrifuged to remove the Pd catalyst, followed by the removal of the solvent in a rotary evaporator. The residue was dissolved in dichloromethane and washed with water three times. The organic layers were dried with anhydrous sodium sulfate. The solvent was removed in vacuo, and the remaining residue was purified by silica-gel column chromatography (eluent: hexane/ethyl acetate) to yield the corresponding coupling product. The product was analyzed by 1H NMR and 13C NMR (Bruker ACF 500 and 125

MHz FT-NMR spectrometers and referenced to the solvent peaks).

The recycling catalyst that is collected by centrifugation was washed with ethanol several times and air dried for repeated use.

Chapter 5: Nanocontact-induced catalytic activation 146

For a Heck cross-coupling reaction, aryl halide (1 mmol), alkene (1.2 mmol), triethylamine (2 mmol) and Pd nanowire catalyst (6.5 mol %) were combined in dimethylformide (10 mL) or water/ethanol (1:1; v:v).

Example (1): Synthesis of 4-Nitrobiphenyl (3c). To a solution (3 mL) of ethanol and water (2:3; v:v) charged with phenylboronic acid (1.2 mmol) and 4-Iodonitrobenzene (1.0 mmol) were added Pd nanowire catalyst (6.5 mol %), and NaOtBu (2 mmol). The reaction was stirred at room temperature under aerobic conditions for 4 h. The resulting reaction mixture was then centrifuged to remove the Pd catalyst, followed by the removal of the solvent in a rotary evaporator. The residue was dissolved in dichloromethane and washed with water three times. The organic layers were dried with anhydrous sodium sulfate. The solvent was removed in vacuo, and the remaining residue was purified by silica-gel column chromatography (eluent: hexane/ethyl acetate) to yield the product 3c

1 in 95% isolated yield as a light-yellow solid. H NMR (500 MHz, CDCl3) δ 8.371 (d, 2H,

J = 8.7 Hz), 8.034 (d, 2H, J = 5.5 Hz), 7.854 (d, 2H, J = 7.5 Hz), 7.549 (t, 3H, J = 7.2 Hz);

13 C (125 MHz, CDCl3) δ 147.5, 147.4, 138.7, 129.6, 129.4, 128.3, 127.7, 124.4. Good agreement was found with literature values.195

Example (2): Synthesis of 4-Phenyl toluene (3b). Reaction and work-up were performed as above, but using 4-bromotoluene (1.2 mmol), to give 95% of product 3b.

The crude material was purified by silica-gel column chromatography (eluent: hexane/ethyl acetate) to yield the product 3b in 95% isolated yield as a white solid. 1H

NMR (500 MHz, CDCl3) δ 7.68 (d, 2H, J = 8.4 Hz), 7.60 (d, 2H, J = 8.1 Hz), 7.47 (t, 2H,

J = 7.8 Hz), 7.36 (t, 1H, J = 7.2 Hz), 7.30 (d, 2H, J = 8.1 Hz), 2.37 (s, 3H); 13C (125 MHz,

Chapter 5: Nanocontact-induced catalytic activation 147

CDCl3) δ 141.0, 138.1, 137.3, 129.8, 129.1, 127.4, 126.9, 126.7, 20.5. Good agreement was found with literature values.196

Experimental Procedure for kinetic Studies: Conditions and apparatus were similar to the cross-coupling procedure given above. The kinetic profiles were studied in ethanol by taking aliquot samples (6 µL) from the reaction solution at different time intervals. The samples were then diluted with ethanol (total volume: 5 mL), centrifuged to remove the catalyst, and analyzed by absorption spectroscopy. UV-vis absorbance spectra were obtained at 23 oC using quartz cells and a SHIMADZU UV-2450 spectrophotometer.

References and Notes 148

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Sadananda Ranjit

Personal Details

Date of Birth 1st May 1983

Gender Male

Nationality Indian

Educations

1989-1998 Primary School (Class I-IX)

1998-1999 Secondary School Examinations (Class X)

1999-2001 Higher Secondary School Examinations (Class XII)

2001-2004 B. Sc. (Honors) in Chemistry, Calcutta University, India

2004-2006 M. Sc. in Chemistry, Indian Institute of Technology Madras, India

2007-2011 Ph. D., in Organic chemistry, National University of Singapore, under the supervision of Prof. Dr. Liu Xiaogang Thesis “Development of Transition-Metal-Catalyzed C―C and C―S Cross-Coupling Reactions”

Research Experiences

Aug 2005-Apr 2006 Laboratory of Prof. Dr. T. Pradeep, IITMadras, India “Novel Routes to Make Shell Protected Nanoparticles”

Aug 2006-Dec 2006 Laboratory of Professor Dr. U. V. Varadaraju, IITMadras, India “Environmentally friendly rare earth based sulfides for surface colorant applications”

Jan 2007- Jan 2011 Laboratory of Prof. Dr. Liu Xiaogang, NUS, Singapore “Development of Transition-Metal-Catalyzed C―C and C―S Cross-Coupling Reactions”

Curriculum Vitae 172

Publications

1. Sadananda Ranjit and Xiaogang Liu, “Direct Arylation of Benzothiazoles and Benzoxazoles with Arylboronic Acids “. Chem.―Eur. J. 2011, 17, 1105-1108.

2. Sadananda Ranjit, Zhongyu Duan, Pengfei Zhang and Xiaogang Liu, “Synthesis of (Z)-Vinyl Sulfides by Copper-Catalyzed Decarboxylative C―S Cross- Coupling”. Org. Letts. 2010, 12, 4134-4136.

3. Sadananda Ranjit, Richmond Lee, Kuo-Wei Huang and Xiaogang Liu, “Copper- Catalyzed C―H Activation/C―S Cross-Coupling of Heterocycles with Thiols”. Manuscript in Preparation.

4. Zhongyu Duan, Sadananda Ranjit and Xiaogang Liu, “One-Pot Synthesis of Amine-Substituted Aryl Sulfides and Benzo[b]thiophene Derivatives”. Org. Letts. 2010, 12, 2430-2433.

5. Zhongyu Duan, Sadananda Ranjit, Pengfei Zhang and Xiaogang Liu, “Synthesis of Aryl Sulfides by Decarboxylative C―S Cross-Couplings”. Chem.―Eur. J. 2009, 15, 3666-3669.

6. Changlong Jiang, Sadananda Ranjit, Zhongyu Duan, Yu Lin Zhong, Kian Ping Loh, Chun Zhang and Xiaogang Liu, “Nanocontact-induced catalytic activation in palladium nanoparticles”. Nanoscale 2009, 1, 391-394.

7. Chao Shen, Haijun Xia, Hua Yan, Xinzhi Chen, Sadananda Ranjit, Xiaogang Liu and Pengfei Zhang, “Concise Synthesis of Glycosyl Benzothiazoles through Palladium-Catalyzed C―S Coupling”. Manuscript in Preparation.

Symposia/Conference Presentations

1. “Magnetic Nanoparticles for Drug Delivery”. 7th Graduate Student Symposium, 19 November 2007, Faculty of Science, National University of Singapore, Singapore (Oral presentation).

2. “Highly Efficient Palladium Nanowire Catalyzed Suzuki-Cross coupling Reactions under mild and Aerobic Conditions”. Singapore International Chemistry Conference (SICC-5), 16-19 December 2007, Singapore (Poster presentation).

3. “Synthesis of Aryl Sulfides via Decarboxylative C―S Cross-Couplings”. The 5th Mathematics and Physical Sciences Graduate Congress (5th MPSGC), 7-9 December 2009, Faculty of Science, Chulalonkorn University, Bangkok, Thiland (Poster presentation).

Curriculum Vitae 173

4. “One-Pot Synthesis of Amine-Substituted Aryl Sulfides and Benzo[b]thiophene Derivatives”. Inaugural Conference on Molecular & Functional Catalysis (ICMFC-1), 11-15 July 2010, Singapore (Poster Presentation).

Appendices (Chapter 2) 174

1H and 13C NMR Spectra for all compounds resulted in Chapter 2 Appendices (Chapter 2) 175

3a 3923 . 3.8198 1.5500 7 7.3660 7.2805 7.2767 7.2729 7.2603 7.2526 7.2460 7.2318 7.2279 6.9222 6.9118 6.9047 6.8894 6.8823 6.8718 6.5119 6.4757 6.4221 6.3859 7.5342 7.5095 7.4537 7.4433 7.4361 7.4142 7.3923 7.3660 7.2805 7.2767 7.2729 7.2603 7.2526 7.2460 7.2318 7.2279

7.50 7.40 7.30 (ppm) Integral 2.0000 4.0316 1.5231 2.0182 1.0293 1.0193 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.0733 3.5 3.0 2.5 2.0 1.5 1.0 0.5 (ppm) Appendices (Chapter 2) 176 9 5 3 4 9 2 5 0 8 9 159.525 136.643 132.934 128.678 128.335 128.292 126.929 126.842 125.770 114.817 77.2587 77.0037 76.7486 55.3966

3a 125.7708 128.6784 128.3359 128.2922 126.9295 126.8420

129.0 128.0 127.0 126.0 (ppm)

190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 (ppm)

Appendices (Chapter 2) 177 2.8227 2.8063 2.7986 2.7822 2.7575 1.7396 1.7171 1.6914 1.6673 1.6415 1.5555 1.4361 1.4136 1.3660 1.2608 0.9036 0.8828 0.8592 7.3753 7.3507 7.3244 7.2959 7.2817 7.2603 7.2269 7.2022 7.1781 6.7541 6.7020 6.4873 6.4489 6.4358 6.4128 6.2676 6.2314

3b 7.4997 7.4740 7.3945 7.3753 7.3507 7.3244 7.2959 7.2817 7.2603 7.2269 7.2022 7.1781 6.7020 6.4873 6.4489 6.4358 6.4128 6.2676 6.2314 2.8063 2.7986 2.7822 2.7575 1.7171 1.6914 1.6673 1.6415

7.40 7.30 7.20 6.6 6.4 2.80 1.7 (ppm) (ppm) (ppm) (ppm)

Z E, Z E Integral 1.9934 2.0385 1.0002 0.1714 0.0900 0.8958 0.8384 2.0909 2.0054 18.042 3.0858 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 (ppm) Appendices (Chapter 2) 178 137.0714 128.5910 128.1838 127.6965 126.7364 126.5328 125.4418 125.3836 125.2455 77.4182 76.9963 76.5672 35.9257 31.8964 30.2309 29.6054 29.5691 29.4745 29.3218 29.1763 28.8054 28.5872 22.6670 14.0849

3b 30.2309 29.6054 29.5691 29.4745 29.3218 29.1763 28.8054 28.5872 128.5910 128.1838 127.6965 126.7364 126.5328 125.4418 125.3836 125.2455

129 128 127 126 30.6 30.0 29.4 28.8 28.2 (ppm) (ppm)

190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 -10 (ppm)

Appendices (Chapter 2) 179 3107 . 1.7555 1.7325 1.7073 1.6832 1.6574 1.5511 1.4536 1.4306 1.4070 1.3840 1.2964 0.9249 0.9036 0.8806 7 7.2964 7.2603 7.2411 7.2373 7.2170 7.2104 7.1924 6.7716 6.7196 6.5048 6.4648 6.4528 6.4281 6.2807 6.2446 2.8183 2.7937 2.7690

3c 7.2170 7.2104 7.1924 6.7716 6.7196 6.5048 6.4648 6.4528 6.4281 6.2807 6.2446 7.5233 7.5189 7.4948 7.4931 7.3907 7.3841 7.3660 7.3397 7.3107 7.2964 7.2603 7.2411 7.2373 1.7555 1.7325 1.7073 1.6832 1.6574 0.9249 0.9036 0.8806

7.5 7.4 7.3 7.2 6.7 6.6 6.5 6.4 6.3 1.65 0.9 (ppm) (ppm) (ppm) (ppm)

Z

E, Z

E Integral 2.1346 2.2528 10.247 3.0776 2.0056 2.1601 0.9988 0.1218 1.0007 0.8821 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 (ppm) Appendices (Chapter 2) 180 137.0605 132.2312 128.5802 128.1656 127.6856 126.7183 126.6746 126.5146 125.4237 125.3800 125.2273 77.4291 77.0000 76.5782 35.9075 32.6347 31.7837 30.2200 29.4418 29.1364 28.8018 28.5836 22.6125 14.0521

3c 128.5802 128.1656 127.6856 126.7183 126.6746 126.5146 125.4237 125.3800 125.2273

129.0 128.0 127.0 126.0 125.0 (ppm)

190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 (ppm) Appendices (Chapter 2) 181 2603 . 1.7106 1.6853 1.6766 1.6623 1.6601 1.6349 1.5593 1.5155 1.4914 1.4657 1.4405 1.4169 1.3928 0.9759 0.9627 0.9518 0.9386 0.9277 0.9140 7 7.2329 7.2285 7.2247 7.2104 7.2044 7.1978 7.1803 6.7574 6.7053 6.4922 6.4517 6.4402 6.4155 6.2709 6.2347 2.8178 2.7937 2.7690 1.7336

3d 6.7574 6.7053 6.4922 6.4517 6.4402 6.4155 6.2709 6.2347 1.6766 1.6623 1.6601 1.6349 1.5593 1.5155 1.4914 1.4657 1.4405 1.4169 1.3928 0.9627 0.9518 0.9386 0.9277 0.9140 7.5057 7.5008 7.4767 7.3972 7.3770 7.3709 7.3523 7.3260 7.2986 7.2844 7.2603 7.2329 7.2285 7.2247 7.2104 7.2044 7.1978 7.1803

7.5 7.4 7.3 7.2 6.6 6.4 1.60 (ppm) (ppm) (ppm) (ppm)

Z E, Z

E Integral 2.1884 2.0753 2.0264 3.2844 2.0048 2.1553 1.0034 0.1196 1.0000 0.8789 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 (ppm) Appendices (Chapter 2) 182 2 8 0 8 2 5 137.064 128.5911 128.183 127.682 126.743 126.5401 125.449 125.376 125.2601 77.4183 76.9964 76.5746 35.5912 32.2893 31.5329 21.6852 13.6122

3d 128.5911 128.1838 127.6820 126.7438 126.5401 125.4492 125.3765 125.2601

129.0 128.0 127.0 126.0 125.0 (ppm)

190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 (ppm) Appendices (Chapter 2) 183 1.5511 7.2712 7.2673 7.2542 7.2487 7.2427 7.2317 7.2262 7.2224 7.2082 7.2038 6.7474 6.6954 6.5403 6.5036 6.4888 6.4675 6.2817 6.2456 3.0708 3.0587 3.0544 3.0423 3.0297 3.0204 3.0089 2.9968 2.9793

3e 6.2817 6.2456 6.7474 6.6954 6.5403 6.5036 6.4888 6.4675 7.5210 7.5161 7.4920 7.4903 7.3977 7.3911 7.3731 7.3468 7.3249 7.3194 7.3035 7.2980 7.2772 7.2712 7.2673 7.2542 7.2487 7.2427 7.2317 7.2262 7.2224 7.2082 7.2038

7.50 7.40 7.30 7.20 6.70 6.60 6.50 6.40 6.30 (ppm) (ppm) Z

E, Z

E Integral 1.8527 8.3471 0.2101 7.51.0000 0.7919 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 (ppm) Appendices (Chapter 2) 184 139.8280 136.8898 128.6276 128.5549 128.5258 128.1912 127.3985 126.9766 126.8821 126.6639 126.4966 125.9221 125.5075 124.7002 77.4184 76.9966 76.5747 37.1041 36.7696 35.9259 34.0277 37.1041 36.7696 3e 128.6276 128.5549 128.5258 128.1912 127.3985 126.9766 126.8821 126.6639 126.4966 125.9221 125.5075 124.7002

129 128 127 126 125 124 37.5 (ppm) (ppm)

190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 (ppm) Appendices (Chapter 2) 185 1.8037 1.7955 1.6607 1.6508 1.6465 1.6306 1.6158 1.5566 1.5396 1.5287 1.5018 1.4925 1.4580 1.4213 1.3912 1.3829 1.3440 1.3145 1.2964 1.2893 1.2624 1.2531 7.2269 7.2230 7.2187 7.2044 7.1984 7.1924 7.1781 7.1743 7.1699 6.7957 6.7437 6.5990 6.5470 6.4550 6.4182 6.3552 6.3185 2.9399 2.9284 2.9164 2.9054 2.8934 2.8808 2.8709 2.8583 2.8457 2.0913 2.0776 2.0568 2.0486 1.8322 1.8196

3f 6.7957 6.7437 6.5990 6.5470 6.4550 6.4182 6.3552 6.3185 2.9284 2.9164 2.9054 2.8934 2.8808 2.8709 2.8583 2.8457 7.5063 7.5019 7.4778 7.3742 7.3682 7.3496 7.3282 7.3233 7.3047 7.2921 7.2893 7.2603 7.2269 7.2230 7.2187 7.2044 7.1984 7.1924 7.1781 7.1743 7.1699

7.50 7.40 7.30 7.20 6.6 6.4 2.85 Z (ppm) (ppm) (ppm) Z

E E Integral 0.9766 2.1002 2.0044 1.0039 5.0141 1.9321 2.1326 0.9975 0.1047 0.1040 7.50.9000 0.9009 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 (ppm) Appendices (Chapter 2) 186

4 2 6 7 4 3 5 9 77.4255 76.9964 76.5746 47.7589 33.6639 25.9690 25.5981 137.151 128.620 128.576 128.154 126.867 126.4601 125.878 125.565 125.041 128.6202 128.5766 128.1547 126.8674 126.4601 125.8783 125.5655 125.0419 3f

128 127 126 125 (ppm)

190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 (ppm) Appendices (Chapter 2) 187

4.0219 4.0060 1.5566 7.2899 7.2871 7.2751 7.2603 7.2373 7.2329 7.2291 7.2148 7.2088 7.2022 7.1885 7.1847 7.1803 6.7530 6.7015 6.5629 6.5108 6.4489 6.4122 6.2780 6.2413

3g 6.7530 6.7015 6.5629 6.5108 6.4489 6.4122 6.2780 6.2413

Z 6.7 6.6 6.5 6.4 6.3 (ppm) Z

E E Integral 10.454 0.0996 0.1024 7.5 0.9049 0.9000 7.0 6.5 6.0 5.5 5.0 4.5 4.02.1128 3.5 3.0 2.5 2.0 1.5 1.0 0.5 (ppm) Appendices (Chapter 2) 188

4 1 3 6 1 7 6 8 1 3 8 7 9 4 9 2 137.391 136.875 128.969 128.816 128.671 128.605 128.205 128.023 127.391 127.318 126.983 126.714 126.001 125.907 125.601 124.358 77.4255 77.0037 76.5819 39.5332

128.9693 128.8166 128.6711 128.6057 128.2056 128.0238 127.3911 127.3183 126.9838 126.7147 126.0019 125.9074 125.6019 124.3582 3g

129 128 127 126 125 124 (ppm)

190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 -10 (ppm)

Appendices (Chapter 2) 189 2978 . 7 7.2638 7.2496 7.2485 7.2375 7.2118 7.1877 7.1723 7.1493 7.1225 6.7428 6.6913 6.5390 6.4875 6.4229 6.3867 6.2646 6.2284 3.9756 3.9597 2.3315 1.5859

3h 6.7428 6.6913 6.5390 6.4875 6.4229 6.3867 6.2646 6.2284 7.4594 7.4550 7.4298 7.3493 7.3241 7.2978 7.2638 7.2496 7.2485 7.2375 7.2118 7.1877 7.1723 7.1493 7.1225

7.5 7.4 7.3 7.2 7.1 6.7 6.6 6.5 6.4 6.3 (ppm) (ppm)

Z Z

E E Integral 3.2664 2.0579 7.4272 0.1044 0.1035 0.9000 7.5 0.8964 7.0 6.5 6.0 5.5 5.0 4.5 4.0 2.0667 3.5 3.0 2.5 2.0 1.5 1.0 0.5 (ppm) Appendices (Chapter 2) 190 128.1874 126.9219 126.6601 126.1146 125.7364 125.5764 124.5655 77.4291 77.0000 76.5782 39.2531 37.1003 21.0851 137.0968 136.9223 134.2822 130.2820 129.3729 128.8711 128.7038 128.6602 128.5874

3h 128.8711 128.7038 128.6602 128.5874 128.1874 126.9219 126.6601 126.1146 125.7364 125.5764 124.5655 137.0968 136.9223 134.2822 130.2820 129.3729

138 136 134 132 130 128 126 (ppm)

20 210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 (ppm)

Appendices (Chapter 2) 191 7.3008 7.2904 7.2811 7.2603 7.2400 7.2362 7.2323 7.2181 7.2115 7.2055 7.1912 7.1874 6.7891 6.7371 6.5716 6.5196 6.4582 6.4221 6.3169 6.2807 4.0126 3.9945 1.5555 1.3342 7.3288

3i 7.3644 7.3583 7.3496 7.3288 7.3008 7.2904 7.2811 7.2603 7.2400 7.2362 7.2323 7.2181 7.2115 7.2055 7.1912 7.1874 7.4920 7.4876 7.4635 7.3923 7.3857 7.3726

7.50 7.45 7.40 7.35 7.30 7.25 7.20 (ppm)

Z Z

E E Integral 9.1017 2.0341 6.0802 1.0004 0.1040 0.1061 7.50.9105 0.9046 7.0 6.5 6.0 5.5 5.0 4.5 4.02.2151 3.5 3.0 2.5 2.0 1.5 1.0 0.5 (ppm)

Appendices (Chapter 2) 192 150.3522 136.9117 134.2425 128.6496 128.6132 128.4678 128.1768 127.5950 126.8968 126.6422 126.3004 125.6386 125.6022 124.7294 77.4185 76.9967 76.5676 39.2062 36.9515 34.4933 31.3004

3i

190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 (ppm) Appendices (Chapter 2) 193 7.2603 7.2334 7.2290 7.2247 7.2104 7.2049 7.1984 7.1847 7.1803 7.1765 6.9020 6.8921 6.8850 6.8702 6.8631 6.8532 6.7546 6.7031 6.5563 6.5048 6.4434 6.4073 6.2785 6.2424 3.9825 3.9666 3.8066 1.5741 7.2690 3j 7.3096 7.3025 7.2871 7.2800 7.2690 7.2603 7.2334 7.2290 7.2247 7.2104 7.2049 7.1984 7.1847 7.1803 7.1765 7.4783 7.4739 7.4504 7.4482 7.3660 7.3600 7.3414 7.3145 6.7546 6.7031 6.5563 6.5048 6.4434 6.4073 6.2785 6.2424

7.45 7.40 7.35 7.30 7.25 7.20 6.70 6.60 6.50 6.40 6.30 (ppm) (ppm)

Z Z

E E Integral 1.9361 5.2387 2.0604 0.2038 0.2044 0.8000 0.7962 2.0702 3.0274 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 (ppm) Appendices (Chapter 2) 194 114.1106 77.4256 77.0037 76.5746 55.2720 38.9587 36.7913 158.9414 136.9188 130.0821 129.9149 129.3039 128.6493 128.5839 128.1839 127.7984 126.9256 126.6565 126.0747 125.7183 125.5656 124.5328

3j 130.0821 129.9149 129.3039 128.6493 128.5839 128.1839 127.7984 126.9256 126.6565 126.0747 125.7183 125.5656 124.5328

130.5 129.0 127.5 126.0 124.5 (ppm)

-1 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 0 (ppm) Appendices (Chapter 2) 195 1.5418 7.3162 7.3036 7.2893 7.2855 7.2603 7.2406 7.2362 7.2121 7.2055 7.1924 7.1880 7.1836 6.6977 6.6462 6.5514 6.4999 6.4572 6.4210 6.2068 6.1706 3.9677 3.9546 3k 7.4279 7.3671 7.3611 7.3430 7.3381 7.3217 7.3162 7.3036 7.2893 7.2855 7.2603 7.2406 7.2362 7.2121 7.2055 7.1924 7.1880 7.1836 7.4586 7.4537 7.4296 6.6977 6.6462 6.5514 6.4999 6.4572 6.4210 6.2068 6.1706

7.45 7.40 7.35 7.30 7.25 7.20 6.6 6.5 6.4 6.3 6.2 (ppm) (ppm)

Z Z E E Integral 1.9344 5.9982 1.0346 0.1527 0.1636 0.8557 0.8500 2.0758 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 (ppm) Appendices (Chapter 2) 196 4 3 4 2 5 7 7 9 2 9 7 8 123.732 77.4256 77.0037 76.5819 38.7987 36.7622 136.722 135.973 133.260 130.271 130.118 128.845 128.685 128.6421 128.2421 127.172 126.860 126.4311 125.652 125.434

3k 125.6529 125.4347 130.2712 130.1185 128.8457 128.6857 128.6421 128.2421 127.1729 126.8602 126.4311

130 129 128 127 126 (ppm)

-1 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 0 (ppm) Appendices (Chapter 2) 197 1.5914 7.2951 7.2600 7.2534 7.2496 7.2447 7.2315 7.2249 7.2184 7.2134 7.2052 7.2008 7.1964 6.7823 6.7308 6.6152 6.5637 6.5051 6.4684 6.3506 6.3440 6.3363 6.3002 6.2898 6.2876 6.2793 4.0101 3.9844 3l 7.3126 7.3066 7.2951 7.2600 7.2534 7.2496 7.2447 7.2315 7.2249 7.2184 7.2134 7.2052 7.2008 7.1964 7.4791 7.4742 7.4501 7.4479 7.4019 7.3992 7.3959 7.3931 7.3844 7.3778 7.3597 7.3548 7.3389 7.3334 6.7823 6.7308 6.6152 6.5637 6.5051 6.4684 6.3506 6.3440 6.3363 6.3002 6.2898 6.2876 6.2793

7.50 7.45 7.40 7.35 7.30 7.25 7.20 6.7 6.6 6.5 6.4 6.3 (ppm) (ppm)

Z

Z

E E Integral 6.2757 0.1603 0.1580 0.8400 2.9998 2.1485 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 (ppm) Appendices (Chapter 2) 198 110.4964 108.0963 107.8490 77.4187 76.9969 76.5751 31.5406 29.6933 150.8034 142.5703 142.3303 136.7374 128.7734 128.6352 128.5989 128.2061 127.1079 126.7733 126.1333 125.6751 125.5224 123.7623

3l

190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 - (ppm) Appendices (Chapter 2) 199 1.5674 7.4336 7.4134 7.3983 7.3832 7.3655 7.3403 7.3315 7.3290 7.3252 7.3176 7.3025 7.2861 6.9621 6.9318 6.8133 6.7818 6.6633 6.6419 6.5725 6.5511

3m 7.6076 7.5925 7.5320 7.5168 7.4916 7.4891 7.4727 7.4639 7.4487 7.4336 7.4134 7.3983 7.3832 7.3655 7.3403 7.3315 7.3290 7.3252 7.3176 7.3025 7.2861 6.9621 6.9318 6.8133 6.7818 6.6633 6.6419 6.5725 6.5511

Z Z

7.60 7.55 7.50 7.45 7.40 7.35 7.30 6.90 6.80 6.70 6.60 (ppm) (ppm)

E E Integral 1.8961 1.8972 6.0923 0.0951 0.0966 0.9080 0.9000 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 (ppm) Appendices (Chapter 2) 200 7 7 2 1 4 1 3 2 5 5 7 0 0 8 7 0 136.456 136.230 131.778 130.051 129.832 129.140 128.739 128.659 128.287 127.551 127.252 127.158 127.107 126.924 125.984 123.405 77.2541 76.9990 76.7439 3m 136.4567 136.2307 130.0511 129.8324 129.1401 128.7393 128.6592 128.2875 127.5515 127.2527 127.1580 127.1070 126.9248 125.9847

131.0 130.0 129.0 128.0 127.0 126.0 (ppm) (ppm)

190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 (ppm) Appendices (Chapter 2) 201 3589 . 2.3565 1.5550 7 7.3518 7.3310 7.3205 7.3123 7.3003 7.2844 7.2806 7.2762 7.2603 7.2493 7.2356 7.2312 7.1781 7.1518 6.8905 6.8390 6.6779 6.6264 6.5700 6.5344 6.4840 6.4484

3n 7.5495 7.5452 7.5211 7.5189 7.4175 7.4115 7.3929 7.3868 7.3803 7.3660 7.3589 7.3518 7.3310 7.3205 7.3123 7.3003 7.2844 7.2806 7.2762 7.2603 7.2493 7.2356 7.2312 7.1781 7.1518

Z 7.55 7.50 7.45 7.40 7.35 7.30 7.25 7.20 7.15 (ppm) Z

E E Integral 3.0342 2.1021 4.8610 0.2560 2.0605 0.0991 0.1038 7.50.9048 0.9020 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 (ppm) Appendices (Chapter 2) 202 6 7 7 3 7 3 3 0 3 5 9 2 0 9 137.409 136.587 132.696 130.6311 130.529 129.925 128.718 128.638 128.282 127.358 127.045 127.001 126.529 125.911 124.470 77.4218 77.0000 76.5709 21.0561

3n 130.6311 130.5293 129.9257 128.7183 128.6383 128.2820 127.3583 127.0455 127.0019 126.5292 125.9110

131.0 130.0 129.0 128.0 127.0 126.0 (ppm)

190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 -10 (ppm) Appendices (Chapter 2) 203 1.5403 7.3514 7.3338 7.3240 7.3163 7.3092 7.2939 7.2878 7.2708 7.2637 7.2577 7.2391 6.8446 6.7931 6.7613 6.7098 6.6353 6.5997 6.4299 6.3943

3o 7.5201 7.4960 7.4944 7.4122 7.4056 7.3875 7.3662 7.3591 7.3514 7.3338 7.3240 7.3163 7.3092 7.2939 7.2878 7.2708 7.2637 7.2577 7.2391 6.8446 6.7931 6.7613 6.7098 6.6353 6.5997 6.4299 6.3943

Z

7.50 7.40 7.30 6.80 6.70 6.60 6.50 6.40 (ppm) (ppm) Z

E Integral 2.0224 7.3305 0.0737 0.0745 0.9349 7.50.9326 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 (ppm) Appendices (Chapter 2) 204 9 1 2 0 2 5 4 3 4 0 2 6 6 9 2 6 136.205 134.744 133.282 132.744 132.482 131.238 130.969 129.289 128.758 128.322 128.060 127.805 127.325 126.081 125.129 122.503 77.4183 76.9964 76.5746 136.2059 134.7441 133.2822 132.7440 132.4822 131.2385 130.9694 129.2893 128.7584 128.3220 128.0602 127.8056 127.3256 126.0819 125.1292 122.5036

3o

136 134 132 130 128 126 124 (ppm)

-1 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 0 (ppm) Appendices (Chapter 2) 205 4532 . 7 7.4351 7.4291 7.4110 7.4066 7.3847 7.3469 7.3381 7.3316 7.3162 7.3097 7.3009 7.2949 7.2883 7.2636 7.2603 6.6665 6.6309 6.4517 6.4161 1.5808 1.4564

3p 7.5474 7.5430 7.5189 7.4992 7.4904 7.4839 7.4685 7.4620 7.4532 7.4351 7.4291 7.4110 7.4066 7.3847 7.3469 7.3381 7.3316 7.3162 7.3097 7.3009 7.2949 7.2883 7.2636 7.2603

Z Z 7.60 7.55 7.50 7.45 7.40 7.35 7.30 7.25 (ppm) Integral 9.0951 1.0000 0.9987 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 (ppm) Appendices (Chapter 2) 206 136.1697 135.4061 132.2059 131.3914 128.7585 128.3222 128.2203 127.3403 124.8529 121.1728 77.4257 77.0038 76.5820

3p 127.3403 128.7585 128.3222 128.2203

129.0 128.0 127.0 (ppm)

190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 (ppm) Appendices (Chapter 2) 207

2783 . 7 7.2757 7.2732 7.2606 7.2468 7.2417 7.1875 7.1837 7.1711 7.1560 7.1535 6.7551 6.7525 6.7462 6.7437 6.7387 6.7362 6.7311 6.7286 6.7160 6.7135 6.5307 6.5092 6.1953 6.1739 4.2387 1.5609

3q 7.4359 7.4321 7.4207 7.4170 7.4144 7.4106 7.3993 7.3867 7.3829 7.2783 7.2757 7.2732 7.2606 7.2468 7.2417 7.1875 7.1837 7.1711 7.1560 7.1535 7.5607 7.5468

7.44 7.40 7.25 7.20 7.15 (ppm) (ppm) (ppm) Integral 2.0000 3.0691 1.2495 1.0236 2.0317 1.0106 1.0038 2.0806 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 (ppm) Appendices (Chapter 2) 208 3 3 3 2 9 8 4 9 2 0 8 7 8 4 147.669 136.563 135.215 130.441 128.765 128.576 128.335 127.709 126.995 126.710 118.694 117.834 116.151 115.313 77.2587 77.0036 76.7559

3q

-1 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 0 (ppm) Appendices (Chapter 2) 209 2852 .

7 7.2682 7.2627 7.2562 7.2430 7.2255 7.2200 7.1964 6.8266 6.7752 6.6596 6.6382 6.6327 6.6157 6.6108 6.6015 6.4432 6.4070 6.3823 6.3467 3.6234 3r 6.8266 6.7752 6.6596 6.6382 6.6327 6.6157 6.6108 6.6015 6.4432 6.4070 6.3823 6.3467 7.5137 7.4885 7.3904 7.3652 7.3389 7.2907 7.2852 7.2682 7.2627 7.2562 7.2430 7.2255 7.2200 7.1964

7.5 7.4 7.3 7.2 6.8 6.7 6.6 6.5 6.4 (ppm) (ppm) Integral 2.0169 2.0145 3.1213 0.0630 2.0503 1.8800 2.1020 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 (ppm) Appendices (Chapter 2) 210 6 8 0 6 4 0 8 6 7 8 2 9 146.504 136.758 134.075 133.289 129.449 128.613 128.234 126.736 125.674 124.983 123.689 115.608 77.4256 77.0038 76.5819

3r 129.4494 128.6130 128.2348 126.7366 125.6747 124.9838 123.6892

129.0 128.0 127.0 126.0 125.0 124.0 (ppm)

190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 (ppm) Appendices (Chapter 2) 211 7.2630 7.2487 7.2416 7.2356 7.2186 7.2142 7.1945 7.1896 7.1677 7.1644 7.1403 7.0187 7.0148 6.9880 6.9841 6.9606 6.9567 6.9255 6.9211 6.8992 6.8948 6.8740 6.8696 6.8488 6.8444 6.5711 6.5289 6.5196 6.4933 6.3514 6.2999 6.2719 6.1728 6.0440 6.0084 1.5505 3s 6.5711 6.5289 6.5196 6.4933 6.3514 6.2999 6.2719 6.1728 6.0440 6.0084 7.0187 7.0148 6.9880 6.9841 6.9606 6.9567 6.9255 6.9211 6.8992 6.8948 6.8740 6.8696 6.8488 6.8444 7.5084 7.5035 7.4794 7.4778 7.4684 7.4482 7.4427 7.3906 7.3665 7.3616 7.3402 7.2926 7.2871 7.2674 7.2630 7.2487 7.2416 7.2356 7.2186 7.2142 7.1945 7.1896 7.1677 7.1644 7.1403

Z

7.50 7.40 7.30 7.20 7.00 6.95 6.90 6.85 6.5 6.4 6.3 6.2 6.1 6.0 (ppm) (ppm) (ppm)

Z

E Integral 3.0572 2.0636 2.2075 2.0140 1.0000 0.1498 0.1497 0.8495 0.8487 7.6 7.2 6.8 6.4 6.0 5.6 5.2 4.8 4.4 4.0 3.6 3.2 2.8 2.4 2.0 1.6 1.2 0.8 0.4 (ppm) Appendices (Chapter 2) 212 1 5 8 3 1 6 9 3 8 4 2 6 1 4 4 2 3 8 121.129 119.347 115.579 77.4184 76.9966 76.5675 156.214 136.031 135.798 135.093 131.864 131.609 129.594 128.751 128.605 128.409 128.111 127.427 126.402 125.878 122.867

3s 136.0315 135.7988 135.0933 131.8641 131.6096 129.5949 128.7513 128.6058 128.4094 128.1112 127.4276 126.4021 125.8784

136 134 132 130.0 129.0 128.0 127.0 126.0 (ppm) (ppm)

- 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 1 (ppm) Appendices (Chapter 2) 213 1.5993 1.2706 7.6005 7.5764 7.5616 7.5556 7.5331 7.5265 7.5205 7.5145 7.5096 7.4986 7.4887 7.4844 7.4778 7.4498 7.4252 7.3989 7.3748 7.3699 7.3611 7.3375 7.2899 7.2603 7.0165 6.9650 6.8313 6.7798 6.6954 6.6598 6.6357 6.6001

3t 6.6001 7.0165 6.9650 6.8313 6.7798 6.6954 6.6598 6.6357 7.9950 7.9895 7.9374 7.9319 7.8399 7.8240 7.8109 7.7983 7.7868 7.6476 7.6410 7.6049 7.6005 7.5764 7.5616 7.5556 7.5331 7.5265 7.5205 7.5145 7.5096 7.4986 7.4887 7.4844 7.4778 7.4498 7.4252 7.3989 7.3748 7.3699 7.3611 7.3375 7.2899 7.2603

Z

8.0 7.9 7.8 7.7 7.6 7.5 7.4 7.3 7.0 6.9 6.8 6.7 (ppm) (ppm)

E E Integral 12.305 0.1048 8.0 0.1000 1.8020 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 (ppm) Appendices (Chapter 2) 214 3 8 8 6 9 6 4 3 0 3 4 6 2 7 8 0 136.4641 133.700 133.525 132.2821 132.194 128.965 128.812 128.7111 128.485 128.3401 128.187 127.758 127.671 127.598 127.467 127.3801 127.3001 127.2201 126.754 126.609 126.223 126.092 125.7291 123.169 77.4291 77.0000 76.5782 3t 128.9656 128.8129 128.7111 128.4856 128.3401 128.1874 127.7583 127.6710 127.5983 127.4674 127.3801 127.3001 127.2201 126.7546 126.6092 126.2237 126.0928 125.7291

129.0 128.0 127.0 126.0 (ppm)

190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 -10 (ppm) Appendices (Chapter 2) 215 6.7404 7.5567 7.5507 7.5320 7.5260 7.5161 7.4285 7.4164 7.4038 7.3797 7.3019 7.2986 7.2959 7.2921 7.2877 7.2751 7.2723 7.2685 7.2603 7.2471 7.2433 7.2389 7.0981 7.0948 7.0817 7.0784 7.0735 7.0702 7.0570 7.0538 6.9201 6.8669 6.7771

3u 8.5379 8.5247 6.7771 6.7404 7.0784 7.0735 7.0702 7.0570 7.0538 6.9201 6.8669 7.5835 7.5770 7.5567 7.5507 7.5320 7.5260 7.5161 7.4285 7.4164 7.4038 7.3797 7.3019 7.2986 7.2959 7.2921 7.2877 7.2751 7.2723 7.2685 7.2603 7.2471 7.2433 7.2389

8.50 7.55 7.50 7.45 7.40 7.35 7.30 7.25 7.1 7.0 6.9 6.8 (ppm) (ppm) (ppm)

Z

E, Z

E Integral 1.0000 2.9976 3.0064 8.5 2.1195 1.0479 8.0 0.0644 7.50.9383 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 (ppm) Appendices (Chapter 2) 216 6 9 7 6 0 9 7 0 6 9 2 0 8 7 0 6 3 156.4491 149.750 149.677 136.644 136.455 136.3901 131.939 128.7171 128.578 128.280 127.648 127.371 127.087 126.215 122.775 121.996 120.527 120.164 120.098 119.691 77.3988 76.9769 76.5551

3u 128.7171 128.5789 128.2807 127.6480 127.3716 127.0879 126.2152 122.7750 121.9968 120.5277 120.1640 120.0986 119.6913

128 127 126 125 124 123 122 121 120 (ppm)

190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30-1 20 10 0 0 (ppm) Appendices (Chapter 2) 217

7.3787 7.3727 7.3694 7.3623 7.3464 7.3212 7.3097 7.3031 7.2977 7.2927 7.2812 7.2746 7.2473 7.1914 7.1689 7.1629 6.9070 6.8555 6.6293 6.5778 6.5581 6.5224 6.5077 6.4715 3aa 7.5146 7.5091 7.4927 7.4867 7.4790 7.4713 7.4658 7.4374 7.4308 7.4248 7.4078 7.4028 7.3853 7.3787 7.3727 7.3694 7.3623 7.3464 7.3212 7.3097 7.3031 7.2977 7.2927 7.2812 7.2746 7.2473 7.1914 7.1689 7.1629

7.50 7.45 7.40 7.35 7.30 7.25 7.20 7.15 (ppm) E E, Z Integral 9.5415 0.7072 1.3000 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 (ppm) Appendices (Chapter 2) 218 8 8 9 3 1 0 8 8 6 8 3 1 1 9 3 4 7 135.769 135.478 135.347 134.584 131.755 131.406 130.256 130.176 129.638 129.216 127.391 127.253 127.173 125.863 124.889 121.187 120.874 77.4257 76.9966 76.5748 3aa

160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 (ppm) Appendices (Chapter 2) 219 1.5485 7.3481 7.3442 7.3377 7.3295 7.3240 7.3207 7.3021 7.2949 7.2878 7.2790 7.2714 7.2664 7.2560 7.2495 7.2292 7.2193 6.8895 6.8380 6.6534 6.6019 6.5181 3ab 7.4752 7.4675 7.4538 7.4467 7.4396 7.4308 7.4078 7.4040 7.3722 7.3673 7.3585 7.3481 7.3442 7.3377 7.3295 7.3240 7.3207 7.3021 7.2949 7.2878 7.2790 7.2714 7.2664 7.2560 7.2495 7.2292 7.2193

Z

7.55 7.50 7.45 7.40 7.35 7.30 7.25 (ppm)

E E Integral 9.4878 0.5580 0.5576 0.8890 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 (ppm) Appendices (Chapter 2) 220 135.8022 135.0531 134.9295 134.6822 133.0967 132.7039 130.2020 130.1657 129.9547 129.7366 129.2129 128.8202 128.4565 127.3728 127.2201 127.0965 126.9437 125.8673 124.6600 77.4218 77.0000 76.5782

3ab 130.2020 130.1657 129.9547 129.7366 129.2129 128.8202 128.4565 127.3728 127.2201 127.0965 126.9437 125.8673 124.6600

131 130 129 128 127 126 125 124 (ppm)

180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 (ppm)

Appendices (Chapter 2) 221 3.7919 2.3221 1.5600 7.3979 7.3689 7.2615 7.2511 7.2346 7.2160 7.2067 7.1853 7.1651 7.1399 7.1163 7.1086 6.8796 6.8511 6.6172 6.5822 6.4578 6.4227

3ac 6.6172 6.5822 6.4578 6.4227 7.5573 7.5321 7.3979 7.3689 7.2615 7.2511 7.2346 7.2160 7.2067 7.1853 7.1651 7.1399 7.1163 7.1086

7.40 7.30 7.20 6.60 6.50 (ppm) (ppm) (ppm) Integral 3.0745 1.0322 1.9950 3.1080 2.0040 1.0000 1.0040 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.0616 3.5 3.0 2.5 2.0 1.5 1.0 0.5 (ppm)

Appendices (Chapter 2) 222 114.7361 77.4183 76.9965 76.5746 55.3374 19.8888 159.3341 136.0023 135.3041 132.6786 130.0385 128.6275 128.3148 127.3184 126.8020 125.5365 124.6492

3ac 130.0385 128.6275 128.3148 127.3184 126.8020 125.5365 124.6492

130 129 128 127 126 125 (ppm)

190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 -10 (ppm) Appendices (Chapter 2) 223 7.2603 7.2395 7.2137 7.1847 7.1557 7.1277 6.7634 6.7113 6.4150 6.3941 6.3733 6.3536 6.3372 6.3059 6.2933 6.2692 6.2566 2.8117 2.7876 2.7630 1.7374 1.7144 1.6892 1.6656 1.6393 1.5900 1.4394 1.4109 1.2832 0.9096 0.8888 0.8658 7.3408 7.3227 7.2943 3ad 7.5035 7.4783 7.4723 7.4559 7.4499 7.4422 7.4356 7.4153 7.4082 7.3874 7.3775 7.3693 7.3408 7.3227 7.2943 7.2603 7.2395 7.2137 7.1847 7.1557 7.1277

7.50 7.40 7.30 7.20 E, Z (ppm)

E Integral 2.0677 2.0173 10.265 3.0890 4.2916 0.3200 7.5 1.6683 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 (ppm) Appendices (Chapter 2) 224 5 5 6 9 2 4 8 0 0 9 8 5 35.9401 32.5727 31.7654 30.2017 29.3799 29.1108 28.7835 28.5289 22.6014 14.0484 136.118 135.958 131.645 131.252 130.089 129.776 128.772 128.300 126.860 126.539 123.979 120.161 77.4181 76.9962 76.5744

3ad 136.1185 135.9585 131.6456 131.2529 130.0892 129.7764 128.7728 128.3000 126.8600 126.5399 30.2017 29.3799 29.1108 28.7835 28.5289

136 134 132 130 128 126 30.0 29.0 (ppm) (ppm)

190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 (ppm)

Appendices (Chapter 2) 225 2692 . 2.8141 2.7900 2.7653 1.7397 1.7173 1.6915 1.6674 1.6417 1.5792 1.4384 1.4099 1.2839 0.9092 0.8878 0.8648 7 7.2626 7.2484 7.2407 7.2155 7.2078 7.1930 7.1865 7.1706 6.7443 6.6923 6.4173 6.3921 6.3652 6.3559 6.2946 6.2579 3ae 7.4352 7.4286 7.4133 7.4067 7.3985 7.3919 7.3722 7.3678 7.3229 7.3163 7.3010 7.2944 7.2862 7.2692 7.2626 7.2484 7.2407 7.2155 7.2078 7.1930 7.1865 7.1706

7.44 7.40 7.36 7.32 7.28 7.24 7.20 (ppm) Z E E, Z Integral 4.3784 0.4937 7.51.0456 0.5100 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.2576 2.0 1.5 1.0 2.1878 0.5 10.322 3.1484 (ppm) Appendices (Chapter 2) 226 4 9 3 7 6 3 0 4 4 6 77.4218 77.0000 76.5782 35.9293 32.6056 31.7765 30.2128 29.3982 29.1218 28.7945 28.5472 22.6125 14.0521 135.6931 135.540 132.223 132.020 129.794 128.725 128.5511 128.318 126.551 126.376 125.096 123.983

3ae 32.6056 31.7765 30.2128 29.3982 29.1218 28.7945 28.5472 129.7947 128.7256 128.5511 128.3183 126.5510 126.3764 125.0964 123.9836 135.6931 135.5404 132.2239 132.0203

136 134 132 130 128 126 124 33 32 31 30 29 28 (ppm) (ppm)

190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 (ppm) Appendices (Chapter 2) 227 3232 .

7 7.3074 7.3008 7.2920 7.2854 7.2685 7.2630 7.2602 7.1194 7.1129 7.0970 7.0910 7.0827 6.8970 6.8872 6.8806 6.8652 6.8587 6.8483 6.7453 6.6938 6.4565 6.4050 6.3579 6.3212 6.3031 6.2664 3.9731 3.9638 3.8028 3af 6.4565 6.4050 6.3579 6.3212 6.3031 6.2664 7.4668 7.4586 7.4525 7.4366 7.4301 7.4224 7.4125 7.4043 7.3978 7.3912 7.3819 7.3758 7.3676 7.3375 7.3298 7.3232 7.3074 7.3008 7.2920 7.2854 7.2685 7.2630 7.2602

7.44 7.40 7.36 7.32 7.28 6.44 6.40 6.36 6.32 6.28 (ppm) (ppm)

Z

E E Integral 5.1011 0.8983 2.0060 0.3007 0.3012 7.51.3976 7.0 6.5 6.0 5.5 5.0 4.5 4.0 2.0376 3.0000 3.5 3.0 2.5 2.0 1.5 1.0 0.5 (ppm) Appendices (Chapter 2) 228 158.9995 158.9268 135.9295 135.8132 131.6603 131.2675 130.1475 130.0675 129.9002 129.0638 128.8602 127.1219 126.9910 126.1691 125.6746 124.4818 120.5035 120.3362 114.1469 114.1105 77.4109 76.9891 76.5673 55.2719 38.9513 36.7112 120.5035 120.3362 114.1469 114.1105 131.6603 131.2675 130.1475 130.0675 129.9002 129.0638 128.8602 127.1219 126.9910 126.1691 125.6746 124.4818 158.9995 158.9268 135.9295 135.8132

159.0 131 130 129 128 127 126 125 120.0 114.4 114.0 113.6 (ppm) (ppm) (ppm) (ppm) (ppm)

3af

-1 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 0 (ppm) Appendices (Chapter 2) 229 2701 . 7 7.2603 7.2537 7.2378 7.2312 7.2241 7.1825 7.1754 7.1600 7.1534 6.9031 6.8938 6.8866 6.8713 6.8647 6.8549 6.7332 6.6812 6.4807 6.4286 6.3782 6.3421 6.2982 6.2615 3.9775 3.9682 3.8061 1.5856

3ag 7.4022 7.3956 7.3802 7.3737 7.3660 7.3381 7.3348 7.3085 7.3030 7.2992 7.2794 7.2756 7.2701 7.2603 7.2537 7.2378 7.2312 7.2241 7.1825 7.1754 7.1600 7.1534

7.40 7.35 7.30 7.25 7.20 7.15 (ppm)

Z E E Integral 6.1596 2.0000 0.4189 0.4218 7.5 1.1624 7.0 6.5 6.0 5.5 5.0 4.5 4.0 2.0059 3.0876 3.5 3.0 2.5 2.0 1.5 1.0 0.5 (ppm) Appendices (Chapter 2) 230 9 4 8 0 9 8 2 1 7 3 9 6 6 4 7 6 2 1 3 9 158.984 158.919 135.485 135.384 132.423 132.154 130.060 129.900 129.834 129.078 128.881 128.714 128.314 126.896 126.663 126.183 125.478 124.438 114.132 114.095 77.4181 76.9963 76.5745 55.2573 38.9221 36.7184 135.4858 135.3840 158.9849 158.9194 114.1323 114.0959 130.0602 129.9001 129.8347 129.0783 128.8819 128.7146 128.3146 126.8964 126.6637 126.1836 125.4782 124.4381 132.4239 132.1548

159.0 132 114.4 114.0 130.0 129.0 128.0 127.0 126.0 125.0 (ppm) (ppm) (ppm) (ppm) (ppm)

3ag

- 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 1 (ppm) Appendices (for Chapter 3) 231

1H and 13C NMR Spectra for all compounds resulted in Chapter 3

S 3a S O N 7.6502 7.6414 7.6262 7.4056 7.3917 7.3892 7.3754 7.3728 7.2606 7.2442 7.2304 7.2278 7.0198 7.0135 7.0085 6.9997 6.9959 6.9896 3.8781 7.2606 7.2442 7.2304 7.2278 7.8658 7.8494 7.4056 7.3917 7.3892 7.3754 7.3728 7.0198 7.0135 7.0085 6.9997 6.9959 6.9896 7.6805 7.6741 7.6704 7.6615 7.6565 7.6502 7.6414 7.6262

7.85 7.65 7.38 7.04 (ppm) (ppm) (ppm) (ppm) (ppm) Integral 1.0000 3.0727 1.0742 1.2376 2.0805 3.0273 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 (ppm)

Appendices (for Chapter 3) 232

S 3a S O N 171.8269 161.7120 154.1841 137.5543 135.4264 126.0694 124.0508 121.7699 120.7205 120.2468 115.5028 77.2586 77.0036 76.7558 55.4548

180 160 140 120 100 80 60 40 20 0 (ppm)

Appendices (for Chapter 3) 233

S 3b S (CH2)2CH3 N

4356 . 7 7.4318 7.4077 7.3847 7.3803 7.3118 7.3080 7.2833 7.2603 3.3558 3.3317 3.3076 1.9259 1.9012 1.8766 1.8525 1.8284 1.8037 1.1140 1.0899 1.0652 7.8783 7.8514 7.7649 7.7627 7.7610 7.7364 7.4356 7.4318 7.4077 7.3847 7.3803 7.3118 7.3080 7.2833 7.2603

7.8 7.7 7.6 7.5 7.4 7.3 (ppm) Integral 2.0052 2.0213 3.0222 1.0000 0.9950 1.0002 1.1911 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 (ppm)

Appendices (for Chapter 3) 234

S 3b S (CH2)2CH3 N

167.4361 153.2538 135.1003 126.0018 124.1254 121.4198 120.8889 77.4254 77.0036 76.5818 35.5693 22.6888 13.3575 121.4198 120.8889

(ppm)

180 160 140 120 100 80 60 40 20 0 (ppm)

Appendices (for Chapter 3) 235

S 3c S (CH2)3CH3 N 4069 . 0.9860 0.9709 0.9570 7 7.3930 7.3905 7.3010 7.2985 7.2846 7.2707 7.2682 7.2606 3.3688 3.3537 3.3398 1.8420 1.8269 1.8231 1.8118 1.8080 1.7966 1.7815 1.5521 1.5369 1.5218 1.5067 1.4916 1.4777 1.2583 7.8759 7.8595 7.7574 7.7422 7.4220 7.4094 7.4069 7.3930 7.3905 7.3010 7.2985 7.2846 7.2707 7.2682 7.2606

7.80 7.70 7.60 7.50 7.40 7.30 (ppm) Integral 2.1240 2.0175 2.0942 3.0634 1.0000 0.9979 1.0509 1.0448 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 (ppm)

Appendices (for Chapter 3) 236

S 3c S (CH2)3CH3 N

153.3736 135.1697 126.0022 124.1075 121.4622 120.9083 77.2788 77.0238 76.7687 33.3651 31.2737 21.9312 13.6018 167.4309

180 160 140 120 100 80 60 40 20 0 (ppm)

Appendices (for Chapter 3) 237

S 3d S (CH2)5CH3 N 1.2962 0.9615 0.9385 7.4497 7.4459 7.4223 7.4185 7.3494 7.3456 7.3232 7.2985 3.4071 3.3825 3.3578 1.9104 1.8868 1.8616 1.8375 1.8118 1.5713 1.5477 1.5220 1.4984 1.4748 1.4184 1.3998 1.3877 1.3762 1.3631 1.3510 1.3395 1.3099 7.8918 7.8036 7.7773 7.4738 7.4700 7.4497 7.4459 7.4223 7.4185 7.3494 7.3456 7.3232 7.2985 7.9192

7.9 7.8 7.7 7.6 7.5 7.4 7.3 (ppm) Integral 2.0259 2.0045 1.9982 4.0016 3.0607 1.0000 0.9966 1.0729 1.1799 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 (ppm)

Appendices (for Chapter 3) 238

S 3d S (CH2)5CH3 N 153.3755 135.1571 125.9677 124.0730 121.4423 120.8811 77.2517 77.0039 76.7488 33.6513 31.2465 29.1550 28.4335 22.4798 13.9754 167.4110

180 160 140 120 100 80 60 40 20 0 (ppm)

Appendices (for Chapter 3) 239

S 3e S (CH2)7CH3 N

3904 . 3.3561 3.3422 3.3271 1.8495 1.8357 1.8205 1.8054 1.7903 1.6756 1.5054 1.4915 1.4764 1.4612 1.4461 1.3679 1.3553 1.3503 1.3427 1.3389 1.3251 1.3213 1.3188 1.3137 1.3024 1.2910 1.2847 1.2772 1.2746 1.2570 0.8939 0.8800 0.8662 0.0706 7 7.3879 7.2984 7.2959 7.2820 7.2681 7.2656 7.2568 7.8733 7.8569 7.7548 7.7384 7.4207 7.4182 7.4068 7.4043 7.3904 7.3879 7.2984 7.2959 7.2820 7.2681 7.2656 7.2568

7.75 7.40 7.30 (ppm) (ppm) (ppm) (ppm) Integral 2.0600 2.0633 2.0226 8.0470 3.0809 1.0000 0.9983 1.0072 0.9983 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 (ppm)

Appendices (for Chapter 3) 240

S 3e S (CH2)7CH3 N

167.4763 153.3242 135.1350 125.9893 124.0946 121.4347 120.8882 77.2587 77.0036 76.7485 33.6802 31.7709 29.1984 29.1110 29.0381 28.7612 22.6252 14.0626 121.4347 120.8882 29.1984 29.1110 29.0381 28.7612

121.5 (ppm) (ppm)

180 160 140 120 100 80 60 40 20 0 (ppm)

Appendices (for Chapter 3) 241

S 3f S (CH2)11CH3 N

4220 . 0.8965 0.8839 0.8687 3.3587 3.3435 3.3284 1.8521 1.8370 1.8218 1.8080 1.7928 1.5067 1.4928 1.4777 1.4625 1.4474 1.3566 1.3415 1.3264 1.3150 1.3012 1.2621 7 7.4069 7.3930 7.3905 7.3010 7.2846 7.2707 7.2682 7.2606 7.8759 7.8595 7.7574 7.7422 7.4220 7.4069 7.3930 7.3905 7.3010 7.2846 7.2707 7.2682 7.2606

7.80 7.70 7.60 7.50 7.40 7.30 (ppm) Integral 2.0513 2.0069 2.0068 16.259 3.1221 1.0000 1.0019 1.0357 0.9952 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 (ppm)

Appendices (for Chapter 3) 242

S 3f S (CH2)11CH3 N

167.4329 153.3610 135.1498 125.9750 124.0803 121.4423 120.8811 77.2589 77.0039 76.7488 33.6586 31.9023 29.6287 29.6141 29.5558 29.4465 29.3299 29.1914 29.0748 28.7615 22.6765 14.0993 29.0748 28.7615 29.6287 29.6141 29.5558 29.4465 29.3299 29.1914

30.0 29.5 29.0 28.5 (ppm)

180 160 140 120 100 80 60 40 20 0 (ppm)

Appendices (for Chapter 3) 243

S 3g S N

7.2492 7.2429 7.2316 7.2290 7.2253 3.6082 3.5931 3.5767 3.1544 3.1380 3.1229 1.5671 7.3413 7.3261 7.3160 7.3123 7.3072 7.2908 7.2870 7.2770 7.2732 7.2568 7.2543 7.7623 7.7472 7.8947 7.8783 7.4333 7.4308 7.4169 7.4018 7.3413 7.3261 7.3160 7.3123 7.3072 7.2908 7.2870 7.2770 7.2732 7.2568 7.2543 7.2492 7.2429 7.2316 7.2290 7.2253

7.80 7.45 7.40 7.35 7.30 7.25 (ppm) (ppm) l egra t n I 2.0250 2.0482 1.0000 0.9975 1.0484 6.1346 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 (ppm)

Appendices (for Chapter 3) 244

S 3g S N

153.3590 139.6806 135.2717 128.6767 128.6111 126.7091 126.0386 124.2168 121.5642 120.9739 77.2788 77.0238 76.7687 35.6607 34.7935 166.6730 128.6767 128.6111

129.0 (ppm)

180 160 140 120 100 80 60 40 20 0 (ppm)

Appendices (for Chapter 3) 245

S 3h S N

2.2026 2.1938 2.1849 1.8282 1.8206 1.8118 1.8017 1.7929 1.7853 1.6718 1.6643 1.6554 1.6479 1.6390 1.6315 1.6252 1.6101 1.6037 1.5836 1.5785 1.5634 1.5571 1.5231 1.5155 1.5092 1.5004 1.4941 1.4878 1.4789 1.4726 1.4676 1.4600 1.4525 1.4449 1.4386 1.3819 1.3756 1.3680 1.3529 1.3491 1.3314 1.3276 1.3201 1.3125 1.3050 1.2987 7.2606 3.9311 3.9235 3.9159 3.9096 3.9021 3.8945 3.8895 3.8819 3.8743 2.2202 2.2127 7.4069 7.3918 7.3892 7.3035 7.3010 7.2871 7.2732 7.2707 7.2606 7.8860 7.8696 7.7561 7.7410 7.4233 7.4208 3.9311 3.9235 3.9159 3.9096 3.9021 3.8945 3.8895 3.8819 3.8743 2.2202 2.2127 2.2026 2.1938 2.1849 1.4789 1.4726 1.4676 1.4600 1.4525 1.4449 1.4386 1.3819 1.3756 1.3680 1.3529 1.3491 1.3314 1.3276 1.3201 1.3125 1.3050 1.2987

7.8 7.6 7.4 3.90 2.20 2.2 2.0 1.8 1.6 1.4 (ppm) (ppm) (ppm) (ppm) l egra t n I 2.1470 2.0611 6.1896 1.0000 0.9938 1.1017 1.0514 0.9995 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 (ppm)

Appendices (for Chapter 3) 246

S 3h S N

166.4270 153.4482 135.3245 125.9311 124.1676 121.6097 120.8591 77.2587 77.0037 76.7486 47.3587 33.2940 25.8390 25.5840 25.8390 25.5840

26.0 (ppm)

180 160 140 120 100 80 60 40 20 0 (ppm)

Appendices (for Chapter 3) 247

S 3i S N 7.2878 7.2845 7.2604 7.2544 7.2369 7.2336 1.6899 1.2543 7.4960 7.4812 7.4702 7.4565 7.4511 7.4412 7.4281 7.4242 7.4001 7.3766 7.3727 7.8652 7.7546 7.7496 7.7359 7.7294 7.7228 7.6598 7.6329 7.5168 7.5031 7.4960 7.4812 7.4702 7.4565 7.4511 7.4412 7.4281 7.4242 7.4001 7.3766 7.3727 7.2878 7.2845 7.2604 7.2544 7.2369 7.2336 7.8921

7.90 7.80 7.70 7.60 7.50 7.40 7.30 7.20 (ppm) 1.0000 2.0133 1.0478 4.0687 1.2277 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 (ppm)

Appendices (for Chapter 3) 248

S 3i S N 153.8940 135.5296 135.3333 130.4385 129.9440 129.9003 126.1402 124.3074 121.9364 120.7654 77.4256 77.0038 76.5819 169.6400 135.5296 135.3333 130.4385 129.9440 129.9003

136 130.2 129.6 (ppm) (ppm)

180 160 140 120 100 80 60 40 20 0 (ppm)

Appendices (for Chapter 3) 249

S 3j S N

7.2110 2.4222 1.6908 7.6027 7.6005 7.4066 7.4033 7.3819 7.3797 7.3556 7.2904 7.2625 7.2444 7.2351 7.8690 7.8416 7.6273 7.6027 7.6005 7.4066 7.4033 7.3819 7.3797 7.3556 7.2904 7.2625 7.2444 7.2351 7.2110

7.80 7.70 7.60 7.50 7.40 7.30 7.20 (ppm) 3.0183 1.0000 3.0062 1.0710 3.1100 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 (ppm)

Appendices (for Chapter 3) 250

S 3j S N

153.9835 141.0739 135.5028 135.4083 130.6881 126.2297 126.0406 124.0987 121.7786 120.6731 77.3915 76.9697 76.5478 21.3748 170.6896 126.2297 126.0406 135.5028 135.4083

(ppm) (ppm)

180 160 140 120 100 80 60 40 20 (ppm)

Appendices (for Chapter 3) 251

3k S S N

8683 . 7.2530 7.2417 7.1332 2.3589 7 7.6539 7.6375 7.4131 7.4106 7.3967 7.3816 7.3791 7.3551 7.2745 7.2719 7.2581 7.4106 7.3967 7.3816 7.3791 7.3551 7.2745 7.2719 7.2581 7.2530 7.2417 7.6539 7.6375 7.8846 7.8683

7.65 7.40 7.30 (ppm) (ppm) (ppm) Integral 6.0029 0.9980 1.0000 1.0774 2.0057 1.2919 1.0040 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 (ppm)

Appendices (for Chapter 3) 252

3k S S N

170.5007 153.8272 139.7407 135.4921 132.8833 132.2638 129.2323 126.1206 124.2404 121.8502 120.7498 77.2587 77.0037 76.7486 21.1678

180 160 140 120 100 80 60 40 20 0 (ppm)

Appendices (for Chapter 3) 253

3l S S N

7.7258 7.7119 7.7081 7.6224 7.6073 7.5934 7.5896 7.5783 7.5745 7.5632 7.5606 7.5493 7.5468 7.4157 7.4030 7.4005 7.3867 7.3841 7.2707 7.2682 7.2543 7.2467 7.2379 8.2755 7.9338 7.9162 7.9036 7.8834 7.8670 7.8645 7.7296 7.7258 7.7119 7.7081 7.6224 7.6073 7.5934 7.5896 7.5783 7.5745 7.5632 7.5606 7.5493 7.5468 7.4157 7.4030 7.4005 7.3867 7.3841 7.2707 7.2682 7.2543 7.2467 7.2379

7.90 7.80 7.70 7.60 7.50 7.40 7.30 (ppm) (ppm) Integral 1.0000 4.0485 1.0438 3.0794 1.0894 1.3352 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 (ppm)

Appendices (for Chapter 3) 254

3l S S N

133.7796 133.7504 131.1634 129.7569 128.1610 127.8987 127.7748 127.0242 126.2153 124.3934 121.9449 120.8081 77.2587 77.0037 76.7486 169.7136 153.7688 135.5431 135.4775 124.3934 135.4775 133.7796 133.7504 131.1634 129.7569 128.1610 127.8987 127.7748 127.0242 126.2153

134 132 130 128 126 (ppm)

180 160 140 120 100 80 60 40 20 0 (ppm)

Appendices (for Chapter 3) 255

S 3m S Br N 0.0703 7.2921 7.2905 7.2680 7.2642 7.2570 1.6054 7.6279 7.6170 7.5972 7.5786 7.5671 7.4471 7.4433 7.4192 7.3956 7.3918 7.3189 7.3151 7.8991 7.8723 7.6970 7.6701 7.6279 7.6170 7.5972 7.5786 7.5671 7.4471 7.4433 7.4192 7.3956 7.3918 7.3189 7.3151 7.2921 7.2905 7.2680 7.2642 7.2570

7.9 7.70 7.60 7.40 7.30 (ppm) (ppm) (ppm) (ppm) (ppm) Integral 1.0041 1.0000 4.0021 1.0777 1.2785 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 (ppm)

Appendices (for Chapter 3) 256

S 3m S Br N 153.6741 136.5197 135.5359 133.1383 129.0720 126.3319 125.1732 124.6267 122.0907 120.8737 77.2515 77.0037 76.7486 168.1177

180 160 140 120 100 80 60 40 20 0 (ppm)

Appendices (for Chapter 3) 257

S 3n S Cl N 7.6537 7.4762 7.4674 7.4608 7.4510 7.4460 7.4389 7.4268 7.4230 7.3995 7.3956 7.3217 7.3178 7.2943 7.2915 7.2707 7.2669 7.2603 7.9051 7.8783 7.6969 7.6816 7.6745 7.6602 7.6537 7.4762 7.4674 7.4608 7.4510 7.4460 7.4389 7.4268 7.4230 7.3995 7.3956 7.3217 7.3178 7.2943 7.2915 7.2707 7.2669 7.2603

8.0 7.70 7.60 7.50 7.40 7.30 (ppm) (ppm) Integral 1.0000 3.0370 3.0217 1.3060 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 (ppm)

Appendices (for Chapter 3) 258

S 3n S Cl N 136.9715 136.4031 135.5067 130.1796 128.3942 126.3319 124.6048 122.0688 120.8664 77.2587 77.0037 76.7486 168.4238 153.6814

180 160 140 120 100 80 60 40 20 0 (ppm)

Appendices (for Chapter 3) 259

S 3o S NH2 N

5166 . 7 7.5027 7.4989 7.4939 7.3968 7.3943 7.3791 7.3653 7.3627 7.2606 7.2468 7.2329 7.2178 6.7715 6.7652 6.7614 6.7526 6.7488 6.7425 7.8519 7.8355 7.6351 7.6199 7.5216 7.5166 7.5027 7.4989 7.4939 7.3968 7.3943 7.3791 7.3653 7.3627 7.2606 7.2468 7.2329 7.2178 6.7715 6.7652 6.7614 6.7526 6.7488 6.7425

7.85 7.6 7.5 7.4 7.3 (ppm) (ppm) (ppm) l egra t n I 1.0000 1.0250 1.9900 1.0597 1.0547 2.0159 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 (ppm)

Appendices (for Chapter 3) 260

S 3o S NH2 N

7 6 1 0 1 8 7 6 9 3 9 173.313 154.293 148.879 137.591 135.412 125.996 123.890 121.631 120.698 116.829 115.983 77.2588 77.0038 76.7487

180 160 140 120 100 80 60 40 20 0 (ppm)

Appendices (for Chapter 3) 261

3p N S O N

2530 . 7 7.2480 7.2442 7.2379 7.2291 7.2227 7.2190 7.2139 7.2101 7.2064 7.2038 7.1963 6.8723 6.8660 6.8622 6.8521 6.8483 6.8420 3.7658 3.7141 7.2480 7.2442 7.2379 7.2291 7.2227 7.2190 7.2139 7.2101 7.2064 7.2038 7.1963 6.8723 6.8660 6.8622 6.8521 6.8483 6.8420 7.6993 7.6955 7.4409 7.4371 7.4282 7.4232 7.4169 7.7157 7.7132 7.7094

7.70 7.45 7.25 7.20 6.84 (ppm) (ppm) (ppm) (ppm) 1.0000 2.0850 3.1550 2.0245 3.0983 3.0811 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 (ppm)

Appendices (for Chapter 3) 262

3p N S O N

159.9557 149.5785 143.0417 136.4977 133.9107 122.7683 122.1270 121.1578 119.5108 115.1165 109.0607 77.2586 77.0036 76.7485 55.3091 30.5830

180 160 140 120 100 80 60 40 20 0 (ppm)

Appendices (for Chapter 3) 263

S 3q S O N

7.5682 7.5619 7.5569 7.5481 7.5443 7.5380 7.2606 6.9341 6.9278 6.9228 6.9139 6.9101 6.9038 3.8264 2.2631 2.2139 6.9139 6.9101 6.9038 7.5682 7.5619 7.5569 7.5481 7.5443 7.5380 6.9341 6.9278 6.9228

(ppm) (ppm) l ntegra I 3.0458 3.0223 2.0000 2.0431 3.0993 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 (ppm)

Appendices (for Chapter 3) 264

S 3q S O N

148.8206 136.2062 127.4613 122.5569 115.1748 77.2586 77.0036 76.7558 55.3601 14.6382 11.2059 162.6302 160.8739

180 160 140 120 100 80 60 40 20 0 (ppm)

Appendices (for Chapter 3) 265

S 3r S O N

7.5985 7.5935 7.5872 7.2606 7.1434 7.1371 6.9757 6.9694 6.9656 6.9568 6.9518 6.9454 3.8491 1.6151 7.6174 7.6111 7.6073 7.5985 7.5935 7.5872 7.1434 7.1371 6.9694 6.9656 6.9568 6.9518 6.9454

7.60 7.15 6.95 (ppm) (ppm) (ppm) 1.0000 2.0630 1.0057 2.1359 3.0564 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 (ppm)

Appendices (for Chapter 3) 266

S 3r S O N

169.1289 161.2512 143.1421 136.7219 121.6079 119.3197 115.4501 77.2643 77.0165 76.7614 55.4313

180 160 140 120 100 80 60 40 20 0 (ppm)

Appendices (for Chapter 3) 267 12.2524 10.8631 8.0680 8.0630 7.9470 7.9319 7.9142 7.8512 7.8335 7.8297 7.8247 7.4730 7.4578 7.4414 7.3570 7.3406 7.3255 2.5044 2.5006 2.4969 7.4730 7.4578 7.4414 7.3570 7.3406 7.3255

7.40 7.30 (ppm) 0.9988 1.0167 1.0000 7.0575 1.1495 1.0826 12.0 11.0 10.0 9.0 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 (ppm)

Appendices (for Chapter 3) 268 5 9 3 7 1 7 1 9 2 2 6 6 0 1 8 5 3 3 5 6 5 4 2 6 3 169.50 166.41 154.16 153.42 140.15 136.17 134.77 132.89 126.64 126.38 124.39 123.74 122.66 122.45 122.40 121.68 121.29 119.69 40.006 39.838 39.671 39.503 39.336 39.175 39.008 126.6456 126.3833 124.3938 123.7452 122.6667 122.4554 122.4044 121.6829 121.2967 119.6935

126.0 125.0 124.0 123.0 122.0 121.0 120.0 (ppm)

190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 (ppm)

Appendices (Chapter 4) 269

1H and 13C NMR Spectra for all compounds resulted in Chapter 5

Appendices (Chapter 4) 270 3 5 9 7 1 6 9 3 7 3 6 8 3 5 8 9 7 9 9 3

0974 3a . 8 8.096 8.087 8.074 8.072 8.071 7.927 7.902 7.901 7.528 7.524 7.521 7.512 7.501 7.491 7.477 7.473 7.419 7.415 7.392 7.260 8.0963 8.0875 8.0749 8.0727 8.0711 7.9276 7.9029 7.9013 7.5287 7.5243 7.5216 7.5128 7.5013 7.4915 7.4778 7.4739 7.4197 7.4159 7.3929 7.2603

8.1 8.0 7.9 7.8 7.7 7.6 7.5 7.4 7.3 (ppm) Integral 3.0416 1.0000 4.0046 1.0459 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 (ppm)

Appendices (Chapter 4) 271 8 4 3 9 3 4 0 0

3a 133.631 130.962 129.012 127.558 126.307 125.180 123.238 121.609 77.4255 76.9964 76.5746 168.090 154.148 135.064

170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 (ppm)

Appendices (Chapter 4) 272 0549 . 3.8882 8 7.8847 7.8696 7.5014 7.4989 7.4851 7.4687 7.3855 7.3829 7.3691 7.3552 7.3527 7.2606 7.0261 7.0198 7.0161 7.0072 7.0022 6.9971 3b 8.0612 8.0549 7.8847 7.8696 7.5014 7.4989 7.4851 7.4687 7.3855 7.3829 7.3691 7.3552 7.3527 7.2606 7.0261 7.0198 7.0161 7.0072 7.0022 6.9971

8.0 7.8 7.6 7.4 7.2 (ppm) l egra t n I 3.0380 1.0001 1.0429 1.0491 2.0443 3.0389 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 (ppm)

Appendices (Chapter 4) 273 168.1469 162.1859 153.3900 134.4137 129.3052 126.4122 125.8875 124.9984 122.6154 121.5223 114.4609 77.2588 77.0038 76.7487 55.4915 3b

180 160 140 120 100 80 60 40 20 (ppm)

Appendices (Chapter 4) 274 5040

. 3c 7.4737 7.4712 7.3905 7.3766 7.3665 7.3628 7.3502 7.2606 3.0271 3.0132 2.9994 2.9855 2.9716 2.9578 2.9452 1.3113 1.2974 7 7.5014 7.4876 3.0271 3.0132 2.9994 2.9855 2.9716 2.9578 2.9452 7.9036 7.8872 7.4876 7.4737 7.4712 7.3905 7.3766 7.3665 7.3628 7.3502 8.0839 8.0675 8.0372 8.0209

8.0 7.90 7.5 7.4 3.00 2.95 (ppm) (ppm) (ppm) (ppm) 1.0248 6.0768 1.0000 1.9980 0.9997 1.0576 3.0656 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 (ppm)

Appendices (Chapter 4) 275 168.2780 154.0385 152.3770 134.8873 131.1999 127.6582 127.1335 126.2663 125.0275 123.0307 121.5660 77.2587 77.0037 76.7486 34.1539 23.7622

3c

180 160 140 120 100 80 60 40 20 0 (ppm)

Appendices (Chapter 4) 276 7.2884 7.2607 2.4245 8.0789 8.0637 7.9994 7.9831 7.8948 7.8784 7.5015 7.4851 7.4712 7.3855 7.3703 7.3552 7.3048 3d 7.5015 7.4851 7.4712 7.3855 7.3703 7.3552 7.3048 7.2884 7.2607 7.8784 8.0789 8.0637 7.9994 7.9831 7.8948

8.08 8.04 8.00 7.96 7.92 7.88 7.50 7.40 7.30 (ppm) (ppm) Integral 3.0061 1.0000 1.9735 0.9718 1.0003 1.0009 1.9953 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 (ppm)

Appendices (Chapter 4) 277 4 4 9 0 4 3 0 7 1 2 6 6 5 4 4 168.25 154.20 141.42 134.98 130.99 129.73 127.51 126.25 125.01 123.07 121.58 77.322 77.067 76.812 21.530

3d

170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 (ppm)

Appendices (Chapter 4) 278

0209 3e . 1.3756 8 7.9061 7.8910 7.5292 7.5254 7.5153 7.5115 7.5052 7.5027 7.4914 7.4888 7.4750 7.4724 7.3943 7.3918 7.3779 7.3640 7.3615 7.2606

7.5153 7.5115 7.5052 7.5027 7.4914 7.4888 7.4750 7.4724 7.3943 7.3918 7.3779 7.3640 7.3615 7.9061 7.8910 8.0852 8.0688 8.0473 8.0423 8.0385 8.0297 8.0259 8.0209

7.90 7.50 7.38 (ppm) (ppm) (ppm) (ppm) 9.0162 1.0000 2.0170 1.0005 3.0787 1.0474 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 (ppm)

Appendices (Chapter 4) 279 9 8 5 7 5 6 0 7 5 9 0 168.197 154.628 154.089 134.923 130.835 127.388 126.259 125.996 125.027 123.059 121.566 77.2588 77.0037 76.7486 34.9920 31.1807

3e

180 160 140 120 100 80 60 40 20 0 (ppm)

Appendices (Chapter 4) 280

7.757 7.5330 7.5304 7.5166 7.5027 7.5002 7.4334 7.4308 7.4170 7.4006 7.3855 7.3716 7.3691 7.3552 7.3413 7.3338 7.3186 7.3035 7.2606 2.6678 3f 8.1192 8.1028 7.9452 7.9301 7.7712 7.7574 7.5330 7.5304 7.5166 7.5027 7.5002 7.4334 7.4308 7.4170 7.4006 7.3855 7.3716 7.3691 7.3552 7.3413 7.3338 7.3186 7.3035

8.1 8.0 7.50 7.45 7.40 7.35 7.30 (ppm) (ppm) (ppm) (ppm) 3.0773 1.0000 1.0018 0.9964 1.0554 4.0117 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 (ppm)

Appendices (Chapter 4) 281 21.3137 168.0158 153.7471 137.2777 135.5943 133.0801 131.5352 130.5441 130.0194 126.1426 126.1061 125.1005 123.3806 121.3548 77.2589 77.0038 76.7487

3f

180 160 140 120 100 80 60 40 20 0 (ppm)

Appendices (Chapter 4) 282

7.9200 7.7485 7.7321 7.6754 7.6603 7.5304 7.5153 7.5014 7.4863 7.4712 7.4220 7.4169 7.4069 7.4018 7.3917 7.2606 3g 8.1784 8.1179 8.1015 7.9364 7.9200 7.7485 7.7321 7.6754 7.6603 7.5304 7.5153 7.5014 7.4863 7.4712 7.4220 7.4169 7.4069 7.4018 7.3917 8.1961

8.1 7.7 7.50 (ppm) (ppm) (ppm) (ppm) (ppm) 9845 . 1 1.0000 0.9364 1.9806 1.9892 2.9995 2.0072 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 (ppm)

Appendices (Chapter 4) 283 126.3319 125.1660 123.1765 121.5951 77.2515 76.9964 76.7414 167.6732 154.1988 143.6905 140.0322 135.0403 132.4752 128.9044 127.9643 127.9279 127.6145 127.0825 3g 127.9643 127.9279 127.6145 127.0825 126.3319

128.0 127.0 126.0 (ppm)

180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 (ppm)

Appendices (Chapter 4) 284 7.9036 7.8973 7.8885 7.8784 7.5771 7.5683 7.5645 7.5594 7.5531 7.5493 7.5380 7.5355 7.5216 7.5077 7.5052 7.4271 7.4245 7.4107 7.3968 7.3943 7.2606 7.9654 7.9477 7.9301

3h 8.2327 8.2289 8.2150 8.2125 7.4245 7.4107 7.3968 7.3943 7.9881 7.9780 7.9654 7.9477 7.9301 7.9036 7.8973 7.8885 7.8784 7.5771 7.5683 7.5645 7.5594 7.5531 7.5493 7.5380 7.5355 7.5216 7.5077 7.5052 8.5768 8.1356 8.1192

8.20 7.90 7.40 (ppm) (ppm) (ppm) (ppm) (ppm) (ppm) Integral 1.0000 1.0138 1.0292 4.0757 3.0822 1.0593 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 (ppm)

Appendices (Chapter 4) 285 168.1031 154.2353 135.1351 134.6249 133.2039 130.9958 128.8315 127.8768 127.5926 127.4614 126.8857 126.3902 125.2534 124.4518 123.2493 121.6388 77.2587 77.0037 76.7559

3h 128.8315 127.8768 127.5926 127.4614 126.8857 126.3902 125.2534 124.4518 123.2493 121.6388

128 126 124 122 (ppm)

180 160 140 120 100 80 60 40 20 0 (ppm)

Appendices (Chapter 4) 286 1.5609 8.0222 7.9175 7.9024 7.5204 7.5053 7.4889 7.4826 7.4662 7.4170 7.4032 7.3868 7.2607 3i 7.9175 7.9024 7.5204 7.5053 7.4889 7.4826 7.4662 7.4170 7.4032 7.3868 8.0776 8.0625 8.0436 8.0310 8.0272 8.0222

8.08 8.04 7.50 7.45 7.40 (ppm) (ppm) (ppm)

3.0776 1.0000 3.0738 1.0987 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 (ppm)

Appendices (Chapter 4) 287 128.7495 126.5123 125.4411 123.3205 121.6662 77.2643 77.0092 76.7541 166.6512 154.0586 137.0863 135.0604 132.1309 129.3034

3i

190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 (ppm)

Appendices (Chapter 4) 288 8.1259 7.9780 7.9539 7.9511 7.5901 7.5857 7.5654 7.5621 7.5589 7.5386 7.5342 7.4970 7.4931 7.4696 7.4668 7.4466 7.4422 7.2603 8.2629 8.2557 8.1533 3j 8.3861 8.3790 8.3724 8.3565 8.3494 8.3428 8.2996 8.2930 8.2853 8.2694 8.2629 8.2557 8.1533 8.1259 7.9780 7.9539 7.9511 7.5901 7.5857 7.5654 7.5621 7.5589 7.5386 7.5342 7.4970 7.4931 7.4696 7.4668 7.4466 7.4422

8.40 8.30 7.60 7.50 (ppm) (ppm) (ppm) (ppm) Integral 2.0000 1.9971 1.0183 1.0087 1.0932 1.0638 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 (ppm)

Appendices (Chapter 4) 289 8 3 5 6 8 5 2 3 9 5 6 5 5 164.83 154.13 149.07 139.201 135.50 128.24 126.91 126.22 124.31 123.94 121.83 77.251 76.996 76.741

3j 124.3134 123.9491

124.4 124.0 (ppm)

190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 (ppm)

Appendices (Chapter 4) 290

8.7886 8.1570 8.1406 8.0284 8.0171 7.9792 7.9629 7.5821 7.5670 7.5531 7.5506 7.5002 7.4976 7.4838 7.4674 7.2606 3k 8.1570 8.1406 8.0284 8.0171 7.9792 7.9629 7.5821 7.5670 7.5531 7.5506 7.5002 7.4976 7.4838 7.4674 8.7975 8.7886

8.8 8.15 7.95 7.50 (ppm) (ppm) (ppm) (ppm) 2.0155 1.0000 2.0596 1.0268 1.0540 1.0409 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 (ppm)

Appendices (Chapter 4) 291 8 0 0 8 0 5 3 8 7 9 126.854 126.250 123.969 121.884 121.280 77.2715 77.0165 76.7614 165.011 154.000 150.589 140.671 135.249

3k

190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 (ppm)

Appendices (Chapter 4) 292 7.3671 7.3578 7.3468 7.3331 7.2603 1.7971 7.6257 7.6230 7.6109 7.6093 7.6005 7.5983 7.5912 7.5895 7.5802 7.5786 7.5621 7.5561 7.5490 7.5413 7.5326 7.5304 7.5260 7.5189 7.5139 7.5002 7.4942 7.3918 7.3775 3l 7.3918 7.3775 7.3671 7.3578 7.3468 7.3331 8.3007 8.2886 8.2809 8.2765 8.2700 8.2678 8.2634 8.2590 8.2557 8.2398 7.8158 7.8032 7.8016 7.7922 7.7840 7.7813 7.7731 7.7714 7.7588 7.6109 7.6093 7.6005 7.5983 7.5912 7.5895 7.5802 7.5786 7.5621 7.5561 7.5490 7.5413 7.5326 7.5304 7.5260 7.5189 7.5139 7.5002 7.4942

8.30 8.25 7.80 7.76 7.60 7.55 7.50 7.35 (ppm) (ppm) (ppm) (ppm) 2.0025 1.0000 4.0889 2.0524 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 (ppm)

Appendices (Chapter 4) 293 110.5976 77.4255 77.0036 76.5818 163.0578 150.7737 142.0606 131.5439 128.9183 127.6456 127.1583 125.1218 124.5982 120.0162 3l 127.6456 127.1583 125.1218 124.5982

127.0 126.0 125.0 (ppm)

180 160 140 120 100 80 60 40 20 0 (ppm)

Appendices (Chapter 4) 294 7.5645 7.5595 7.5532 7.5481 7.5406 7.3552 7.3514 7.3401 7.3363 7.3288 7.3212 7.3174 7.3061 7.3023 7.2607 7.0451 7.0274 3.8996 7.7259 7.5746 7.5670 3m 8.2163 8.1987 7.7599 7.7511 7.7461 7.7397 7.7360 7.7322 7.7259 7.5746 7.5670 7.5645 7.5595 7.5532 7.5481 7.5406 7.0451 7.0274

8.2 7.74 7.56 7.05 (ppm) (ppm) (ppm) (ppm) 2.0000 1.0049 1.0042 2.0853 2.0662 3.0158 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 (ppm)

Appendices (Chapter 4) 295

3m 163.1970 162.3589 150.6991 142.2895 129.4127 124.6030 124.4281 119.7278 119.6330 114.3788 110.3854 77.2788 77.0238 76.7687 55.4604 163.1970 162.3589 124.6030 124.4281 119.7278 119.6330

163 125 120.0 (ppm) (ppm) (ppm)

180 160 140 120 100 80 60 40 20 0 (ppm)

Appendices (Chapter 4) 296 2.4446 1.7336 7.7561 7.7498 7.5897 7.5834 7.5783 7.5733 7.5645 7.5569 7.3640 7.3539 7.3489 7.3438 7.3401 7.3350 7.3287 7.2606 3n 8.1633 8.1469 7.7687 7.7662 7.7599 7.7561 7.7498 7.5897 7.5834 7.5783 7.5733 7.5645 7.5569 7.3640 7.3539 7.3489 7.3438 7.3401 7.3350 7.3287

8.15 7.56 7.35 (ppm) (ppm) (ppm) (ppm) 3.0421 2.0000 0.9999 1.0007 4.0207 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 (ppm)

Appendices (Chapter 4) 297 21.6343 163.3052 150.6865 142.1407 142.0825 129.6457 127.6020 124.8673 124.4819 124.3873 119.8271 110.4886 77.4255 77.0037 76.5819 3n 142.1407 142.0825 124.8673 124.4819 124.3873

142.2 125.0 (ppm) (ppm)

180 160 140 120 100 80 60 40 20 0 (ppm)

Appendices (Chapter 4) 298 1.3819 7.5897 7.5859 7.5809 7.5771 7.5721 7.5595 7.5557 7.5469 7.5431 7.5380 7.3653 7.3615 7.3540 7.3502 7.3464 7.3439 7.3401 7.3363 7.3250 7.2607 3o 7.7738 7.7675 7.7637 7.7813 7.7763 8.2012 8.1974 8.1886 8.1848 7.5897 7.5859 7.5809 7.5771 7.5721 7.5595 7.5557 7.5469 7.5431 7.5380 7.3615 7.3540 7.3502 7.3464 7.3439 7.3401 7.3363 7.3250

8.20 7.60 7.56 7.36 (ppm) (ppm) (ppm) (ppm) 9.0338 2.0000 0.9922 3.0706 2.0406 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 (ppm)

Appendices (Chapter 4) 299 124.4663 124.3643 119.8753 110.5110 77.2587 77.0037 76.7559 35.0722 31.1515 163.2497 155.1389 150.7300 142.2184 127.4760 125.9020 124.8526

3o 124.8526 124.4663 124.3643

125.0 124.5 124.0 (ppm)

190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 (ppm)

Appendices (Chapter 4) 300

7.7939 7.6136 7.6048 7.5985 7.5947 7.5922 7.5872 7.5796 7.4371 7.4346 7.4195 7.4069 7.4044 7.3829 7.3741 7.3678 7.3565 7.3514 7.3375 7.2606 2.8204 3p 8.1898 8.1734 7.6136 7.6048 7.5985 7.5947 7.5922 7.5872 7.5796 7.8305 7.8280 7.8204 7.8154 7.8128 7.8091 7.8015 7.7939 7.4371 7.4346 7.4195 7.4069 7.4044 7.3829 7.3741 7.3678 7.3565 7.3514 7.3375

8.2 7.80 7.62 7.44 7.40 7.36 (ppm) (ppm) (ppm) (ppm) 3.0558 1.0000 0.9982 0.9964 1.0248 4.0358 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 (ppm)

Appendices (Chapter 4) 301 22.1736 163.4320 150.3221 142.0946 138.8736 131.7903 130.9158 129.9684 126.2446 126.0624 125.0203 124.3790 120.1378 110.4820 77.2589 77.0038 76.7487 3p 126.2446 126.0624 125.0203 124.3790

126.0 125.0 124.0 (ppm)

180 160 140 120 100 80 60 40 20 0 (ppm)

Appendices (Chapter 4) 302

3q 7.7599 7.7561 7.6855 7.6817 7.6678 7.6225 7.6149 7.6099 7.6073 7.6035 7.5972 7.5884 7.5039 7.4888 7.4724 7.4245 7.4220 7.4195 7.4069 7.4031 7.3905 7.3817 7.3741 7.3703 7.3678 7.3627 7.3539 7.2606 7.3703 7.3678 7.3627 7.3539 8.3461 8.3423 8.3335 8.3297 7.7914 7.7813 7.7775 7.7637 7.7599 7.7561 7.6855 7.6817 7.6678 7.6225 7.6149 7.6099 7.6073 7.6035 7.5972 7.5884 7.5039 7.4888 7.4724 7.4245 7.4220 7.4195 7.4069 7.4031 7.3905 7.3817 7.3741

7.80 7.70 7.60 7.50 7.40 (ppm) (ppm) Integral 2.0000 3.0842 2.0456 1.0480 2.0402 2.9960 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 (ppm)

Appendices (Chapter 4) 303 5 6 4 2 4 9 5 1 6 8 3 4 9 0 7

162.936 150.817 144.244 142.211 140.010 128.940 128.095 128.059 127.563 127.162 125.960 125.100 124.604 119.992 110.576 77.2588 77.0038 76.7487 3q 127.1628 128.9409 128.0955 128.0591 127.5636

129.0 128.0 127.0 (ppm)

180 160 140 120 100 80 60 40 20 0 (ppm)

Appendices (Chapter 4) 304 7.8065 7.6527 7.6452 7.6389 7.6338 7.6263 7.6187 7.6086 7.6061 7.5960 7.5922 7.5884 7.5821 7.5758 7.5733 7.5695 7.5594 7.5557 7.4056 7.3968 7.3905 7.3855 7.3791 7.3703 7.2606 7.8267 7.8204 7.8141

3r 8.8025 8.3461 8.3423 8.3285 8.3260 7.3968 7.3905 7.3855 7.3791 7.3703 7.9162 7.9112 7.8986 7.8330 7.8267 7.8204 7.8141 7.8065 7.5922 7.5884 7.5821 7.5758 7.5733 7.5695 7.5594 7.5557 8.0108 7.9982 7.9931 7.9818

8.80 8.00 7.90 7.80 7.65 7.40 (ppm) (ppm) (ppm) (ppm) (ppm) (ppm) (ppm) 1.0000 1.0083 2.0081 1.0311 1.0016 3.0131 2.0650 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 (ppm)

Appendices (Chapter 4) 305 163.2407 150.8959 142.1583 134.8126 133.0199 128.9900 128.8151 128.2249 127.9334 127.8459 126.9350 125.2297 124.6905 124.3844 123.9909 120.0338 110.6186 77.2643 77.0092 76.7541

3r 123.9909 128.9900 128.8151 128.2249 127.9334 127.8459 126.9350 125.2297 124.6905 124.3844

129 128 127 126 125 124 (ppm)

180 160 140 120 100 80 60 40 20 0 (ppm)

Appendices (Chapter 4) 306

3s 1.6378 7.7637 7.5935 7.5872 7.5834 7.5796 7.5758 7.5229 7.5178 7.5140 7.5040 7.5002 7.3880 7.3854 7.3779 7.3728 7.3703 7.3678 7.3653 7.3602 7.3501 7.2606 8.2100 8.2062 8.2024 8.1923 8.1885 8.1835 7.7813 7.7775 7.7737 7.7700 7.7637 7.5935 7.5872 7.5834 7.5796 7.5758 7.5229 7.5178 7.5140 7.5040 7.5002 7.3880 7.3854 7.3779 7.3728 7.3703 7.3678 7.3653 7.3602 7.3501

8.20 7.80 7.75 7.60 7.55 7.50 7.40 7.35 (ppm) (ppm) (ppm) (ppm) 2.0375 1.0011 1.0000 2.0382 2.0368 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 (ppm)

Appendices (Chapter 4) 307 150.7736 142.0215 137.7730 129.2759 128.8532 125.6832 125.3407 124.7359 120.0938 110.6202 77.2441 76.9890 76.7339 162.0764

3s 125.6832 125.3407 124.7359

(ppm)

190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 (ppm)

Appendices (Chapter 4) 308

7.8443 7.8393 7.8305 7.8267 7.6515 7.6477 7.6376 7.6338 7.4636 7.4598 7.4485 7.4460 7.4371 7.4333 7.4296 7.4220 7.4195 7.4081 7.4044 7.2606 3t 8.4558 8.4520 8.4419 8.4381 8.4066 8.4028 8.3978 8.3890 8.3839 7.8443 7.8393 7.8305 7.8267 7.4636 7.4598 7.4485 7.4460 7.4371 7.4333 7.4296 7.4220 7.4195 7.4081 7.4044

8.40 (ppm) (ppm) (ppm) 4.1519 0.9165 1.0000 2.0245 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 (ppm)

Appendices (Chapter 4) 309 160.6700 151.0507 149.4329 141.9488 132.8250 128.4088 126.3392 125.2242 124.2259 120.6988 110.9410 77.2588 77.0037 76.7486 3t

180 160 140 120 100 80 60 40 20 0 (ppm)

Appendices (Chapter 4) 310

8.0915 8.0877 7.8355 7.8318 7.8217 7.8179 7.6389 7.6351 7.6250 7.6212 7.4523 7.4497 7.4384 7.4346 7.4233 7.4195 7.4094 7.4056 7.3943 7.3918 7.2606 3u 8.8277 8.8252 8.8189 8.8164 8.1003 8.0978 8.0915 8.0877 7.8355 7.8318 7.8217 7.8179 7.6389 7.6351 7.6250 7.6212 7.4523 7.4497 7.4384 7.4346 7.4233 7.4195 7.4094 7.4056 7.3943 7.3918

8.10 7.60 7.45 7.40 (ppm) (ppm) (ppm) (ppm) (ppm) 2.0332 2.0000 0.9788 0.9905 2.0513 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 (ppm)

Appendices (Chapter 4) 311 8 1 9 3 2 9 1 0 8 3

160.589 150.883 150.649 141.759 134.428 126.331 125.144 121.034 120.698 110.948 77.2587 77.0037 76.7486 3u 150.8831 150.6499 121.0340 120.6988

151.0 (ppm) (ppm)

180 160 140 120 100 80 60 40 20 0 (ppm)