Development of Copper-Catalyzed Electrophilic Trifluoromethylation And

Home , Trifluoromethylation

Development of Copper-Catalyzed Electrophilic Trifluoromethylation and

Exploiting Cu/Cu2O Nanowires with Novel Catalytic Reactivity

Dissertation by

Huaifeng Li

In Partial Fulfillment of the Requirements

For the Degree of

Doctor of Philosophy

King Abdullah University of Science and Technology

Thuwal, Kingdom of Saudi Arabia

June, 2014

EXAMINATION COMMITTEE APPROVALS FORM

The dissertation of Huaifeng Li is approved by the examination committee.

Committee Chairperson: Prof. Kuo-Wei Huang

Committee Member: Prof. Jorg Eppinger

Committee Member: Prof. Yu Han

Committee Member: Prof. Zhiping Lai

June, 2014

Huaifeng Li

ABSTRACT

Development of Copper-Catalyzed Electrophilic Trifluoromethylation and Exploiting

Cu/Cu2O Nanowires with Novel Catalytic Reactivity

Huaifeng Li

This thesis is based on research in Cu-catalyzed electrophilic trifluoromethylation and exploiting Cu/Cu2O nanowires with novel catalytic reactivity for developing of catalytic and greener synthetic methods.

A large number of biological active pharmaceuticals and agrochemicals contain fluorine substituents (-F) or trifluoromethyl groups (-CF3) because these moieties often result in profound changes of their physical, chemical, and biological properties, such as metabolic stability and lipophilicity. For this reason, the introduction of fluorine or trifluoromethyl groups into organic molecules has attracted intensive attention. Among them, transition metal-catalyzed trifluoromethylation reactions has proved to be an efficient and reliable strategy to construct carbon-fluorine (C-F) and carbon- trifluoromethyl (C-CF3) bond.

We have developed a catalytic process for the first time for trifluoromethylation of terminal alkynes with Togni’s reagent, affording trifluoromethylated acetylenes in good to excellent yields. The reaction is conducted at room temperature and exhibits tolerance to a range of functional groups. Derived from this discovery, the extension of work of copper catalyzed electrophilic trifluoromethylation were investigated which include the 5 electrophilic trifluoromethylation of arylsulfinate salts and electrophilic trifluoromethylation of organotrifluoroborates.

Because of growing environmental concern, the development of greener synthetic methods has drawn much attention. Nano-sized catalysts are environment-friendly and an attractive green alternative to the conventional homogeneous catalysts. The nano-sized catalysts can be easily separated from the reaction mixture due to their insolubility and thus they can be used recycled. Notably, because of the high reactivities of nano-sized metal catalysts, the use of ligands can be avoided and the catalysts loadings can be reduced greatly. Moreover, the nano-sized catalysts can increase the exposed surface area of the active component, thereby enhancing the contact between reactants and catalyst dramatically.

Based on the above-mentioned concepts and with the aim of achieving one “green and sustainable” approach, C-S bond formation and click reactions catalyzed by Cu/Cu2O nanowires were investigated. It was found that the recyclable core-shell structured

Cu/Cu2O nanowires could be applied as a highly reactive catalysts for the cross-coupling reaction between aryl iodides and the cycloaddition of terminal alkynes and azides under ligand-free conditions. Furthermore, these results were the first report for the cross- coupling reaction and click reaction catalyzed by one-dimensional (1D) copper nanowires.

ACKNOWLEDGEMENTS

First and foremost, I heartily thank Professor Kuo-Wei Huang, my advisor for offering me the great opportunity to work in his lab over the years. I am extremely grateful to him for transmitting me great ideas in chemistry from his unfathomable both chemistry and philosophy knowledge. Along the way, he trained me how to think about chemical problems and design innovative solutions for them in simple, yet excellent ways. He showed me how to analyze the experiment data and get the useful information, instead of just robotic scientific research. This dissertation would not have been possible without his continual guidance, advice and kind support that he grants me. Moreover, I am deeply grateful to his help for my family. He has been not only a forever-supportive teacher and supervisor to me but also a great human being. I was fortunate enough to be the first

Ph.D. student of Professor Huang, and from him I learned not only knowledge and experimental skills, but also the persistent pursuit of higher quality in both academic and personal life.

I would also like to thank our collaborators, Professor Zhiqiang Weng at the Fuzhou

University and Professor Zhiping Lai at KAUST for their helpful advice and invaluable assistance on my doctoral work. Without these help, much of my work would not be achieved.

I must acknowledge my thesis committee members Professor Jorg Eppinger, Professor

Yu Han, and Professor Zhiping Lai for their time, guidance and helpful discussions throughout the course of this research. I would like to express my gratitude to Professor 7

Jorg Eppinger for his helpful comments and his exceptional knowledge. I would like to thank Professor Yu Han, who is a brilliant and extremely helpful chemist with his expertise and insights in chemistry. Professor Zhiping Lai is to be thanked not only for his service as my Ph.D. committee members but also his mentorship during our coorperation in copper nanowires project.

I am also grateful to one of my mentors, Professor Jinbo Hu at the Shanghai Institute of Organic Chemistry (SIOC) who set an outstanding model for me to pursue in my life and scientific research, for introducing me into organic chemistry and recommending me joining the research group led by Professor Huang.

I would also take this opportunity to thank all the talent members in Professor Huang’s lab who have worked with me, namely, Dr. Tao Chen, Dr. Weiguo Jia, Dr. Liangfeng

Yao, Dr. Dirong Gong, Dr. Xiaoyu Guan, Dr. Lipeng He, Dr. Xiao Han, Dr. Bin Zheng,

Dr. Zhenhua Dong, Dr. Qianyi Zhao, Dr. Lei Hu, Dr. Yupeng Pan, Dr. Chenglin Pan, Dr.

Yuan Wang, Dr. Shixiong Min, Dr. Limin Yang, Dr. Xianbing Liu, Dr. Amol Hengne,

Richmond Lee, Davin Tan, XiaoZhi Lim, Ahmed Elshewy and Maha Alhaddad. Without their numerous help, it would have been impossible for me to finish some of my projects.

They had given me a lot of assistance not only in chemistry but also in life.

I especially thank Dr. Wei Chen who provide me the nanowire catalysts and characterize the materials. He gave me too much help during my research work.

I also want to express my appreciation to the members of core lab at KAUST for technical support. I especially thank Dr. Xianrong Guo for NMR experiments, Dr. Liang 8

Li for X-ray characterization, Dr. Qingxiao Wang for microscopy characterization, Dr.

Zeyad A. Al-Tallaand for HRMS, and Dr. Mustafa Altunkaya for element analysis.

My appreciation also goes to my friends and colleagues and the department faculty and staff for making my time at KAUST a great experience. I would like to thank all my good friends in KAUST Catalysis Center (KCC) for their kind support.

My deepest appreciation goes to my family for their selflessly support over the past years. Words cannot express my gratitude for their support. Without their help, I could not have completed this work.

TABLE OF CONTENTS

EXAMINATION COMMITTEE APPROVALS FORM ...... 2 ABSTRACT ...... 4 ACKNOWLEDGEMENTS ...... 6 TABLE OF CONTENTS ...... 9 LIST OF ABBREVIATIONS ...... 12 LIST OF SCHEMES ...... 15 LIST OF FIGURES ...... 19 LIST OF TABLES ...... 21 Chapter 1 ...... 23 Introduction of Copper-Mediated Reactions: A Short Survey from A Historical Contextual Perspective ...... 23 1.1 Historical background ...... 24

1.2 Renaissance of copper mediated reactions: progress in modern copper chemistry 30

1.2.1 Pioneering studies on the ligand effect for the copper catalyzed reactions ...... 31 1.2.2 Copper mediated regular cross-coupling reactions ...... 35 1.2.2.1 C-N bonds cross-coupling reactions ...... 35 1.2.2.2 C-O bonds cross-coupling reactions ...... 44 1.2.2.3 C-S bonds cross-coupling reactions ...... 50 1.2.3 Copper mediated oxidative cross-coupling reactions ...... 53 1.2.4 Copper mediated Umpolung cross-coupling reactions using electrophilic nitrogen sources ...... 56 1.2.5 Cu-catalyzed azide-alkyne cycloaddition ...... 58 1.3 Mechanistic aspects of copper mediated reactions ...... 61

1.3.1 Electronic properties of copper and the key mechanistic aspects ...... 61 1.3.2 General catalytic cycles for the copper catalyzed reactions ...... 62 1.3.2.1 Proposed mechanism for the Ullmann type cross-coupling reactions ...... 62 1.3.2.2 General proposed mechanism for the CuAAC reactions ...... 66 1.4 Prospective ...... 68 10

1.5 References ...... 68

Chapter 2 ...... 77 Investigations in Copper Catalyzed Electrophilic Trifluoromethylation ...... 77 2.1 Introduction ...... 78

2.2 Results and discussion ...... 85

2.2.1 Copper-catalyzed electrophilic trifluoromethylation for the synthesis of trifluoromethylated acetylenes ...... 85 2.2.1.1 Copper-catalyzed electrophilic trifluoromethylation of terminal alkynes at room temperature ...... 85 2.2.1.2 Synthesis of trifluoromethylated acetylenes employing alkynyltrifluoroborates as coupling partners ...... 97 2.2.1.3 Experimental ...... 102 2.2.1.3.1 General ...... 102 2.2.1.3.2 General operation for the copper-catalyzed electrophilic trifluoromethylation of terminal alkynes ...... 102 2.2.1.3.3 General procedure for the synthesis of trifluoromethylated acetylenes employing alkynyltrifluoroborates as coupling partners ...... 102 2.2.2 Copper-catalyzed electrophilic trifluoromethylation of arylsulfinate salts for the preparation of aryltrifluoromethylsulfones ...... 110 2.2.2.1 Copper-catalyzed electrophilic trifluoromethylation of arylsulfinate salts ...... 112 2.2.2.2 Experimental ...... 116 2.2.2.2.1 General ...... 116 2.2.2.2.2 General procedure for the copper-catalyzed trifluoromethylation of arylsulfinate salts ...... 116 2.2.3 Copper-catalyzed electrophilic trifluoromethylation of organotrifluoroborates for the synthesis of trifluoromethylarenes ...... 122 2.2.3.1 Copper-catalyzed electrophilic trifluoromethylation of organotrifluoroborates ...... 122 2.2.3.2 Experimental ...... 126 2.2.3.2.1 General ...... 126 11

2.2.3.2.2 General procedure for the copper-catalyzed trifluoromethylation of potassium aryltrifluoroborates ...... 127 2.2.4 Proposed mechanism copper-catalyzed electrophilic trifluoromethylation of organometallic compounds ...... 136 2.3 References ...... 137

Chapter 3 ...... 145

Exploiting Cu/Cu2O Nanowires with Novel Catalytic Reactivity: Application for C-S Bond Cross-Coupling Reaction and CuAAC Reaction ...... 145 3.1 Introduction ...... 146

3.2 Results and discussion ...... 152

3.2.1 Efficient C-S cross-coupling reactions catalyzed by novel core-shell structured

Cu/Cu2O nanowires ...... 152 3.2.1.1 Experimental ...... 163 3.2.1.1.1 General ...... 163 3.2.1.1.2 Preparation and Characterization of Cu-based catalysts ...... 164 3.2.1.1.3 Typical procedure for the C-S bond cross-coupling in the presence of a

core-shell structured Cu/Cu2O nanowires ...... 165 3.2.1.1.4 General procedure of the recycle process for the C-S bond cross- coupling reaction ...... 165 3.2.2 Azide-alkyne cycloaddition reaction in water catalyzed by recoverable copper(I) oxide nanowires ...... 171 3.2.2.1 Experimental ...... 183 3.2.2.1.1 General ...... 183

3.2.2.1.2 Typical procedure for the core-shell structured Cu/Cu2O nanowires- catalyzed click reactions ...... 184

3.2.2.1.3 Typical procedure for the core-shell structured Cu/Cu2O nanowires- catalyzed click reactions ...... 185 3.2.2.1.4 General procedure of the recycle process for the core-shell structured

Cu/Cu2O nanowires-catalyzed click reactions ...... 185 3.3 References ...... 193

APPENDICES ...... 203 1H NMR, 13C NMR, 19F NMR Data of Some Selected Examples ...... 203 12

LIST OF ABBREVIATIONS

Ac Acetyl

Ar Aromatic

BINAM 1,1-Binaphthyl-2,2-diamine

Bn Benzyl

Boc tert-Butyloxycarbonyl

Bu Butyl

Bz Benzoyl

Cat. Catalyst

DBA Dibenzylideneacetone

DBU 1,8-Diazabicyclo[5,4,0]undec-7-ene

DCE 1,2-Dichloroethene

DCM Dichloromethane

DFT Density functional theory

Diglyme 1-Methoxy-2-(2-methoxyethoxy)ethane

DIPEA Diisopropylethylamine

DMAC N, N-Dimethylacetamide 13

DMAP 4-Dimethylaminopyridine

DME 1,2-Dimethoxyethane

DMF Dimethylformamide

DMSO Dimethyl sulfoxide

EDG Electron-donating group

Ee Enantiomeric excess

Et Ethyl

EWG Electron-withdrawing group

H Hour i-Pr iso-Propyl

KHMDS Potassium bis(trimethylsilyl)amide

Me Methyl

Mes 1,3,5-Trimethyl benzene

ND Not detected

NHC N-heterocyclic carbene

NMP N-Methyl-2-pyrrolidone

Ph Phenyl 14

Phen Phenanthroline

Rt Room temperature

Rxn Reaction tBu tert-Butyl

TEA Triethylamine

TFA Trifluoroacetic acid

THF Tetraydrofuran

TMEDA Tetramethylethylenediamine

TMHD 2,2,6,6-Tetramethylheptane-3,5-dione

TMS Trimethylsilyl

Ts p-Toluenesulfonyl

LIST OF SCHEMES

Scheme 1.1 The discovery of the Glaser-Hay coupling reaction...... 24

Scheme 1.2 The introduction of the Ullmann-Goldberg reaction...... 25

Scheme 1.3 Hurtley reaction: The introduction of the Cu-mediated arylation of CH-acid derivatives...... 27

Scheme 1.4 The earlier prototypes of copper catalysis in couplings for C-C bond coupling...... 28

Scheme 1.5 The pioneering preparation of organocopper reagents...... 29

Scheme 1.6 The pioneering preparation of Gilman reagent...... 29

Scheme 1.7 Pioneering work for diarylether synthesis reported by Buchwald...... 31

Scheme 1.8 Goodbrand’s synthesis of triarylamines...... 32

Scheme 1.9 Goldberg amidation by Buchwald...... 33

Scheme 1.10 C-S bond formation studied by Venkataraman with copper as a catalyst. . 34

Scheme 1.11 Copper catalyzed regular cross-coupling reaction...... 35

Scheme 1.12 The copper catalyzed reaction of aryl halides and imidazoles...... 36

Scheme 1.13 The Cu-catalyzed N-arylation of imidazoles using diamine as ligands...... 36

Scheme 1.14 The reaction of indoles and aryl halide in the presence of copper as catalyst.

...... 37

Scheme 1.15 The reaction of alkylamines and aryl iodides in the presence of copper as catalyst...... 38

Scheme 1.16 The reaction of aryl bromides and primary alkylamines in the presence of copper as catalyst...... 38 16

Scheme 1.17 An efficient amidation process of aryl halides in the presence of copper as catalyst...... 39

Scheme 1.18 Copper-catalyzed C-N coupling reactions with higher selectivity at room temperature...... 40

Scheme 1.19 A room temperature method for the Ullmann type of C-N couplings...... 41

Scheme 1.20 Amino acid promoted Ullmann-type condensation reactions...... 41

Scheme 1.21 Selected cases of copper/ligand systems for the development of vinyl carbon-nitrogen bond...... 42

Scheme 1.22 The N-arylation of amines employing aryl chlorides as substrates...... 43

Scheme 1.23 Ligand assisted Ullmann diaryl ether synthesis...... 44

Scheme 1.24 Amino acid promoted Ullmann diaryl ether synthesis...... 45

Scheme 1.25 Highly efficient synthesis of Ullmann-type ethers...... 46

Scheme 1.26 The studies on the reactivity of aryl chlorides for the diaryl ether formation.

...... 46

Scheme 1.27 The reaction of aryl-aliphatic ether formation...... 47

Scheme 1.28 Amino acid assisted aryl-aliphatic ether formations...... 47

Scheme 1.29 General diaryl ether formation procedures with the help of (2- pyridyl)acetone...... 48

Scheme 1.30 Aryl vinyl ethers formation reaction in the presence of copper as catalyst. 49

Scheme 1.31 Copper-catalyzed synthesis of enol ether...... 49

Scheme 1.32 Amino acid promoted aryl vinyl ether formation...... 50

Scheme 1.33 A general catalyst scheme for the formation of aryl thioethers...... 50

Scheme 1.34 A powerful procedures for the formation of aryl thioethers...... 51 17

Scheme 1.35 High active C-S bond forming reaction with the aid of BINAM...... 52

Scheme 1.36 The vinyl sulfides formation in a stereo- and regiospecific manner...... 52

Scheme 1.37 The N- and O-Arylations at room temperature...... 53

Scheme 1.38 Lam’s pioneering work for the reaction of N-heteroaryl ring and arylboronic acid...... 54

Scheme 1.39 Chan’s pioneering work for the synthesis of diaryl ethers...... 54

Scheme 1.40 The reaction of aryl boronic acids and alkyl thiols in the presence

Cu(OAc)2...... 55

Scheme 1.41 Buchwald’s protocol for the formation of C-N bond under the oxidative conditions...... 55

Scheme 1.42 Hydroxylamines as the electrophilic source in the process of amination. .. 56

Scheme 1.43 N-chloroamides as the electrophilic source in the process of amination. ... 57

Scheme 1.44 Huisgen’s 1,3-dipolar cycloaddtion and CuAAC reaction...... 58

Scheme 1.45 The ligands effect on the copper catalyzed Huisgen’s 1,3-dipolar cycloaddtion...... 59

Scheme 1.46 CuAAC reaction under neat condition and employing a low loading of copper...... 60

Scheme 1.47 Click reaction “on water”...... 60

Scheme 1.48 Proposed mechanism for the Ullmann type reaction...... 62

Scheme 1.49 The observation of reductive elimination and oxidative addition via Cu(I) and Cu(III)...... 63

Scheme 1.50 Proposed mechanism for Chan-Lam-Evans coupling reactions...... 65

Scheme 1.51 Proposed mechanisms for Umpolung C-N cross-coupling...... 65 18

Scheme 1.52 Earlier proposed catalytic cycle for CuAAC...... 66

Scheme 1.53 General proposed catalytic cycle for CuAAC...... 67

Scheme 2.1 Examples for traditional trifluoromethylation methods...... 80

Scheme 2.2 The representative metal catalyzed trifluoromethylation protocols...... 84

Scheme 2.3 Proposed mechanism for the copper-catalyzed electrophilic trifluoromethylation of terminal alkynes...... 96

Scheme 2.4 A possible mechanism for copper-catalyzed electrophilic trifluoromethylation of organometallic compounds...... 136

Scheme 3.1 Selected examples of the metal based nanocatalysts for the organic transformations...... 148

Scheme 3.2 Typical protocols of the Cu nanostructured material catalyzed transformations under the ligands free condition...... 149

Scheme 3.3 Selected protocols of the Cu(I) and Cu(II) oxide nanostructured material catalyzed transformations under the ligands free condition...... 150

Scheme 3.4 Huisgen reaction and Cu(I) catalyzed azide/alkyne cycloaddition (CuAAC).

...... 172

Scheme 3.5 Nanostructured copper catalyzed azide/alkyne cycloaddition (CuAAC). .. 173

Scheme 3.6 Cu/Cu2O nanowires catalyzed one pot process for the synthesis of triazole.

...... 180

LIST OF FIGURES

Figure 1.1 Oxidation state of copper cation and their reduction potential...... 61

Figure 2.1 Examples for the CF3-containing drugs for human use...... 78

Figure 2.2 Examples for the CF3-containing drugs for veterinary use...... 79

Figure 2.3 Typical trifluoromethylating reagents...... 81

Figure 2.4 The application of trifluoromethylated acetylenes...... 86

Figure 2.5 Methods for preparation of trifluoromethyl-substituted terminal alkynes. .... 87

Figure 2.6 The application of aryltrifluoromethylsulfones...... 111

Figure 2.7 Traditional methods for the preparation of aryltrifluoromethylsulfones...... 112

Figure 3.1 (A) Schematic illustration showing the general procedure for the preparation of Cu/Cu2O nanowires; SEM images of (B), (C) CuO nanowires, and (D), (E) Cu/Cu2O.

...... 154

Figure 3.2 HRTEM/TEM images of individual (A), (C) CuO nanowire and (B), (D)

Cu/Cu2O nanowire; (E) The EELS spectra 1, 2 and 3 correspond to the areas marked with circles in (C) and (D), respectively...... 156

Figure 3.3 (A) XRD patterns and (B) Raman spectra of (a) blank Cu foam, (b) CuO nanowires, and (c) Cu/Cu2O nanowires...... 157

Figure 3.4 TEM images of the catalyst Cu/Cu2O nanowires after reactions. A) after the first run. B) after the fifth run...... 162

th Figure 3.5 TEM images of the catalyst Cu/Cu2O nanowires after reactions of the 10 run...... 181

Figure 3.6 XPS spectrum of the fresh prepared Cu/Cu2O nanowires...... 182 20

Figure 3.7 XPS spectrum of the the catalyst Cu/Cu2O nanowires after reactions of the

10th run...... 182

LIST OF TABLES

Table 2.1 Initial studies on the direct electrophilic trifluoromethylation of sp C-H bonds:

+ screening of various copper source, ligands, solvents and CF3 source...... 88

Table 2.2 CuI-catalyzed trifluoromethylation of 1a with electrophilic trifluoromethylating reagents...... 91

Table 2.3 Reaction condition optimization with respect to base and solvent...... 92

Table 2.4 The studies on the substrate scopes...... 94

Table 2.5 Optimization of the Cu-catalyzed trifluoromethylation of alkynyltrifluoroborates...... 99

Table 2.6 Copper-catalyzed trifluoromethylation of alkynyltrifluoroborates...... 100

Table 2.7 Optimization of copper-catalyzed trifluoromethylation of sulfinate salts. .... 113

Table 2.8 Copper-catalyzed electrophilic trifluoromethylation of sulfinate salts...... 115

Table 2.9 Optimization of the reaction condition with respect to copper source, ligand and solvent...... 124

Table 2.10 The substrate scope of the copper-catalyzed electrophilic trifluoromethylation of potassium aryltrifluoroborates...... 125

Table 3.1 The C-S cross-coupling over different Cu-based catalysts...... 158

Table 3.2 Cu/Cu2O nanowires catalyzing the coupling reactions of aryl iodides with thiols...... 160

Table 3.3 Recycling of Cu/Cu2O nanowires for the reaction of 4-iodotoluene and 1- octanethiol...... 162

Table 3.4 Nanostructured copper catalyzed azide/alkyne cycloaddition (CuAAC)...... 174 22

Table 3.5 Cu/Cu2O nanowires catalyzed CuAAC reaction of benzyl azide with various alkynes in water...... 176

Table 3.6 Cu/Cu2O nanowires catalyzed CuAAC reaction of phenylacetylenes with various azides in water...... 179

Table 3.7 Recyclability of the Cu/Cu2O nanowires catalytic system...... 180

Chapter 1

Introduction of Copper-Mediated Reactions: A Short Survey from

A Historical Contextual Perspective

1.1 Historical background

The origin of the organic copper chemistry could trace back to 1869, in which Carl

Glaser found 1,3-diynes formation through homo-coupling reaction of terminal alkynes

1 with the addition of ammonia, copper(I) chloride, and O2 (Scheme 1.1).

In 1962, Allan Hay revolutionized the homo-coupling of terminal alkynes using a catalytic amount of copper and TMEDA (Scheme 1.1).2 The copper-TMEDA system used is soluble in a wider range of solvents, so that the reaction is more versatile.2

The Glaser-Hay coupling reaction has been employed in various research fields, including the organic synthesis, the preparation of linear acetylenic oligomers and polymers, and the polymerization of diacetylenes.3

Scheme 1.1 The discovery of the Glaser-Hay coupling reaction.

The foundations of modern copper catalysis were established from Fritz Ullmann and

Irma Goldberg’s pioneering and remarkable research in the 1900s (Scheme 1.2).4 25

NO2 NO2 Cu (stoichiometric) 76% Ullmann 1901 2 o o Br 210 C-220 C O2N

NO2 NO2 Cu (stoichiometric) 2 60% Ullmann 1901 o o Cl 250 C-260 C O2N

O2N

I NO2 Cu (stoichiometric) 2 52% Ullmann 1901 220oC-225oC NO2

CO2H HO2C Cu (stoichiometric) NH NH2 + Ullmann 1903 Cl reflux

CO H Cu (catalytic) 2 CO2H K2CO3 99% Goldberg 1906 + Br NH NH2 nitrobenzene reflux

Cu (catalytic) Y Y K2CO3 or NaOAc O O + Br 50-80% Goldberg 1906 nitrobenzene HN NH2 reflux

Y=H,OH

Cu (catalytic) KOH or K O OH + Br 90% Ullmann 1905 210oC-230oC

Scheme 1.2 The introduction of the Ullmann-Goldberg reaction.

The homo-coupling of two molecules of aryl halides can be achieved with copper powder: This synthesis indicated the creation of the Ullmann coupling reaction (Scheme

1.2).4a In 1901, Ullmann reported that the homo-coupling of 1-bromo-2-nitrobenzene can be performed when adding a stoichiometric amount of metallic copper to afford the desired products. The reaction could be performed with aryl iodides or even with aryl chlorides which is very amazing (Scheme 1.2).

Inspired by the earlier Glaser’s discoveries of the conceptually related copper mediated homo-coupling processes, the construction of C-X bond with two different partners rather than two same structural fragments has been studied. Evidently the facilitation with the copper powder, Ullmann then reported a cross-coupling reaction of ortho-chlorobenzoic acid and aniline with the adding of copper at high temperature in 1905, and the reaction proceeded smoothly to give the corresponding cross-coupling product in good yields

(Scheme 1.2).4b

Following Ullmann’s reports, Goldberg then found the coupling reaction can be proceeded employing only catalytic amounts of copper.4c The coupling reaction of bromobenzene and anthranilic acid with the use of potassium carbonate and catalytic amounts of copper proceeded well at high temperature, and the desired product can be afforded with high efficiency (Scheme 1.2). The arylation of amides can be employed effectively by this catalysis system as well (Scheme 1.2).

It is also important that Ullmann investigated the C-O bond formation reaction including phenols as well. The copper catalyzed coupling reaction of aryl bromides and 27 phenols can proceeded well, where the copper catalyst obviously plays a dramatic role in the reaction.4d

Scheme 1.3 Hurtley reaction: The introduction of the Cu-mediated arylation of CH-acid derivatives.

These reactions can be found various applications in polymer industry, in organic synthesis as a building blocks and in the medical science.5 These earlier studies evidently opened an access to the advancement of Cu mediated cross-coupling reactions and became the foundations of modern achievements.

In 1929, another notable discovery was revealed by William R. H. Hurtley who described the C-arylation of active methylene compounds and o-bromobenzoic acid and its analogues with copper as the catalyst (Scheme 1.3).6

Distinct with the other Ullmann type reaction in which overheating and excess amount of copper often be utilized, this reaction condition is pretty mild. However, there are several drawbacks in this procedure such as using strong bases and ortho-directing group.

In the absence of this type of substituent capable to ligate with the copper intermediate, rigid reaction conditions need to be reused with poor yields of the wanted products. The success of Hurtley reaction is bound up with this kind of coordinated substrates. The 28

Hurtley reaction is the pioneering example for mild and valuable copper-catalyzed reaction.

Scheme 1.4 The earlier prototypes of copper catalysis in couplings for C-C bond coupling.

The study of the roles of catalytic copper on the reaction of substituted alkenes and aryldiazonium salts was reported by Hans Meerwein in 1939, which is the starting point of copper catalysis for the formation of C-C bonds (Scheme 1.4).7 The substrate scope was limited to alkenes substituted by electron-withdrawing groups. This work can be extended to the decarboxylative coupling of aryldiazonium salts with α, β-unsaturated carboxylic acid (Scheme 1.4).

The earlier development in the area of coupling chemistry accelerated largely the progress in another area: organocopper chemistry. Another important early finding in 29 copper chemistry is the synthetically useful organocopper reagent. The reaction of ketones or aldehydes and the organocopper complexes have been discovered.

Scheme 1.5 The pioneering preparation of organocopper reagents.

Scheme 1.6 The pioneering preparation of Gilman reagent.

In 1923, Rene Reich reported the observation of impure phenylcopper from the reaction of a phenyl Grignard reagent and CuI. And this discovery could be treated as the beginning of organocopper chemistry.8 Seminal achievement of Henry Gilman established the versatile application of organocopper reagents as synthetic tools in methodology chemistry (Scheme 1.5).9 30

Moreover, the insoluble methyl copper dissolved again in Et2O when the second equivalent of methyl lithium was added as discovered by Gilman and co-workers

(Scheme 1.6).10 This was the report for the preparation of Gilman reagents for the first time.

Even with these outstanding success, the initial copper mediated reactions suffered from three major drawbacks: i) the employment of hardly soluble and stoichiometric copper source. ii) regularly under high temperatures. iii) nonselective protocols and usually formation of a large number of side reactions.

However, up until the 21st century, copper mediated transformations had not been applied broadly due to the challenges mentioned above. On the other hand, even though

Pd catalyzed reactions have dominated the coupling chemistry since 1970s, chemists continued efforts on cheaper catalytic systems such as copper toolbox.

Finally, in the early years of this decade revolutionary breakthrough to the Cu mediated cross-coupling chemistry were achieved after the introduction of the ligand into the copper-catalyzed reaction system.

1.2 Renaissance of copper mediated reactions: progress in modern copper chemistry

For a rather long time, tremendous development of cross-coupling methods has focused on the use of precious metal catalysts, like palladium.11 However, from an ordinary perspective, the copper catalysis system with low cost of catalysts and ligands 31 bears some advantages. Moreover, some problematic functional group tolerances in the palladium catalyzed reactions forced chemists to investigate alternative transition metal as catalysts.

Remarkable studies of the copper-mediated processes facilitated by the presence of very effective ligands. This progress finally resulted in the renaissance of copper catalysis. Among the research efforts in this field, the Ma, Buchwald, and Taillefer scientific groups had a great contributions in the revolution of copper catalysis. Now the modern Cu catalyzed reactions can be proceeded under pretty mild conditions along with higher yields and it has been regarded as an effective tool in organic synthesis.12

1.2.1 Pioneering studies on the ligand effect for the copper catalyzed reactions

The keys to the success of copper assisted reactions were the ideas of ‘ligated copper catalysis’ and ‘new reaction substrates’.

Ma developed the first example of copper catalyzed coupling with chelating substrates under mild reaction conditions.13 However, Ma did not attempted to design a versatile ligand for this type of coupling reaction at that time.

Scheme 1.7 Pioneering work for diarylether synthesis reported by Buchwald. 32

The Buchwald’s pioneering work on the copper-catalyzed C-O bond construction representatives a milestone in this area.14 This reaction employing a small amount of catalyst, EtOAc as the ligand and Cs2CO3 as the base is still one of the most useful methods among the methodology of diarylether formation so far (Scheme 1.7). A various aryl bromides or iodides can be applied in this protocol. However, the accelerating effect in this reaction boosted by ligands was not clearly indicated at that time.

Following comprehensive mechanistic investigations of the Ullmann reaction by Paine, who established that the real catalytic intermediates are the soluble copper cation,15 and seminal contribution by Bryant16 and Capdevielle,17 who studied the effect in the presence of esters as ligand, Goodbrand demonstrated the notion of a ‘ligated catalysis’ for the traditional Ullmann reaction and finally figured out that diamine was a powerful ligand in 1999.18 Reactions are rapid and clean at temperatures of 50-100 °C lower than was usually required (Scheme 1.8).

Scheme 1.8 Goodbrand’s synthesis of triarylamines.

After Goodbrand’s finding of the positive effect of a ligand, important breakthrough came in 2001 when Buchwald reported that diamine ligands enabled the Goldberg 33 reaction to be conducted under pretty mild conditions using copper as the catalyst.19 This catalytic system tolerated various amides to be reacted with aryl bromide or aryl iodide involving open chain alkylamides (Scheme 1.9).

Scheme 1.9 Goldberg amidation by Buchwald.

Venkataraman investigated the reactions for the preparation of biaryl or arylalkyl thioethers with the help of adding diamine ligand.20 In this protocol, a various aryl sulfides can be afforded in higher yields using copper(I) catalysts (Scheme 1.10). Except for the synthetic achievement, the employment of cheaper bases and ligands indeed boosted the economic advantage of this type of reaction.

Scheme 1.10 C-S bond formation studied by Venkataraman with copper as a catalyst.

After these pioneering studies, the studies on copper-catalyzed coupling reactions have blossomed. It is likely to conduct various cross-coupling reactions under very mild conditions, even at room temperature. It is not amazing that the advancement of copper catalyzed reactions have greatly promote the other fields of organic synthetic chemistry since its particular aspects of low price, nontoxicity, and excellent function group tolerance.

Copper catalyzed cross-coupling could be further subdivided by the essence of the two reaction substrates, which implies regular cross-coupling, oxidative cross-coupling and umpolung cross-coupling. The key developments of each type of cross-coupling processes have been collected in the following sections. 35

1.2.2 Copper mediated regular cross-coupling reactions

Regular cross-coupling is often be employed to indicate a σ-bond metathesis reaction between an electrophilic and nucleophilic reagent, and hence could be treated as a broader term of ipso nucleophilic substitution (Scheme 1.11). This strategy is now a attractive way for a fascinating number of C-C, C-N, C-O, C-S, or C-P bond-forming protocols.

Scheme 1.11 Copper catalyzed regular cross-coupling reaction.

1.2.2.1 C-N bonds cross-coupling reactions

The majority of the publications on copper catalyzed regular cross-coupling reactions employed N-nucleophiles such as aliphatic and aromatic amines, amides and N- heterocycles. Functionalized amines and N-arylation of heterocycles are extremely important because of their abundance in various natural products and are essential intermediates for the synthesis of medicines and polymers.21 The construction of the C-N bonds by a controlled manner has drawn much attention.22 Buchwald and co-workers have made major achievement in the area of the copper-catalyzed amination of aryl halides.

Scheme 1.12 The copper catalyzed reaction of aryl halides and imidazoles.

The reaction of aryl halides and imidazoles in the presence of copper as catalyst can be accomplished smoothly in which the assembly of 1,10-phenanthroline and trans, trans- dibenzylideneacetone was the key to the achievement of this reaction (Scheme 1.12).23

The N-arylimidazoles could be afforded in higher isolated yields.

Scheme 1.13 The Cu-catalyzed N-arylation of imidazoles using diamine as ligands.

4,7-Dimethoxy-1,10-phenanthroline showed the best behavior in the copper-catalyzed reaction of common nitrogen heterocycles and aryl halide under mild conditions (Scheme 37

1.13).24 Particularly, a range of substrates were successfully performed, for which the palladium catalysts can not be easily achieved.

Scheme 1.14 The reaction of indoles and aryl halide in the presence of copper as catalyst.

Buchwald and co-workers showed that a catalytic general method for the reaction of indoles and aryl halide (Scheme 1.14).25 The key factor in this reaction was the use of diamine ligands. However, it was found that the ligand was also arylated as a side reaction (up to 10%) in each case.

Scheme 1.15 The reaction of alkylamines and aryl iodides in the presence of copper as catalyst.

A easily handled C-N bond construction process combination with CuI and ethylene glycol in 2-propanol was reported (Scheme 1.15).26 The wanted products can be afforded in higher yields in the presence of air or moisture. A variety of aryl iodides and a few amines can be applied in this process. Promising results on the reaction of aryl bromides were disclosed as well. Nevertheless, the ethylene glycol was also arylated in a larger amounts.

Scheme 1.16 The reaction of aryl bromides and primary alkylamines in the presence of copper as catalyst.

With the purpose of development of more efficient conditions for the reaction of primary alkyl amine, a series of anionic O-donor ligands were investigated by Buchwald and co-workers. And finally they found that the commercially available N,N- diethylsalicylamide was the optimal one with respect to yield and conversion (Scheme

1.16).27 Various functional groups can be tolerated under the standard reaction conditions. Remarkably, several ortho-substituted and heteroaryl compounds can also be tolerated under this reaction condition, which normally show significant challenges since their poor reactivity.

Cul(0.2-10%), L(5-20%) O K3PO4,Cs2CO3, O RHN NHR R or K2CO3 R Ar X + HN Ar N R' R' RHN NHR X=I, Br or Cl R=H, Me

Scheme 1.17 An efficient amidation process of aryl halides in the presence of copper as catalyst.

An experimentally simple catalysis combination including N,N- dimethylethylenediamine or trans-N,N-dimethyl-1,2-cyclohexanediamine were the optimal choice for the amidation of aryl halide (Scheme 1.17).28 Except for aryl iodides and bromides, several aryl chlorides could also conducted the amidation reaction.

Various functional groups can be compatible, involving several groups that can not be tolerated under palladium catalyzed amidation conditions. In this study the role of the catalyst is also investigated with respect to the better solubility of the catalytic 40 intermediate due to the ligated nitrogen ligands. However, several nucleophillic amides could cause the catalyst inactive by complexation. Thus, the sterically hindered and strong ligated ligands should avoid this complexation and show better reactivity.

Scheme 1.18 Copper-catalyzed C-N coupling reactions with higher selectivity at room temperature.

Buchwald and coworkers described the earlier examples of a room-temperature

Ullmann reaction (Scheme 1.18).29 Through the catalytic system including cyclic β- diketones and CuI, the reaction of aryl iodides and alkyl amines performed in excellent yields at 25oC. This protocol also exhibits higher functional groups tolerance.

Scheme 1.19 A room temperature method for the Ullmann type of C-N couplings.

Fu and co-workers reported that the use of light can enable the room temperature copper-catalyzed C-N bond formation (Scheme 1.19).30 In this study, they demonstrated that the reaction of aryl bromide or several aryl chloride and nitrogen heterocycles could be proceeded at room temperature in the presence of copper as a catalyst.

NuH, CuI, L-proline X Nu base, solvet X=Br, I Y Y Nu=NRR', N ,RSO rt-90oC 3 2 CH(COR)COR'

NuH, CuI N,N-dimethylglycine X Nu base, solvet X=Br, I Y Y o Nu=OAr, R 90 C

Scheme 1.20 Amino acid promoted Ullmann-type condensation reactions.

Ma and co-workers showed that when L-proline or N,N-dimethylglycine were employed as a ligand, cross-coupling reaction of aryl halides with various amine performed at 40-90°C to afford the respective desired products in good to excellent yields 42

(Scheme 1.20).31 These coordinated copper(I) species are more reactive in these reactions. The low price of natural amino acids and their easily availability make this protocol more economic attractiveness.

Scheme 1.21 Selected cases of copper/ligand systems for the development of vinyl carbon-nitrogen bond.

Ma and co-workers reported that the coupling reaction of vinyl halides and amides or carbamates proceeds well to form various enamides employing N,N-dimethylglycine as the ligand and CuI as the catalyst (Scheme 1.21, Eq. 1).32 Taillefer and co-workers also reported that the CuI catalyzed formation of numerous N-vinylazoles can be promoted by tetradentate ligand (Scheme 1.21, Eq. 2).33 Finally, Xi and co-workers reported the vinylation of azoles and vinyl bromides in the presence of CuI and ethylenediamine

(Scheme 1.21, Eq. 3).34

Iodo derivatives occupy the predominant position of the parexcellence substrates for copper catalysis although more and more processes employing aryl bromides as the substrates in recent years. On the other hand, the aryl chlorides as substrates are still elusive for Cu catalysis and so far a smattering of inactivated chlorides employed as substrates were reported for copper catalysis. A notable protocol was reported by Wan and coworkers in which a variety of aryl chlorides can proceed well in an aqueous system with oxalyldihydrazide for the first time (Scheme 1.22).35 However, they figured out that the understanding of the real role of Cu was tricky as well.

Scheme 1.22 The N-arylation of amines employing aryl chlorides as substrates.

1.2.2.2 C-O bonds cross-coupling reactions

The ethers structure unit are important class of organic intermediates in organic synthesis and life sciences industries.36 Moreover, poly(aryl ethers) are important market polymers used as engineering thermoplastics.37 Similar with the formation of C-N bonds, the addition of ligands gave rise to the significant advances for the Cu catalyzed C-O bond construction.

Ullmann diaryl ether formation was developed by Song and co-workers in which various substrates could be tolerated (Scheme 1.23).38 It was found that TMHD can be regarded as an effective ligand that promotes the reaction smoothly although the amount of catalyst is higher upto 10%.

Scheme 1.23 Ligand assisted Ullmann diaryl ether synthesis.

Scheme 1.24 Amino acid promoted Ullmann diaryl ether synthesis.

Ma and co-workers reported that copper catalyzed Ullmann diaryl ether synthesis can be performed at 90°C in the presence of N,N-dimethylglycine (Scheme 1.24).39 Various aryl iodides are compatible with the reaction condition to afford the desired products high efficiently.

Using the inexpensive and air-stable ligands, such as oxime and Schiff base, O- arylation of phenols with aryl iodides has been devised by Taillefer’s research group

(Scheme 1.25).40 A variety of desired products were afforded in a high efficient manner in acetonitrile. Notably, the reaction tolerates substrates with unfavorable substitution patterns, such as sterically hindered coupling partners or electron-rich aryl halides.

However, this protocol can not tolerate the electron poor phenols. 46

Cu2O(5%), L(20%) Cs2CO3,CH3CN X OH X=I, 82oC, X=Br, 110oC O R1 + R2 R1 R2

OH N L: N N or OH N N

Scheme 1.25 Highly efficient synthesis of Ullmann-type ethers.

Scheme 1.26 The studies on the reactivity of aryl chlorides for the diaryl ether formation.

A problem commonly encountered is that aryl chlorides remain inert even in various reaction conditions. Finally in 2008, Taillefer’s group developed the reaction of phenols and aryl chlorides employing diketone as ligands in the presence copper as catalyst.

(Scheme 1.26).41

Scheme 1.27 The reaction of aryl-aliphatic ether formation.

An experimentally easy bench process for the formation of aryl-aliphatic ethers has been developed (Scheme 1.27).42 The coupling reactions could be proceeded either in neat alcohol or in toluene.

Scheme 1.28 Amino acid assisted aryl-aliphatic ether formations.

Ma and co-workers have devised a powerful amino acid promoted arylation process which complements the Buchwald’s protocol.43 It was found that amino acid is an efficient additive for the formation of aryl-aliphatic ether.

Scheme 1.29 General diaryl ether formation procedures with the help of (2- pyridyl)acetone.

With the aid of (2-Pyridyl)acetone, the Ullmann O-arylation of diverse aromatic or heteroaromatic iodides, bromides, and chlorides and different phenols proceeded smoothly in high efficient manner (Scheme 1.29).44 The electron-deficient aromatic chlorides afforded desired products in moderate to excellent yields at 120oC. However, acceptable yields were formed only with aryl chlorides bearing electron donating groups in the presence of excess substrates.

Vinyl ethers are one kind of useful compounds due to their application in polymer chemistry as monomers and in organic chemical industry as building blocks.45

Scheme 1.30 Aryl vinyl ethers formation reaction in the presence of copper as catalyst.

It has been studied on the employment of amino alcohol as ligand in the process of aryl vinyl ethers formation reaction by Wan and co-workers. It was found that copper- catalyzed vinyl halide coupling with phenol was an efficient method affording the target product in good to excellent yield (Scheme 1.30).46

Scheme 1.31 Copper-catalyzed synthesis of enol ether.

Buchwald and co-workers have developed a high efficient copper/tetramethyl-1,10- phenanthroline catalysis system for the preparation of enol ethers.47 A range of different vinyl ethers can be afforded when applying this methodology (Scheme 1.31).

Scheme 1.32 Amino acid promoted aryl vinyl ether formation.

Another examples for the preparation of aryl vinyl ethers employed Ma’s N,N- dimethylglycine ligand (Scheme 1.32).48 The desired products were afforded in good yields, however, isomerization was also found either raising the reaction temperatures or employing vinyl bromides as substrates.

1.2.2.3 C-S bonds cross-coupling reactions

A large amount of biological active compounds contain sulfur moiety.49 As such, the construction of C-S bonds have drawn much attention.

Scheme 1.33 A general catalyst scheme for the formation of aryl thioethers.

A universal and high-yielding Cu-catalyzed reaction of aryl iodide and thiols have been devised by Buchwald and co-workers (Scheme 1.33).50 Particularly, the method uses a less amount of copper iodide and in the presence of cheaper K2CO3 as the base.

Scheme 1.34 A powerful procedures for the formation of aryl thioethers.

Employing oxime-phosphine oxide as ligand which can be easily prepared, the reaction of aryl iodides and thiols was devised (Scheme 1.34).51 Notably, various substituents can be applied into this protocol particularly the hydroxyl group.

Scheme 1.35 High active C-S bond forming reaction with the aid of BINAM.

A powerful and experimentally easy process for the arylation of thiols has been

52 developed in the presence of Cu(OTf)2 as catalyst (Scheme 1.35). A variety of desired products could be afforded in high efficiency. Relatively inert aryl bromides could be applied into this reaction to give good yields as well under the identical reaction conditions.

Scheme 1.36 The vinyl sulfides formation in a stereo- and regiospecific manner.

A mild, efficient and regio- and stereospecific copper catalyzed system for the vinyl sulfides formation has been reported (Scheme 1.36).53 The desired products can be 53 afforded in high efficiency, at the same time, the stereochemistry was retained. Notably, this protocol is very useful due to its easily handled operation and versatility.

1.2.3 Copper mediated oxidative cross-coupling reactions

When introducing the ligands into the copper catalyzed system, significant breakthrough was occurred especially for the aim at achieving the room-temperature

Ullmann condensation reactions. With the promotion of ligands, lower temperature can be achieved.

Another important breakthrough came in 1998 developed by Chan, Evans, and Lam, who independently devised a new milder conditions for the C-X bond cross-coupling reactions employing boronic acids and copper(II) acetate.54

In the seminal communication, the Chan group demonstrated a new method that various NH-containing substrates proceeded this type of arylation reaction at room temperature (Scheme 1.37).54a

Cu(OAc)2,CH2Cl2 Et N or pyridine 3 1 B(OH)2 room temperature XR R1-XH + R2 R2

X=N,O

Scheme 1.37 The N- and O-Arylations at room temperature. 54

Scheme 1.38 Lam’s pioneering work for the reaction of N-heteroaryl ring and arylboronic acid.

Many aromatic heterocycles including imidazoles, pyrazole, triazoles, tetrazole, benzimidazole, and indazole could react with arylboronic acids to afford the corresponding anilines (Scheme 1.38).54b

Cu(OAc) I 2 I pyridine,CH2Cl2 OH (HO) B room temperature O NHAc 2 NHAc + EtO EtO I OR I OR O O

R=Me R=Me 81% R=Si-t-BuMe2 R=Si-t-BuMe2 84%

Scheme 1.39 Chan’s pioneering work for the synthesis of diaryl ethers.

Chan first described the discovery for O-arylation reaction (Scheme 1.39).54a Evans and co-workers then optimized this mentioned carbon(aryl)-oxygen bond formation and applied it into their expedient synthesis of Thyroxine.54c 55

Scheme 1.40 The reaction of aryl boronic acids and alkyl thiols in the presence

Cu(OAc)2.

When applying the above reaction condition to the C-S bond construction, the reactions were too sluggish because the thiols could be oxidized to form disulfide as a byproduct. Guy’s group finally revealed a Cu(OAc)2 mediated protocol for the construction of aryl alkyl sulfides at 155oC (Scheme 1.40).55 Refluxing in DMF under an inert gas was necessary with the aim to reduce the formation of side product.

Scheme 1.41 Buchwald’s protocol for the formation of C-N bond under the oxidative conditions.

A universal method for the formation of C-N bond under the oxidative conditions was proposed by Buchwald and co-workers (Scheme 1.41).56 The reaction can be proceeded 56 at room-temperature with catalytic amount of Cu(OAc)2 under air atmosphere. Various diarylamines were afforded in higher yields.

To date, the Chan-Lam coupling procedure provides the mildest conditions for C-X bond formation although at room temperature it required long reaction times in some cases. The leading contributions of Chan-Lam coupling is evidently the employment of new aryl donor and more broader functional groups tolerance compared with other processes appeared in the literatures. The general absence of ligands is an additional advantage which is beneficial to product purification. However, there is still room for improvement because large excess amount of Cu(OAc)2 and boronic acid have to be used and sterically demanding boronic acids were demonstrated to be unreactive.

1.2.4 Copper mediated Umpolung cross-coupling reactions using electrophilic nitrogen sources

The third prototype in the copper mediated-coupling chemistry is Umpolung cross- coupling which is regarded as copper-mediated electrophilic substitution, since N moiety is transferred as an electrophile.

Scheme 1.42 Hydroxylamines as the electrophilic source in the process of amination. 57

The reaction of arylboronates and hydroxylamines has been developed by Hirano,

Miura, and co-workers (Scheme 1.42).57 The secondary acyclic amines can also be tolerated in this protocol and they are inactive substrate types for the Chan-Lam couplings. The phosphine as a ligand in the copper catalysis is uncommon, and is likely the first report regarding phosphine as a ligand combination with copper.

Scheme 1.43 N-chloroamides as the electrophilic source in the process of amination.

Except for N-O electrophilic source, another alternative is N-Cl electrophilic source.

The copper catalyzed arylation of N-chloroamides and arylboronic acids was reported by

Lei and co-workers (Scheme 1.43).58 This reaction performed in high efficiency to afford desired products and a wide range of functional groups can be tolerated.

This umpolung strategy using electrophilic nitrogen sources for the copper catalyzed cross-coupling reaction is an appealing field in the area of organic synthesis. This strategy allows the access to significantly broaden the scope of the copper catalyzed reactions. 58

1.2.5 Cu-catalyzed azide-alkyne cycloaddition

The introduction of Cu(I) catalysis into the Huisgen 1,3-dipolar cycloaddition of organic azides and alkynes has become well known as a ‘click reaction’ which was defined by Sharpless and associates in 2001.59 In 2002, the Fokin, Sharpless’s group and

Meldal’s group have independently reported the CuI catalysis of Huisgen 1,3-dipolar cycloaddition in which a major improvement in both rate and regioselectivity of the reaction were achieved (Scheme 1.44).60 This click chemistry has recently become a promising strategy and the powerful tools in various fields.61

A number of CuAAC protocols have been reported since it was discovered although the CuSO4 with ascorbate system is still one of the most reliable protocol as the products can be afforded in general with a direct purification procedure. The most attention has been drawn to decrease the loading of copper used, the development of “green” catalytic systems and reducing reaction time because these points are extremely important with the aim of industrial applications.

Scheme 1.44 Huisgen’s 1,3-dipolar cycloaddtion and CuAAC reaction. 59

Scheme 1.45 The ligands effect on the copper catalyzed Huisgen’s 1,3-dipolar cycloaddtion.

The ligands effect on the promotion of CuAAC was revealed.62 With the assistance of sophisticated ligands, it was found that the catalysis system become to be very effective with the small amount of copper. The most frequently used accelerating ligand is tris((1- benzyl-1H-1,2,3-triazol-4-yl)methyl)amine discovered by the Sharpless and co-workers

63 (Scheme 1.45). The C3-symmetric analogue was found to be an effective ligand, protecting the catalyst from disproportionation and oxidation, and thus improving its reactivity.

Scheme 1.46 CuAAC reaction under neat condition and employing a low loading of copper.

Chen and co-workers reported an efficient solvent-free, environmentally friendly system for CuAAC reaction at room temperature.64 The protocol uses the cheap and easy available Cu(PPh3)2NO3 complex as the catalyst and the catalyst loadings is much lower.

In addition, the catalysis system could be applied to the one-pot process of triazoles through aliphatic bromides, alkyne and sodium azide (Scheme 1.46).

Scheme 1.47 Click reaction “on water”.

A powerful strategy for copper-catalyzed CuAAC “on water” at room temperature was developed by Fu and co-workers in which environmentally, nontoxic, cheap and abundant water was the solvent (Scheme 1.47).65 Moreover, the catalysis system is commercially available and inexpensive. 61

This powerful click method has been found many applications in organic synthesis, drug discovery, molecular biology, and materials science since it’s discovery.

1.3 Mechanistic aspects of copper mediated reactions

The status of mechanism of copper mediated reactions is much less understood, and is still very far from maturity, though basic facts in copper catalysis have been demonstrated already, especially for classical Ullmann reactions and click reaction.

Currently, there probably is a general viewpoint that pathways of the copper catalyzed reaction undergo the typical process including oxidative addition, ligand exchange, and reductive elimination, though the catalytic cycle is via Cu+/Cu3+ oxidation states.

1.3.1 Electronic properties of copper and the key mechanistic aspects

Figure 1.1 Oxidation state of copper cation and their reduction potential.

The copper chemistry is very rich as it has four oxidation states from 0 to +3, as a consequence it can react via one-electron or two-electron processes. Thus, radical and two-electron bond-forming pathways can occur (Figure 1.1). 62

Reductive elimination from Cu(III) species in Cu-catalyzed processes to form the target product is fast and spontaneous, not strictly relying on coordinated ligands. The

Cu(III) species are typically unstable unless in the presence of extraordinary ligands for stabilization and a potent strong oxidizer.

Cu(I) is formally isoelectronic not with 4d10 Pd(0) but with Ni(0), and it is a smaller metal center which can be thought to form shorter bonds.

As a result of positive charge and smaller size, Cu(I) is a harder Lewis acid and thus has higher affinity for ligands, such as second-period elements O and N.

1.3.2 General catalytic cycles for the copper catalyzed reactions

1.3.2.1 Proposed mechanism for the Ullmann type cross-coupling reactions

Scheme 1.48 Proposed mechanism for the Ullmann type reaction.

Although many mechanisms have been suggested, two electron processes of a

Cu(I)/Cu(III) catalytic cycle has usually been proposed for the Ullmann-type coupling.66

Among of them, two different mechanism are proposed based on the coordination of the nucleophile (Scheme 1.48). One was shown that copper(I) coordinated with the base- deprotonated nucleophile at the first step (path A). For another mechanism, the oxidative addition of aryl halide first occurs and then the coordination may be proceeded (path B).

The experimental data of the reactivity of isolated Cu(I) intermediate with aryl halides supports path A as the most plausible pathway in which nucleophile serves as an ancillary ligand in the catalytic cycle.67

Scheme 1.49 The observation of reductive elimination and oxidative addition via Cu(I) and Cu(III).

Unstable copper(III) complexes have been observed under the catalytic Ullmann reaction conditions recently by Xavi and co-workers (Scheme 1.49).67 They revealed that copper(III) species can be likely intermediates employing in situ spectroscopic studies in the catalytic cycle. 64

Most of the proposed mechanisms are deduced from kinetic and computational studies, however, experimental and computational data could not support a exclusive or universal mechanism. The most frequently proposed mechanisms except the oxidative addition/reductive elimination pathway are (i) single electron transfer,68 (ii) concerted mechanism via σ -bond metathesis69 or (iii) a mechanistic pathway including copper(I) π- complexes,31c even there is little experimental and computational evidence for the above mentioned pathways.

As for the mechanistic aspects for the Chan-Lam-Evans coupling reactions under catalyzed reaction condition in the presence oxygen or air, it is worth mentioning the

Stahl and co-worker’s mechanistic proposal in which the catalytic cycle includes the rate- limiting transmetallation of the Cu(II) with an arylboronic acid (Scheme 1.50).70

Scheme 1.50 Proposed mechanism for Chan-Lam-Evans coupling reactions.

Scheme 1.51 Proposed mechanisms for Umpolung C-N cross-coupling.

To date, the Umpolung C-N cross-coupling catalytic transformations are very limited.

Thus, the mechanism is also remained unexplored. The general proposed catalytic cycle involves transmetalation and then undergoes electrophilic substitutions (Scheme 1.51).57

Though the already published data have afforded important mechanistic clues of

Ullmann type reactions, there are still many aspects to be solved. As a consequence, the deep knowledge of the mechanistic aspects is necessary for the catalyst design.

Furthermore, mechanistic understanding of these classic reactions may give additional hints for other copper-catalyzed reactions, beyond the Ullmann type reaction.

1.3.2.2 General proposed mechanism for the CuAAC reactions

Scheme 1.52 Earlier proposed catalytic cycle for CuAAC.

The mechanism of copper catalyzed azide-alkyne cycloaddition has remained elusive to understand due to the exist of multiple equilibrium between a few intermediates. The mechanism of CuAAC was postulated early based on a computational investigation

(Scheme 1.52).60a, 71 In the proposed sequence, the click reaction is not a real concerted cycloaddition and its regiospecificity is illustrated by the coordination of both azide and alkyne to copper before the formation of the C-N bond.

Scheme 1.53 General proposed catalytic cycle for CuAAC.

Most recently, Fokin and co-workers stated the stepwise character of the carbon- nitrogen bond-forming process and the equivalence of the two copper atoms within the cycloaddition steps (Scheme 1.53).72 It was found that monomeric copper acetylide species were not reactive to azides unless an external copper catalyst was introduced. 68

1.4 Prospective

The topic of copper-catalyzed methodology was investigated from the beginning of the twentieth century by Ullmann, Goldberg, and others and it has a renaissance in the past two decades with the notion of ‘ligated copper catalysis’ and ‘new reaction partners’.

One of the main benefit of using copper catalysts (except the low price) are that they generally show superior functional group tolerance and indeed usually behave best in facilitating the reactions of substrates bearing coordinating functional groups.

With mechanistic insights into these reactions, these transformations will be found remarkable breakthrough in the fields where the reaction are obviously challenged and pushed way beyond their limits. The modern copper-catalyzed reactions emerging as reliable and powerful methods in both industry and academic settings can be expected to grow.

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Chapter 2

Investigations in Copper Catalyzed Electrophilic

Trifluoromethylation

2.1 Introduction

The introduction of trifluoromethyl groups (-CF3) into organic moleculars could

1 greatly modulate their various properties due to the inherent properties of CF3 group.

The introduction of trifluoromethyl groups can boost the metabolic stability, lipophilicity and the performance of blood-brain barrier of organic compounds. Numerous biologically active pharmaceuticals and agrochemicals contain CF3 group(s) as the crucial component (Figure 2.1and 2.2).1a, 1b, 2

CN O H NO S 2 2 CF HN 3 HN CF3 HO F3C O N N O N Cl O CF3 O S O N O O H OH F HO Bicalutamide/Casodex Celecoxib/Celebrex Trifluridine/Viroptic Efavirenz/Sustiva

OH O O O O NH O F3C HO CF3 N N O O O S F3C NH2 HO OH N

O O Cl

Valrubicin/Valstar Halazepam/Paxipam Riluzole/Rilutek

Figure 2.1 Examples for the CF3-containing drugs for human use. 79

Figure 2.2 Examples for the CF3-containing drugs for veterinary use.

On the other hand, there are no more than a dozen of naturally occurring fluorine containing compounds and none containing more than one fluorine atom.3 Thus, organofluorine chemistry is nearly an entire man-made subject of organic chemistry.

Generally, two strategies could be employed for the synthesis of trifluoromethylated targets which involve ‘building block’ methods and direct trifluoromethylation methods.4

5 The former employs functionalized CF3 containing compounds as a synthon. Although great advances have been made in direct trifluoromethylation, the most often used method by chemists is ‘building block’ approach because of higher efficiency and functional group compatibility.

Scheme 2.1 Examples for traditional trifluoromethylation methods.

Industrially, trifluoromethylated chemicals are chiefly prepared via the Swarts reaction

6 and the reaction of carboxylic acid and carboxylic acid derivatives with SF4.

In 1892, the Belgian chemist Frédéric Swarts who can be regarded as a real pioneer of organofluorine chemistry developed a procedure for the synthesis of trifluoromethylated compounds via halogen exchange with hydrogen fluoride and antimony trifluoride

(Scheme 2.1).7

Notably, the harsh reaction condition employed in the conventional protocols renders their synthetic application is largely confined to quite simple molecules, although some of these conventional methods are still broadly employed.

Therefore, much effort was devoted toward the development of mild and versatile alternative protocols for the introduction of CF3 groups based on nucleophilic, electrophilic, and radical pathways with satisfactory chemo-, regio-, and/or stereoselectivity.2c, 8

Figure 2.3 Typical trifluoromethylating reagents.

As a result of the nature of the trifluoromethyl group, trifluoromethylation usually requires unique reagents typically including nucleophilic, electrophilic and radical trifluoromethylating reagents (Figure 2.3). Among them, nucleophilic trifluoromethylation has prevailed with respect to the easy availability of the reagents and the higher reactivity. However, the lack of electrophilic trifluoromethylating reagents heavily hampered the development of electrophilic trifluoromethylating chemistry. 82

In the midst of diverse methods for the preparation of trifluoromethylated compounds, metal-catalyzed trifluoromethylation methodology is particularly valuable.9 Several examples have been reported for the transition metal-catalyzed trifluoromethylation, employing either the nucleophilic or electrophilic trifluoromethylating reagents, for example, Ruppert-Prakash’s reagent9a or its ethyl derivative,9b-e Umemoto’s reagent9h, 10,

11 Togni’s reagent, and potassium (trifluoromethyl)trimethoxyborate as CF3 sources.

The report of copper-catalyzed trifluoromethylation of aromatic iodides and

(trifluoromethyl)-triethylsilane was disclosed by Amii and co-workers.12 With the addition of a diamine ligand, the catalytic cycle can be achieved successfully. Moreover, heteroaromatic iodides were also proceeded smoothly under this ligand assist conditions.

A concerted effect of silver and copper for the copper-catalyzed trifluoromethylation

13 and much cheaper Me3SiCF3 was demonstrated by Weng and our group. Notably, the well-defined dinitrogen-coordinated trifluoromethylated Ag(I) and Cu(I) complexes were prepared successfully.

The reductive elimination of Aryl and CF3 groups from the palladium(II) center is challenging. The first report of palladium-catalyzed trifluoromethylation of aryl halides was developed by Buchwald and co-workers using Et3SiCF3 as the trifluoromethylatipsng reagent with the assist of a bulky ligand.9d A mechanistic investigation by the authors validates that the reaction involves classical Pd(0)-Pd(II) catalytic cycle.

Pd-catalyzed electrophilic trifluoromethylation reaction of C-H bond was firstly

10 investigated by Yu and co-workers. The stoichiometric amount of Cu(OAc)2 as the 83 oxidant facilitates the catalytic turnover. And it was found that TFA was crucial for this transformation.

Carreira and co-workers have devised a valuable protocol for the in situ generation of trifluoromethyl diazomethane, which can be regarded as a “CF3CH” equivalent in many transformations.14 Notably, this procedure employs water as the solvent, iron as catalyst, and the experimentally safe reaction conditions.

CuI(10%), phen(10%) I CF3 o R +TESCF3 KF, 60 C R

Amii, H. Chem. Commun. 2009, 1909.

OMe [(allyl)PdCl]2(3%), BrettPhos(9%) KF, Cl CF3 o MeO PCy2 R +TESCF3 130 C R i-Pr i-Pr

Buchwald,S.L.etal.Science 328, 1679–1681 (2010). i-Pr

Pd(OAc)2(10%), DG DG Cu(OAc)2, TFA, CF3 H o + 110 C R R S BF4 CF3

Yu, J.-Q. et al. J. Am. Chem. Soc. 2010, 132, 3648.

[Fe(TPP)Cl] (3%) R DMAP (10%) R + F3C NH3Cl CF3 Ar NaNO2 Ar room temperature

Carreira,E.M.etal.Angew. Chem., Int. Ed. 2010, 49, 938.

CuI(10%), DMEDA (20%) I CF NaOtBu (20%), AgF(1.33 equiv) 3 R + TMSCF3 R NMP, 90oC

Weng, Z.; Huang, K.-W. et al. Organometallics 2011, 30, 3229.

F3C I O CuI(5%), phen(10%) o B(OH)2 K2CO3, diglyme, 35 C CF3 R + R

Shen, Q. et al. Org. Lett. 2011, 13, 2342.

Scheme 2.2 The representative metal catalyzed trifluoromethylation protocols. 85

In the past two decades, great advances have been made and a few excellent reagents have been developed, such as trifluoromethyl chalcogenium salts,15 hypervalent iodine- based trifluoromethylating compounds,16 and trifluoromethylated Johnson-type reagents

(Figure 2.3).17 Moreover, many electrophilic trifluoromethylation processes employing these reagents can be achieved otherwise difficult to reach.

In 2011, Shen and co-workers first reported a Cu-catalyzed electrophilic trifluoromethylation reaction of boronic acid with the aid of a diamine ligand under rather mild reaction condition which could pave the way for the application of electrophilic trifluoromethylating reagent.18

While great advances have been made for the trifluoromethylation reactions, catalytic trifluoromethylation procedures are still challenging.8d, 19

2.2 Results and discussion

2.2.1 Copper-catalyzed electrophilic trifluoromethylation for the synthesis of trifluoromethylated acetylenes

2.2.1.1 Copper-catalyzed electrophilic trifluoromethylation of terminal alkynes at room temperature

Trifluoromethylated acetylenes are a kind of valuable compounds as a result of their function for the preparation of pharmaceuticals and materials (Figure 2.4).20 The common routes for the synthesis of trifluoromethylated acetylenes involve the reaction of aryl iodides with trifluoropropynyl metal reagents,21 dehalogenation of trifluoromethylethenes,22 electrophilic trifluoromethylation of alkynyl lithium reagent23 86 or trifluoromethylation of stannylacetylenes.24 Although direct trifluoromethylation of alkynes stand for a concise method for the preparation of trifluoromethylated acetylenes, available methods are limited. Only lately, Qing and co-workers have described a notable

25 procedure for the direct coupling of terminal alkynes and TMSCF3. This reaction, yet, employs stoichiometric amount of copper, a high reaction temperature (100°C) and

26 excess stoichiometric amounts of TMSCF3. Herein, we developed a copper-catalyzed electrophilic trifluoromethylation of terminal alkynes at room temperature.

Figure 2.4 The application of trifluoromethylated acetylenes. 87

Figure 2.5 Methods for preparation of trifluoromethyl-substituted terminal alkynes. 88

Table 2.1 Initial studies on the direct electrophilic trifluoromethylation of sp C-H bonds:

+ screening of various copper source, ligands, solvents and CF3 source.

Initially, we explored the coupling of phenylacetylene (1a) and Togni’s reagent (3a) as a model reaction (Table 2.1). Combination of 1a with 1.5 equiv of 3a in the presence of

20 mol % of CuI, 40 mol % of 2,4,6-trimethylpyridine (L1), and 1.5 equiv of NEt3 in dimethylacetamide (DMAC) at room temperature for 24 hours, the desired product 2a was detected in 5% yield (Table 2.1, entry 1). Copper sources optimization revealed that several were effective and the desired trifluoromethylated product could be observed at room temperature, albeit in low yields (Table 2.1, entry 2-7). We are delighted to find that the desired trifluoromethylated acetylenes was afforded in 39% yield with the catalytic amounts of CuOAc as the catalyst (Table 2.1, entry 8). And then we studied several phenylthroline type ligand and it was found that 2,4,6-trimethylpyridine was superior to the bidentate nitrogen ligands (Table 2.1, entry 9-11). When using the

Umemoto’s reagent as the electrophilic trifluoromethylation, the target products were afforded in low yields (Table 2.1, entry 12-13). The target product was not formed without the catalyst (Table 2.1, entry 14). When combination of CuI and phenylthroline as the catalyst and ligand, 42% yield of product was afforded (Table 2.1, entry 15).

Further decreasing the loading of CuI and ligand (5% of CuI loading and 10% of ligand loading), the yield can be up to 44% in the presence of K2CO3 as base and DCM as solvent (Table 2.1, entry 17). When the reaction was performed in toluene or DME, poor yields were obtained (Table 2.1, entry 18 and 19).

Next, we turn our attention to using the CuI-phen catalytic system. A catalytic amount combination of CuI (20 mol %) and 1,10-phenanthroline L1 (40 mol %) afforded a promising yield of 43% from a mixture of 1a, Togni’s reagent (1.5 equiv) and potassium carbonate (2.0 equiv) in CH2Cl2 at ambient temperature (Table 2.2, entry 1). After the 90 analysis of the crude product, we found that the homo-coupling diyne was formed in a large amount (51%, Table 2.2, entry 1). In order to reduce the formation of the diyne, slow addition technology was employed. The alkyne was injected into the reaction mixture by a syringe pump over a period of 6 h, and it was found that the yield of desired product was given in 75% (Table 2.2, entry 2). Then the other nitrogen containing ligands, such as 3,4,7,8-tetramethyl-1,10-phenanthroline L2, 4,7-diphenyl-1,10- phenanthroline L3, or 2,9-dimethyl-4,7-diphenyl-1,10-phenanthroline L4 were screened, however, they showed inferior reactivity (Table 2.2, entries 3-5). Subsequent screening of Umemoto’s regent as the electrophilic trifluoromethylating reagents showed that the desired product was afforded in only trace by using 5-(trifluoromethyl)- dibenzothiophenium trifluoromethanesulfonate 3b or 5-(Trifluoromethyl)- dibenzothiophenium tetrafluoroborate 3c (Table 2.2, entry 6 and 7).

Table 2.2 CuI-catalyzed trifluoromethylation of 1a with electrophilic trifluoromethylating reagents.

Table 2.3 Reaction condition optimization with respect to base and solvent.

The influence of bases and solvents on this electrophilic trifluoromethylation protocol was also investigated, as shown in Table 2.3. It was found that KHCO3 was the most effective base (Table 2.3, entry 3). Cs2CO3 and NaOAc could also be applied into this protocol, but the yield were lower than KHCO3 (Table 2.3, entries 2 and 4). The other bases, such as KF, K3PO4 and Et3N, similar yields with KHCO3 were afforded (Table

2.3, entries 5-7). Without the addition of copper catalyst, no desirable product was found

(Table 2.3, entry 8). Hence, the copper catalyst is crucial for this procedure. Amazingly, the solvent has a large influence on the reaction. Examination of a wide range of solvents with the KHCO3 as base indicated that CH2Cl2 was the optimal solvent, although this reaction did not work in hexane or toluene (Table 2.3, entries 3, 15 and 16). Polar aprotic solvents, such as DMSO, DMF, CH3CN, NMP, and DMAC had not enhanced the yield of the target product (Table 2, entries 10-14). For the polar protic solvent (CH3OH), only

6% of desired product was formed (Table 2.3, entry 17). Ether-type solvents were not effective under the current reaction condition (Table 2.3, entries 18-22).

Under the optimized reaction conditions, the substrate scope was also studied with respect to terminal alkynes (Table 2.4). The para-substituted phenyl alkynes could proceed well to give the desired products in good to excellent yield (Table 2.4, entries 1 and 3-5). Notably, the polycyclicaromatic, 9-ethynylphenanthrene could be served as a good substrate to afford the target product in 91% yield (Table 2.4, entry 6). The electron rich substrates showed higher reactivity (Table 2.4, entries 7 and 8). Remarkably, halide substituted aryl alkynes could also be applied into the current reaction conditions (Table

2.4, entries 9 and 10). 94

The amine-containing substrate was also compatible and the target product was afforded in excellent yield (Table 2.4, entry 11). Moreover, aliphatic alkynes and heterocycles could be subjected to the current reaction condition and the desired products could be produced in good yields (Table 2.4, entry 12 and 13).

Table 2.4 The studies on the substrate scopes.

Scheme 2.3 Proposed mechanism for the copper-catalyzed electrophilic trifluoromethylation of terminal alkynes.

We proposed a mechanism for the electrophilic trifluoromethylation of terminal alkynes (Scheme 2.3). Initially, the coordination of CuI with phen in CH2Cl2 could form complex A. Then the complex A could undergo the coordination with the deprotonated alkyne to generate a intermediate B. Complex B would undergo oxidative addition with electrophilic trifluoromethylating reagent to form complex C. Finally, complex C would undergo reductive elimination to release the product regenerate the catalytic active species complex A.

In conclusion, a copper-catalyzed electrophilic trifluoromethylation of terminal alkynes has been developed for the first time. The current catalytic system allows for the 97 formation trifluoromethylated acetylenes at room temperature and a wide range of functional groups are compatible with this system.

2.2.1.2 Synthesis of trifluoromethylated acetylenes employing alkynyltrifluoroborates as coupling partners27

Although the copper-catalyzed electrophilic trifluoromethylation of terminal alkynes has been established by us, this methods suffered from the demand of employing large amounts of base. As a result, there is still room for further development of an efficient methods for the synthesis of trifluoromethylated acetylenes with avoiding using base.

Potassium organotrifluoroborates shows superior reactivity towards the cross-coupling reactions in contrast with the other boronic acid or their derivatives because of their easier availability and stronger nucleophilicity.28 As a result, organotrifluoroborates as a coupling partners have drawn much attention. An efficient synthesis of vinyl-CF3 containing products via potassium vinyltrifluoroborates by using iron as the catalyst has been developed by Buchwald and co-workers.29 We herein report an alternative copper- catalyzed electrophilic trifluoromethylation method for the synthesis of trifluoromethylated acetylenes using alkynyltrifluoroborates as substrates.

We examined the trifluoromethylation of p-tolylacetylenetrifluoroborate (1a) with

Togni’s reagent (2) in the presence of ligand at the beginning (Table 2.5). CuSCN can serve as a valid catalyst in a lately report of oxidative trifluoromethylthiolation of an arylboronic acid.30 Gratifyingly, combination of 1a with 2 in the presence of 30 mol % of

CuSCN, 30 mol % of 2,2’-bipyridine (L1), and 4 Å molecular sieves in acetonitrile produced the target product 3a in excellent yield (Table 2.5, entry 1). Interestingly, the 98 presence of molecular sieves has a large effect on the efficient trifluoromethylation to proceed (Table 2.5, entry 2). After screening the other nitrogen containing ligands, such as 1,10-phenanthroline (L2), N,N,N’,N’-tetramethylethylenediamine (L3), and 2,4,6- trimethylpyridine (L4), it was found that much poorer reactivity was occurred (Table 2.5, entries 3-5). For the case in the absence of ligand, low yield was afforded (Table 2.5, entry 6). A successive screening of copper sources, employing 2,2’-bipyridine as the ligand, revealed that CuI and CuCl gave poorer yields (Table 2.5, entries 7 and 8), for the case of Cu(OTf)2 and Cu(TFA)2 indicated only modest yields (Table 2.5, entries 9 and

10). Examination of a wide range of solvents showed that the similar yield was found when using diglyme as solvent (Table 2.5, entry 11). If using dimethylacetamide

(DMAC) or CH2Cl2 as the solvents, lower yields were afforded (Table 2.5, entries 12 and

13).

Table 2.5 Optimization of the Cu-catalyzed trifluoromethylation of alkynyltrifluoroborates.

100

Table 2.6 Copper-catalyzed trifluoromethylation of alkynyltrifluoroborates.

101

Under the optimized reaction conditions, we next examined the substrate scope of the copper-catalyzed trifluoromethylation of alkynyltrifluoroborates and found that a wide range of alkynyltrifluoroborates can be subjected to the reaction condition and the corresponding products were formed in moderate to good yields (Table 2.6). The analogues of the para-substituted phenyl alkynyltrifluoroborates gave a various products in higher efficiency (Table 2.6, entries 1 and 3-7). Phenyl alkynyltrifluoroborate is also compatible with this catalytic system, afforded the product in 75% yield (Table 2.6, entry

2). Biphenyl alkynyltrifluoroborate can also work well to afford the corresponding product in a good yield (Table 2.6, entry 8). Notably, halogen-substituted substrates can also be tolerated under the current reaction conditions and afforded the respective trifluoromethylated acetylenes in good yields (Table 2.6, entries 9 and 10). For the substrates bearing electron rich substituents such as p-methoxy, it can also be well- tolerated (Table 2.6, entry 11). To extension of the generality of this method, the nonaromatic alkynyltrifluoroborates, hept-1-ynyltrifluoroborate, was also employed as the substrate. To our delight, the desired product was afforded in good yield (Table 2.6, entry 12).

In conclusion, we have further developed an alternative effective copper catalyzed trifluoromethylation reaction employing alkynyltrifluoroborates as the coupling partners without the addition of base. The results indicate that the catalytic reactions were under rather mild reaction conditions smoothly. At the same time, a wide range of functional groups were well tolerated. 102

2.2.1.3 Experimental

2.2.1.3.1 General

All solvents were purified according to the standard procedure. 1H NMR, 13C NMR and 19F NMR spectra were documented using Bruker AVIII 400 or AVIII 500. Chemical shifts of 1H NMR and 13C NMR (in ppm) were determined by tetramethylsilane and 19F

NMR chemical shifts were obtained relative to CFCl3 as outside standard. Coupling constants (J) are recorded in Hertz (Hz). Flash column chromatography purifications were carried out on Merck silica gel 60.

2.2.1.3.2 General operation for the copper-catalyzed electrophilic trifluoromethylation of terminal alkynes

The starting material including CuI, phen, base, and Togni’s reagent were weighted in a glovebox and were dissolved in the solvent. The acetylene with the same solvent was added into the other vial. Then they were taken out from the glovebox. The solution of alkyne was injected into the reaction tube by using a syringe pump over 6 h under Ar atmosphere. After that, the reaction mixture was stirring for additional 18 h at room temperature. Next, the system was extracted with CH2Cl2 and the combined organic extracts were dried over anhydrous Na2SO4, and concentrated in vacum. The product was isolated by flash chromatography. NMR yield was carried out by 19F NMR using trifluorobenzene as an internal standard before working up the reaction.

2.2.1.3.3 General procedure for the synthesis of trifluoromethylated acetylenes employing alkynyltrifluoroborates as coupling partners

103

In a glovebox, CuSCN (0.12 mmol), bipy (0.12 mmol) , and electrophilic trifluoromethylating reagent (0.48 mmol), potassium trifluoroborates (0.40 mmol) were added to an dried reaction tube. Freshly distilled dried MeCN (2 ml) was injected into this tube and the tube was sealed. The reaction mixture was stirred at room temperature for 16 h and then 20 mL of distilled water was added at 0oC. The resulting mixture was extracted with Et2O (3x10 ml) and the combined organic extracts were dried over anhydrous Na2SO4. The product was isolated by flash chromatography.

1-Methyl-4-(3,3,3-trifluoroprop-1-ynyl)benzene22b

1 H NMR (500 MHz, CDCl3, 293K): δ ppm 7.45 (d, J = 8.1 Hz, 2H), 7.20 (d, J = 7.9 Hz,

19 2H), 2.39 (s, 3H). F NMR (470 MHz, CDCl3): δ ppm -52.00 (s, 3F). GC-MS m/z 184

+ + (M ), 115 (M -CF3).

1-Methyl-3-(3,3,3-trifluoroprop-1-ynyl)benzene31

1 19 H NMR (400 MHz, CDCl3, 293K): δ ppm 7.37 (m, 2H), 7.30 (m, 2H), 2.37 (s, 3H). F

13 NMR (377 MHz, CDCl3): δ ppm -49.7 (s, 3F). C NMR (100.7 MHz, CDCl3): δ ppm 104

138.71 (s), 133.06 (s), 131.93 (s), 129.68 (s), 128.69 (s), 116.36 (q, J = 256.7 Hz), 86.97

(d, J = 6.8 Hz), 75.50 (d, J = 52.8 Hz), 21.23 (s).

1-Ethyl-4-(3,3,3-trifluoroprop-1-ynyl)benzene

1 H NMR (500 MHz, CDCl3, 293K): δ ppm 7.48 (d, J = 8.1 Hz, 2H), 7.22 (d, J = 8.1 Hz,

19 2H), 2.69 (q, J = 7.6 Hz, 2H), 1.26 (t, J =7.5 Hz, 3H). F NMR(470 MHz, CDCl3): δ

13 ppm -51.78 (s, 3F). C NMR (126 MHz, CDCl3): δ ppm 147.69 (s), 132.48 (q, J = 1.5

Hz), 128.24 (s), 115.65 (s), 113.95 (s), 86.98 (q, J = 6.5 Hz), 75.42 (q, J=52.4), 28.98 (s),

+ + 15.15 (s). GC-MS m/z 198 (M ), 183 (M -CH3).

1-Propyl-4-(3,3,3-trifluoroprop-1-ynyl)benzene32

1 H NMR (500 MHz, CDCl3, 293K): δ ppm 7.47 (d, J = 8.1 Hz, 2H), 7.19 (d, J = 8.0 Hz,

19 2H), 2.61 (t, J = 7.5 Hz, 2H), 1.65 (m, 2H), 0.94 (t, 3H). F NMR (470 MHz, CDCl3): δ

13 ppm -51.77 (s, 3F). C NMR (126 MHz, CDCl3): δ ppm 146.18 (s), 132.39 (q, J = 1.4

Hz), 128.82 (s), 115.66 (s), 113.95 (s), 87.00 (q, J = 6.5 Hz), 75.25 (q, J = 52.3 Hz),

+ + 38.06 (s), 24.19 (s), 13.69 (s). GC-MS m/z 212 (M ), 143 (M -CF3).

1-Butyl-4-(3,3,3-trifluoroprop-1-ynyl)benzene 105

1 H NMR (500 MHz, CDCl3, 293K): δ ppm 7.47 (d, J = 8.1 Hz, 1H), 7.20 (t, J = 8.7 Hz,

1H), 2.73 – 2.53 (m, 1H), 1.60 (ddt, J = 11.9, 10.7, 5.2 Hz, 1H), 1.35 (tt, J = 15.5, 7.8 Hz,

19 13 2H), 0.97 – 0.91 (m, 2H). F NMR (470 MHz, CDCl3): δ ppm -51.77 (s, 3F). C NMR

(126 MHz, CDCl3): δ ppm 146.43 (s), 132.40 (q, J = 1.4 Hz), 128.77 (s), 115.62 (q, J =

1.8 Hz), 113.96 (s), 87.00 (q, J = 6.5 Hz), 75.24 (q, J = 52.4 Hz), 35.73 (s), 33.22 (s),

22.28 (s), 13.87 (s). GC-MS m/z 226 (M+).

9-(3,3,3-Trifluoroprop-1-ynyl)phenanthrene

1 H NMR (400 MHz, CDCl3, 293K): δ ppm 8.63 (m, 2H), 8.25 (t, J = 5.2 Hz, 1H), 8.06 (s,

19 1H), 7.81 (d, 1H), 7.70 (m, 3H), 7.62 (t, J = 7.6 Hz 1H). F NMR (377 MHz, CDCl3): δ

13 ppm -50.1 (s, 3F). C NMR (100.7 MHz, CDCl3): δ ppm 134.98 (d, J = 1.9 Hz), 131.19

(s), 130.30 (s), 130.07 (s), 129.92 (s), 129.06 (s), 128.87 (s), 127.63 (d, J = 3.34 Hz),

127.30 (s), 126.10 (s), 122.97 (s), 122.72 (s), 114.84 (q, J = 158.4 Hz), 85.43 (q, J = 6.2

Hz), 79.71 (q, J = 52.1 Hz). GC-MS m/z 270 (M+). HRMS (EI) m/z: calcd for [M+]:

C10H11F3O2S: 270.06563; found: 270.06461.

106

1-Methoxy-4-(3,3,3-trifluoroprop-1-ynyl)benzene33

1 H NMR (400 MHz, CDCl3, 293K): δ ppm 7.54 (d, J = 8.8 Hz, 2H), 6.94 (d, J = 8.9 Hz,

19 13 2H). F NMR (377 MHz, CDCl3): δ ppm -49.4 (s, 3F). C NMR (100.7 MHz, CDCl3): δ ppm 161.68 (s), 134.30 (s) , 114.49 (s), 87.20 (d, J = 6.5 Hz), 74.91(d, J = 52.4 Hz),

55.51(s). GC-MS m/z 200 (M+).

1-Phenoxy-4-(3,3,3-trifluoroprop-1-ynyl)benzene34

1 H NMR (400 MHz, CDCl3, 293K): δ ppm 7.58 (d, J = 8.6 Hz, 2H), 7.48 (t, J = 7.6 Hz,

2H). 7.29 (t, J = 7.3 Hz, 1H), 7.15 (d, J = 7.8 Hz, 2H), 7.04 (d, J = 8.3 Hz, 2H). 19F NMR

13 (377 MHz, CDCl3): δ ppm -49.5 (s, 3F). C NMR (100.7 MHz, CDCl3): δ ppm 160.24

(s), 155.62 (s), 134.43 (s), 130.24 (s), 124.79 (s), 120.23 (s), 118.06 (s), 113.87 (s), 86.65

(d, J = 6.9 Hz), 75.38 (q, J = 52.9 Hz).

1-Bromo-2-(3,3,3-trifluoroprop-1-ynyl)benzene

1 19 H NMR (400 MHz, CDCl3, 293K): δ ppm 7.63 (m, 1H), 7.56 (m, 1H). 7.34 (m, 2H), F

13 NMR (377 MHz, CDCl3): δ ppm -50.2 (s, 3F). C NMR (100.7 MHz, CDCl3): δ ppm 107

134.51(s), 133.00 (s), 132.16 (s), 127.41 (s), 126.22 (s), 121.20 (s), 113.62 (s), 84.73 (d, J

= 6.8 Hz), 79.27 (d, J = 53.1 Hz). GC-MS m/z 250 (M++H).

1-Bromo-4-(3,3,3-trifluoroprop-1-ynyl)benzene20c

1 H NMR (400 MHz, CDCl3, 293K): δ ppm 7.54 (d, J = 8.4 Hz, 2H), 7.40 (d, J = 8.5 Hz,

19 13 2H). F NMR (377 MHz, CDCl3): δ ppm -50.1 (s, 3F). C NMR (100.7 MHz, CDCl3): δ ppm 133.90 (s), 132.23 (s), 125.89 (s), 117.56 (s), 113.61(s), 85.50 (q, J = 6.0 Hz), 76.55

(s). GC-MS m/z 248 (M+).

3-(3,3,3-Trifluoroprop-1-ynyl)aniline

CF3

H2N

1 H NMR (500 MHz, CDCl3, 293K): δ ppm 7.19 (t, J = 7.9 Hz, 1H), 6.97 (d, J = 7.6 Hz,

1H), 6.86 (t, J = 3.8 Hz, 1H), 6.79 (ddd, J = 7.5, 4.6, 2.9 Hz, 1H), 3.90 – 3.71 (m, 2H).

13 C NMR (126 MHz, CDCl3) δ 146.52 (s), 129.62 (s), 122.63 (q, J = 1.6 Hz), 118.15 (q, J

= 1.5 Hz), 117.63 (s), 115.92 (s), 113.88 (s), 86.95 (q, J = 6.5 Hz), 75.03 (q, J = 52.4 Hz).

19 + + F NMR (470 MHz, CDCl3): δ ppm -51.86 (s, 3F). GC-MS m/z 185 (M ), 116 (M -

CF3).

108

(3,3,3-Trifluoroprop-1-ynyl)benzene26

1 H NMR (400 MHz, CDCl3) δ 7.48 (d, J = 7.6 Hz, 2H), 7.40 (t, J = 7.4 Hz, 1H), 7.32 (t, J

19 13 = 7.4 Hz, 2H). F NMR (376 MHz, CDCl3) δ -49.79 (s, 3F). C NMR (101 MHz,

CDCl3) δ 132.43 (s), 130.85 (s), 128.63 (s), 118.55 (q, J = 2.1 Hz), 114.86 (q, J = 257.1

Hz), 86.52 (q, J = 6.8 Hz), 75.72 (q, J = 52.3 Hz). GC-MS: 170 (M+).

1-t-Butyl-4-(3,3,3-trifluoroprop-1-ynyl)benzene26

1 H NMR (400 MHz, CDCl3) δ 7.52 (d, J = 7.6 Hz, 2H), 7.44 (d, J = 7.4 Hz, 2H), 1.35 (s,

19 13 9H). F NMR (376 MHz, CDCl3) δ -49.55 (s, 3F). C NMR (101 MHz, CDCl3) δ

154.54 (s), 132.24 (q, J = 1.5 Hz), 125.69 (s), 115.44 (q, J = 1.6 Hz), 114.96 (q, J = 256.6

Hz), 86.93 (q, J = 6.5 Hz), 75.22 (q, J = 52.3 Hz), 35.05 (s), 31.03 (s). GC-MS: 226(M+).

1-Pentyl-4-(3,3,3-trifluoroprop-1-ynyl)benzene35

1 H NMR (400 MHz, CDCl3) δ 7.39 (d, J = 7.6 Hz, 2H), 7.13 (d, J = 7.6 Hz, 2H), 2.56 (t,

J = 7.6 Hz, 2H), 1.58 - 1.52 (m, 2H), 1.29 -1.21 (m, 4H), 0.82 (t, J = 6.0 Hz, 3H). 19F 109

13 NMR (376 MHz, CDCl3) δ -49.56 (s, 3F). C NMR (101 MHz, CDCl3) δ 146.45 (s),

132.39 (d, J = 1.5 Hz), 128.76 (s), 115.60 (d, J = 1.9 Hz), 114.96 (q, J = 257.0 Hz), 87.00

(q, J = 6.6 Hz), 75.22 (q, J = 52.5 Hz), 35.99 (s), 31.38 (s), 30.75 (s), 22.47 (s), 13.97 (s).

GC-MS: 240(M+).

4-(3,3,3-Trifluoroprop-1-ynyl)biphenyl35

1 19 H NMR (400 MHz, CDCl3) δ 7.56 – 7.48 (m, 6H), 7.42 – 7.28 (m, 3H). F NMR (376

13 MHz, CDCl3) δ -49.69 (s, 3F). C NMR (101 MHz, CDCl3) δ 143.74 (s), 139.71 (s),

132.89 (s), 128.99 (s), 128.23 (s), 127.30 (s), 127.14 (s), 117.23 (q, J = 2.3 Hz), 114.93

(q, J = 256.4 Hz), 86.57 (q, J = 6.2 Hz), 76.24 (q, J = 52.8 Hz). GC-MS: 246(M+).

1-Fluoro-4-(3,3,3-trifluoroprop-1-ynyl)benzene36

1 19 H NMR (400 MHz, CDCl3) δ 7.62-7.56 (m, 2H), 7.12 (t, J = 8.1 Hz, 2H). F NMR (376

13 MHz, CDCl3) δ -49.92 (s, 3F), -106.09 (s, F). C NMR (101 MHz, CDCl3) δ 164.03 (d, J

= 253.4 Hz), 134.69 (d, J = 8.6 Hz), 116.21 (d, J = 22.5 Hz), 114.78 (q, J = 257.3 Hz),

114.65 (q, J = 2.5 Hz), 85.50 (q, J = 6.4 Hz), 75.64 (q, J = 53.9 Hz). GC-MS: 188 (M+).

110

1,2-Dichloro-4-(3,3,3-trifluoroprop-1-ynyl)benzene35

1 H NMR (400 MHz, CDCl3) δ 7.68 (s, 1H), 7.52 (d, J = 8.3 Hz, 1H), 7.42 (d, J = 8.3 Hz,

19 13 1H). F NMR (376 MHz, CDCl3) δ -50.29 (s, 3F). C NMR (101 MHz, CDCl3) δ

135.93 (s), 134.02 (q, J = 1.3 Hz), 133.30 (s), 131.38 (q, J = 1.4 Hz), 130.87 (s), 118.32

(q, J = 1.7 Hz), 114.53 (q, J = 257.6 Hz), 83.85 (q, J = 6.2 Hz), 77.23 (q, J = 53.1 Hz).

GC-MS: 238 (M+).

2.2.2 Copper-catalyzed electrophilic trifluoromethylation of arylsulfinate salts for the preparation of aryltrifluoromethylsulfones27

Aryltrifluoromethylsulfones are often employed as critical structural units in biologically active moleculars,37 chiral catalysts,38 and specified materials.39 Also, They could be regarded as the versatile synthons for the synthesis of many other organic compounds which include either various trifluoromethylated compounds40 or aryl sulfones (Figure 2.6).41

On the other hand, the synthetic methods for the aryltrifluoromethylsulfones are limited. Oxidation of aryl trifluoromethylsulfoxides represents the traditional methods for the preparation of aryltrifluoromethylsulfones.42 Alternatively, the fluoride-catalyzed reaction of arenesulfonyl fluorides with (trifluoromethyl)-trimethylstannane and

(trifluoromethyl) trimethylsilane has been developed by Yagupolski and co-workers

(Figure 2.7).43 In spite of these procedures being appealing for their simplicity, these 111 methods suffer from the functional groups tolerance, the availability of the starting materials, low yields and poor selectivity. As the continuing efforts to developing copper catalyzed electrophilic trifluoromethylation chemistry, we attempt to develop an effective method for the synthesis of aryltrifluoromethylsulfones. Herein, we investigate a copper- catalyzed electrophilic trifluoromethylation reaction of arylsulfinate salts and Togni’s reagent.

Figure 2.6 The application of aryltrifluoromethylsulfones.

112

Figure 2.7 Traditional methods for the preparation of aryltrifluoromethylsulfones.

2.2.2.1 Copper-catalyzed electrophilic trifluoromethylation of arylsulfinate salts

Our study commenced by examining the electrophilic trifluoromethylation reactions of benzenesulfinate sodium salts in the presence of a ligand (Table 2.7). Several copper sources, reaction temperatures, bidentate ligands, solvents, and reaction time were screened for the reaction of 1a with Togni’s reagent (2a) or (2b). To our delight, the mixture of Cu(TFA)2, phenanthroline (L1), and tetrabutylammonium fluoride resulted in the desired product in 78% yield (Table 2.7 entry 1). It was also found that the electrophilic trifluoromethylating reagent 2a is superior to 2b (Table 2.7, entry 2).

Notably, without the addition of either of the copper sources, ligands, or Bu4NF, the yield was dramatically decreased (Table 2.7, entries 3 and 8). The same result was obtained as lowering the reaction temperature (Table 2.7, entry 4). Employing several copper sources as catalyst, such as CuI, Cu(OTf)2, and Cu(MeCN)4PF6, could not improve the yields

(Table 2.7, entries5-7). The ligand effect on the reaction was also investigated (Table

2.7, entries 9 and 10). Extension of the reaction time resulted in a extremely lower yield, 113

Table 2.7 Optimization of copper-catalyzed trifluoromethylation of sulfinate salts.

seemingly because of the decomposition of the product (Table 2.7, entry 11). The solvents have a big effect on the efficiency of the reaction (Table 2.7, entries 12-14).

After the optimization of the reaction conditions, we next studied the substrate scope with a variety of sulfinate sodium salts (Table 2.8). Alkyl substituents on the phenyl ring are well compatible with the reaction condition which include methyl-, t-butyl, and i- propyl- to afford the desired products in good yields, in spite of altering the catalyst in the 114 case of p-methyl phenyl sulfinate (Table 2.8, entries 2-5). Additionally, the phenyl substituent on the aromatic ring provide the respective products in good yields (Table

2.8, entries 6). Both of the 1- and 2-naphthyl sulfinate sodium salts can form the desired products in good yields (Table 2.8, entries 7 and 8). Notably, the electron-withdrawing and electron-donating functional groups can be tolerated, such as methoxy, cyano, nitro, and fluoro under the current reaction conditions, although the catalytic system was changed in some cases (Table 2.8, entries 9-12). Notably, pharmaceutically important substrate, such as heteroaryl groups was also well tolerated (Table 2.8, entry 13). 115

Table 2.8 Copper-catalyzed electrophilic trifluoromethylation of sulfinate salts.

116

In summary, the copper catalyzed electrophilic trifluoromethylation reactions of aryl sodium sulfinate for synthesis of aryltrifluoromethylsulfones has been developed. A various functional groups can be tolerated under the reaction conditions.

2.2.2.2 Experimental

2.2.2.2.1 General

2.2.2.2.2 General procedure for the copper-catalyzed trifluoromethylation of arylsulfinate salts

The starting material including arylsulfinate salts, copper source, phen, Bu4NF, and

Togni’s reagent were weighted in a glovebox and were dissolved in the solvent. Then it was taken out from the glovebox. The reaction mixture was stirred at 130oC for 8 h. After filtration, extraction, washing by water and dried over magnesium sulfate, the target product was isolated by column chromatography.

Trifluoromethyl phenylsulfone40d, 42c 117

1 H NMR (500 MHz, CDCl3): δ 8.08 (d, J = 7.8 Hz, 2H), 7.88 (t, J = 7.8 Hz, 1H), 7.72 (t,

19 13 J = 7.8 Hz, 2H). F NMR (470 MHz, CDCl3): δ -78.42 (s, 3F). C NMR (126 MHz,

+ CDCl3): δ 131.8, 126.7, 126.0, 125.1, 115.0 (q, J = 325 Hz). GC-MS m/z 210 (M ).

1-Methyl-4-(trifluoromethylsulfonyl)benzene42e, 44

1 H NMR (500 MHz, CDCl3): δ 7.94 (d, J = 8.1 Hz, 2H), 7.49 (d, J = 8.1 Hz, 2H), 2.54 (s,

19 13 3H). F NMR (470 MHz, CDCl3): δ 78.67 (s, 3F). C NMR (126 MHz, CDCl3): δ

148.4, 130.8, 130.6, 128.2, 119.9 (q, J = 323 Hz), 22.0. GC-MS m/z 224 (M+).

1-Methyl-2-(trifluoromethylsulfonyl)benzene44

1 H NMR (500 MHz, CDCl3): δ 8.10 (d, J = 8.0 Hz, 1H), 7.73-7.68 (m, 1H), 7.43-7.53 (m,

19 13 2H), 2.76 (s, 3H). F NMR (470 MHz, CDCl3): δ -78.08 (s, 3F). C NMR (126 MHz,

CDCl3): δ 142.2, 136.4, 133.6, 133.4, 129.8, 127.2, 120.1 (q, J = 323 Hz), 20.7. GC-MS m/z 224 (M+). 118

1-Isopropyl-4-(trifluoromethylsulfonyl)benzene

1 H NMR (500 MHz, CDCl3): δ 7.98 (d, J = 8.4 Hz, 2H), 7.54 (d, J = 8.4 Hz, 2H), 3.13-

19 13 3.02 (m, 1H), 1.33 (d, J = 6.9 Hz, 6H). F NMR (470 MHz, CDCl3): δ -78.60 (s, 3F). C

NMR (126 MHz, CDCl3): δ 158.8, 131.0, 128.6, 128.1, 119.8 (q, J = 323 Hz), 34.6, 23.5.

+ + GC-MS m/z 252 (M ). HRMS (EI) m/z: calcd for [M ]: C10H11F3O2S: 252.0432; found:

252.0434.

1-tert-Butyl-4-(trifluoromethylsulfonyl)benzene

1 H NMR (500 MHz, CDCl3): δ 7.98 (d, J = 8.5 Hz, 2H), 7.70 (d, J = 8.5 Hz, 2H), 1.40 (s,

19 13 9H). F NMR (470 MHz, CDCl3): δ -78.57 (s, 3F). C NMR (126 MHz, CDCl3): δ

161.1, 130.7, 128.1, 127.0, 119.9 (q, J = 323 Hz), 35.7, 30.9. GC-MS m/z 266 (M+).

+ HRMS (EI) m/z: calcd for [M ]: C11H13F3O2S: 266.0588; found: 266.0596.

4-(Trifluoromethylsulfonyl)biphenyl

119

1 H NMR (500 MHz, CDCl3): δ 8.13 (d, J = 8.4 Hz, 2H), 7.89 (d, J = 8.4 Hz, 2H), 7.67-

19 13 7.65 (m, 2H), 7.57-7.50 (m, 3H). F NMR (470 MHz, CDCl3): δ 78.60 (s, 3F). C NMR

(126 MHz, CDCl3): δ 149.6, 138.4, 131.3, 129.6, 129.4, 129.3, 128.4, 127.6, 119.9 (q, J =

+ + 323 Hz). GC-MS m/z 286 (M ). HRMS (EI) m/z: calcd for [M ]: C13H9F3O2S: 286.0275; found: 286.0274.

1-(Trifluoromethylsulfonyl)naphthalene45

1 H NMR (500 MHz, CDCl3): δ 8.84 (d, J = 8.7 Hz, 1H), 8.50 (dd, J = 7.5, 1.2 Hz, 1H),

8.33 (d, J = 8.2 Hz, 1H), 8.04 (d, J = 8.2 Hz, 1H), 7.82-7.76 (m, 1H), 7.74-7.68 (m, 2H).

19 13 F NMR (470 MHz, CDCl3): δ -77.80 (s, 3F). C NMR (126 MHz, CDCl3): δ 138.4,

135.2, 134.3, 130.2, 129.7, 129.3, 127.7, 126.9, 124.5, 124.4, 120.3 (q, J = 323 Hz). GC-

MS m/z 260 (M+).

2-(Trifluoromethylsulfonyl)naphthalene

1 H NMR (500 MHz, CDCl3): δ 8.69 (s, 1H), 8.16-8.07 (m, 2H), 8.03 (d, J = 8.2 Hz, 1H),

7.98 (d, J = 9.8 Hz, 1H), 7.81(t, J = 7.6 Hz, 1H), 7.74 (t, J = 7.6 Hz, 1H). 19F NMR (470 120

13 MHz, CDCl3): δ -78.18 (s, 3F). C NMR (126 MHz, CDCl3): δ 136.6, 134.1, 132.1,

130.9, 130.2, 129.9, 128.4, 128.2, 128.1, 123.8, 120.0 (q, J = 323 Hz). GC-MS m/z 260

+ + (M ). HRMS (EI) m/z: calcd for [M ]: C11H7F3O2S: 260.0119; found: 260.0121.

1-Methoxy-4-(trifluoromethylsulfonyl)benzene42e, 46

1 H NMR (500 MHz, CDCl3): δ 7.98 (d, J = 9.0 Hz, 2H), 7.14-7.11 (m, 2H), 3.96 (s, 3H).

19 13 F NMR (470 MHz, CDCl3): δ -78.88 (s, 3F). C NMR (126 MHz, CDCl3): δ 166.4,

133.2, 122.0, 119.9 (q, J = 323 Hz), 115.3, 55.7. GC-MS m/z 240 (M+).

4-(Trifluoromethylsulfonyl)benzonitrile42d

1 19 H NMR (500 MHz, CDCl3): δ 8.21 (d, J = 8.3 Hz, 2H), 8.02 (d, J = 8.3 Hz, 2H). F

13 NMR (470 MHz, CDCl3): δ -77.67 (s, 3F). C NMR (126 MHz, CDCl3): δ 135.6, 133.5,

131.4, 120.8, 119.3 (q, J = 323 Hz), 116.4. GC-MS m/z 235 (M+).

1-Nitro-3-(trifluoromethylsulfonyl)benzene47 121

1 H NMR (500 MHz, CDCl3): δ 8.91 (s, 1H), 8.75-8.72 (m, 1H), 8.41 (d, J = 8.0 Hz, 1H),

19 13 7.99 (t, J = 8.0 Hz, 1H). F NMR (470 MHz, CDCl3): δ -77.53 (s, 3F). C NMR (126

MHz, CDCl3): δ 148.8, 136.0, 133.8, 131.5, 130.9, 126.0, 119.5 (q, J = 323 Hz). GC-MS m/z 255 (M+).

1-Fluoro-4-(trifluoromethylsulfonyl)benzene48

1 19 H NMR (500 MHz, CDCl3): δ 8.14-8.09 (m, 2H), 7.42-7.36 (m, 2H). F NMR (470

13 MHz, CDCl3): δ -78.16 (s, 3F), -97.40 (s, 1F). C NMR (126 MHz, CDCl3): δ 167.7 (d, J

= 260.3 Hz), 134.0 (d, J = 10.3 Hz), 127.2, 119.7 (q, J = 323 Hz), 117.5 (d, J = 22.7 Hz).

GC-MS m/z 228 (M+).

8-(Trifluoromethylsulfonyl)quinoline

1 H NMR (500 MHz, CDCl3): δ 9.21-9.18 (m, 1H), 8.70-8.66 (m, 1H), 8.35 (dd, J = 8.3,

1.5 Hz, 1H), 8.31 (dd, J = 8.3, 1.5 Hz, 1H), 7.81 (t, J = 7.8 Hz, 1H), 7.66-7.64 (m). 19F 122

13 NMR (470 MHz, CDCl3): δ -74.35 (s, 3F). C NMR (126 MHz, CDCl3): δ 152.5, 145.1,

137.2, 136.5, 136.1, 130.7, 129.1, 125.7, 123.0, 120.2 (q, J = 323 Hz). GC-MS m/z 261

+ (M ). Anal. Calcd for C10H6F3NO2S: C, 45.98; H, 2.32; N, 5.36. Found: C, 45.88; H,

2.60. N, 5.35.

2.2.3 Copper-catalyzed electrophilic trifluoromethylation of organotrifluoroborates for the synthesis of trifluoromethylarenes27

The construction of aryl-CF3 bonds has received much attention because of the aromatic pharmaceuticals as mentioned above. In general, much more efforts towards Cu and Pd catalyzed aromatic trifluoromethylations have been devoted (Scheme 2.2).

However, most of these protocols suffer from the narrow functional group compatibility because of the harsh reaction condition, such as higher temperatures, base conditions or the requirement of oxidants. As a consequence, the development of a room temperature, base-free procedure for the synthesis of trifluoromethylarenes is still desirable. We have already developed a copper-catalyzed electrophilic trifluoromethylation method for the synthesis of trifluoromethylated acetylenes using alkynyltrifluoroborates as substrates at room temperature and under base free reaction condition.49 Inspired by this part of work, herein, we developed a copper-catalyzed trifluoromethylation of organotrifluoroborates for the synthesis of trifluoromethylarenes under rather mild conditions with much more broader substrate scopes.

2.2.3.1 Copper-catalyzed electrophilic trifluoromethylation of organotrifluoroborates

123

We have studied the trifluoromethylation of potassium4-biphenylborate with Togni’s reagent at the beginning. The presence of copper and ligand were demonstrated to be crucial for this process (Table 2.9, entries 1-2). Gratifyingly, when the catalytic system involving combination of Cu(TFA)2 (30 mol %) and L1 (30 mol %), the desired product was formed in 96% yield (Table 2.9, entry 3). Notably, this reaction occurs at room temperature and under base or oxidant free condition. Similar with the trifluoromethylation of alkynyltrifluoroborates, the use of molecular sieves was indicated to be crucial for the trifluoromethylation reaction (Table 2.9, entry 4). It has been observed that the other nitrogen containing ligands (L2, L3and L4) can also promoted the reaction but with lower yields (Table 2.9, entries 5-7).

The effect of different copper precursors on the trifluoromethylation have also been investigated, and they showed inferior results (Table 2.9, entries 8-13). Several solvents including acetone, DCE, and diglyme were also examined but showed poor yields (Table

2.9, entries 14-16).

124

Table 2.9 Optimization of the reaction condition with respect to copper source, ligand and solvent.

125

Table 2.10 The substrate scope of the copper-catalyzed electrophilic trifluoromethylation of potassium aryltrifluoroborates.

BF K F3C I O 3 Cu(TFA)2, L1 CF3 R + R MeCN, 4 Å MS, r.t. 1 23 entry product yield(%)b entry product yield(%)b

CF3 CF3 1 91 92 11 t-Bu BnO

CF3 BnO CF3 2 89 12 90 n-Bu

CF3 CF3 3 95 13 94 Ph PhO

Ph CF3 MeO CF3 4 82 14 65 MeO

CF3 CF3 c 5 69 15 60 MeO

CF CF 3 3 65 61 6 16 MeOOC

CF3 CF3 7 c 72 50 17 EtOOC

CF3 CF3 51d 42 8 18 MeOC

CF3 CF3

d e 9 70 19 O 39 H

CF3 CF3 10 20 50 65d MeO Cl

a Reaction conditions: ArBF3K (0.10 mmol), 2 (0.12 mmol), Cu(TFA)2 (0.030 mmol), bipy (0.030 mmol), 4Å mol sieves (200 mg/mmol ), MeCN (1.0 mL), r.t, 16 h under Ar atmosphere. b Isolated yield. c GC yield. d Addition of Ag2O (0.030 mmol). 126

With the optimized reaction conditions in hand, various substrates were studied (Table

2.10). The wide range of aryltrifluoroborates with substituents on the aromatic rings at the ortho, meta, or para position can proceed trifluoromethylation well and produced the desired products in good to excellent yields. Various functional group such as butyl-, phenyl-,methyl-, benzyloxy- , phenyloxy- and methyloxy- can be tolerated (Table 2.10, entries 1-6 and 11-15). Several naphthyltrifluoroborate substrates were also examined.

The 1- and 2- naphthyltrifluoroborate afforded the corresponding products in moderate yields (Table 2.10, entries 7 and 8), while the 4-methyl 1-naphthyltrifluoroborate afforded the desired product in 70% yield (Table 2.10, entry 9). Notably, for the substrates containing base unstable functional groups, such as ketone, aldehyde and esters, they were also worked well under the standard reaction conditions in spite of the lower yields in some cases (Table 2.10, entries 16-19). Moreover, halide-containing organotrifluoroborate was also transformed into the product in moderate yields (Table

2.10, entry 20).

In summary, copper-catalyzed electrophilic trifluoromethylation reaction at room- temperature under base-free condition has been developed. The mild reaction condition allows for the catalytic reactions to tolerate a variety of functionalities.

2.2.3.2 Experimental

2.2.3.2.1 General

2.2.3.2.2 General procedure for the copper-catalyzed trifluoromethylation of potassium aryltrifluoroborates

The starting material including Cu(TFA)2, bipy, potassium organotrifluoroborates, and

Togni’s reagent were weighted in a glovebox and were dissolved in the solvent. Then it was taken out from the glovebox. The reaction mixture was stirred at room temperature for 12 h. After filtration, extraction, washing by water and dried over magnesium sulfate, the target product was isolated by column chromatography.

1-tert-Butyl-4-(trifluoromethyl)benzene25

1 H NMR (500 MHz, CDCl3) δ 7.58 (d, J = 8.4 Hz, 2H), 7.52 (d, J = 8.4 Hz, 2H), 1.37 (s,

19 13 9H). F NMR (470 MHz, CDCl3) δ -62.29 (s, 3F). C NMR (126 MHz, CDCl3) δ 155.2,

127.8 (q, J = 32.5 Hz), 125.6, 125.0 (q, J = 3.7 Hz), 124.4 (q, J = 271.8 Hz), 35.0, 31.2.

GC-MS m/z 202 (M+).

1-Butyl-4-(trifluoromethyl)benzene50 128

1 H NMR (500 MHz, CDCl3) δ 7.55 (d, J = 8.0 Hz, 2H), 7.31 (d, J = 8.0 Hz, 2H), 2.69 (t,

J = 7.7 Hz, 2H), 1.63 (dd, J = 14.4, 6.8 Hz, 2H), 1.41-1.36 (m, 2H), 0.96 (t, J = 7.4 Hz,

19 13 3H). F NMR (470 MHz, CDCl3) δ -62.24 (s, 3F). C NMR (126 MHz, CDCl3) δ 147.0,

128.7, 128.0 (q, J = 32.2 Hz), 125.2 (q, J = 3.8 Hz), 124.4 (q, J = 271.6 Hz), 35.5, 33.3,

22.3, 13.9. GC-MS m/z 202 (M+).

4-(Trifluoromethyl)-1,10-biphenyl25

1 H NMR (500 MHz, CDCl3) δ 7.72 (s, 4H), 7.63 (d, J = 7.1 Hz, 2H), 7.51 (t, J = 7.1 Hz,

19 13 2H), 7.46-7.42 (m, 1H). F NMR (470 MHz, CDCl3) δ -62.37 (s, 3F). C NMR (126

MHz, CDCl3) δ 144.8, 139.8, 129.4 (q, J = 32.5 Hz), 128.4, 128.2, 127.5, 127.3, 125.8 (q,

J = 3.7 Hz), 124.4 (q, J = 271.8 Hz). GC-MS m/z 222 (M+).

3-(Trifluoromethyl)biphenyl51

129

1 H NMR (500 MHz, CDCl3) δ 7.87 (s, 1H), 7.80 (d, J = 7.6 Hz, 1H), 7.67-7.56 (m, 4H),

19 7.51 (t, J = 7.6 Hz, 2H), 7.44 (t, J = 7.6 Hz, 1H). F NMR (470 MHz, CDCl3) δ -62.57

13 (s, 3F). C NMR (126 MHz, CDCl3) δ 142.0, 139.8, 131.1 (q, J = 32.3 Hz), 130.5, 129.3,

129.0, 128.1, 127.2, 125.3, 124.2 (q, J = 272.3 Hz),124.0 (q, J = 3.7 Hz). GC-MS m/z

222 (M+).

4-Trifluoromethyltoluene52

1 H NMR (500 MHz, CDCl3) δ 7.53 (d, J = 8.1 Hz, 2H), 7.30 (d, J = 8.1 Hz, 2H), 2.44 (s,

19 13 3H). F NMR (470 MHz, CDCl3) δ -62.27 (s, 3F). C NMR (126 MHz, CDCl3) δ 142.0,

129.3, 127.9 (q, J = 32.4 Hz), 125.1 (q, J = 3.8 Hz), 124.4 (q, J = 271.6 Hz), 21.4. GC-

MS m/z 160 (M+).

2,3-Dimethylbenzotrifluoride53

1 H NMR (500 MHz, CDCl3) δ 7.50 (d, J = 7.5 Hz, 1H), 7.34 (d, J = 7.5 Hz, 1H), 7.19 (t,

19 J = 7.5 Hz, 1H), 2.39 (s, 3H), 2.35 (s, 3H). F NMR (470 MHz, CDCl3) δ -60.39 (s, 3F).

13 C NMR (126 MHz, CDCl3) δ 138.6, 135.3 (d, J = 1.5 Hz), 133.2, 129.0 (q, J = 28.9 130

Hz), 125.3, 124.8 (q, J = 273.8 Hz), 123.5 (q, J = 5.9 Hz), 20.4, 15.4. GC-MS m/z 174

(M+).

1-(Trifluoromethyl)naphthalene54

1 H NMR (500 MHz, CDCl3) δ 8.24 (d, J = 9.4 Hz, 1H), 8.06 (d, J = 8.3 Hz, 1H), 7.97-

19 7.89 (m, 2H), 7.69-7.59 (m, 2H), 7.54 (t, J = 7.8 Hz, 1H). F NMR (470 MHz, CDCl3) δ

13 -59.74 (s, 3F). C NMR (126 MHz, CDCl3) δ 133.9, 132.8, 129.0, 128.8, 127.7, 126.6,

126.1 (q, J = 30.1 Hz), 124.8 (q, J = 273.5 Hz), 124.7 (q, J = 6.0 Hz), 124.3 (q, J = 2.5

Hz), 124.2. GC-MS m/z 196 (M+).

2-(Trifluoromethyl)naphthalene25

1 19 H NMR (500 MHz, CDCl3) δ 8.19 (s, 1H), 8.02-7.91 (m, 3H), 7.72-7.57 (m, 3H). F

13 NMR (470 MHz, CDCl3) δ -62.25 (s, 3F). C NMR (126 MHz, CDCl3) δ 134.6, 132.2,

129.0, 128.8, 128.1, 127.9, 127.2, 125.7 (q, J = 4.5 Hz), 124.4 (q, J = 272.1 Hz), 121.5

(q, J = 3.1 Hz). GC-MS m/z 196 (M+).

131

1-Methyl-4-(trifluoromethyl)naphthalene55

1 H NMR (500 MHz, CDCl3) δ 8.26-8.20 (m, 1H), 8.13-8.10 (m, 1H), 7.79 (d, J = 7.4 Hz,

1H), 7.69-7.62 (m, 2H), 7.38 (d, J = 7.4 Hz, 1H), 2.78 (s, 3H). 19F NMR (470 MHz,

13 CDCl3) δ -59.31 (s, 3F). C NMR (126 MHz, CDCl3) δ 139.6, 133.0, 129.0, 127.2,

126.4, 125.0, 124.9 (q, J = 273.1 Hz), 124.8, 124.7, 124.5 (q, J = 6.0 Hz), 20.0. GC-MS m/z 210 (M+).

Methoxy-6-(trifluoromethyl)naphthalene25

1 H NMR (500 MHz, CDCl3) δ 8.09 (s, 1H), 7.90-7.80 (m, 2H), 7.63 (d, J = 8.6 Hz,1H),

7.26 (dd, J = 9.0, 2.5 Hz, 1H), 7.20 (d, J = 2.4 Hz, 1H), 3.98 (s, 3H). 19F NMR (470

13 MHz, CDCl3) δ -61.88 (s, 3F). C NMR (126 MHz, CDCl3) δ 159.3, 136.1, 130.3, 127.7,

127.6, 125.5 (q, J = 32.2 Hz), 125.4 (q, J = 4.4 Hz),124.6 (q, J = 271.9 Hz), 122.0 (q, J =

3.2 Hz), 120.2, 105.7, 55.4. GC-MS m/z 226 (M+).

1-(Benzyloxy)-4-(trifluoromethyl)benzene56 132

1 H NMR (500 MHz, CDCl3) δ 7.58 (d, J = 8.6 Hz, 2H), 7.50-7.32 (m, 5H), 7.06 (d, J =

19 13 8.6 Hz, 2H), 5.14 (s, 2H). F NMR (470 MHz, CDCl3) δ -61.48 (s, 3F). C NMR (126

MHz, CDCl3) δ 161.2, 136.3, 128.8, 128.3, 127.5, 127.0 (q, J = 3.7 Hz), 124.5 (q, J =

271.1 Hz). 123.1 (q, J = 32.7 Hz), 114.9, 70.2. GC-MS m/z 252 (M+).

1-(Benzyloxy)-3-(trifluoromethyl)benzene54

1 H NMR (500 MHz, CDCl3) δ 7.50-7.33 (m, 6H), 7.27-7.22 (m, 2H), 7.16 (dd, J = 8.3,

19 13 2.1 Hz, 1H), 5.12 (s, 2H). F NMR (470 MHz, CDCl3) δ -62.69 (s, 3F). C NMR (126

MHz, CDCl3) δ 158.9, 136.3, 131.9 (q, J = 32.3 Hz), 130.0, 128.7, 128.3, 127.6, 124.0 (q,

J = 272.3 Hz), 118.3, 117.7 (q, J = 3.9 Hz), 111.8 (q, J = 3.7 Hz), 70.3. GC-MS m/z 252

(M+).

Phenoxy-4-(trifluoromethyl)benzene18

133

1 H NMR (500 MHz, CDCl3) δ 7.60 (d, J = 8.7 Hz, 2H), 7.45-7.39 (m, 2H), 7.22 (t, J =

19 13 7.4 Hz, 1H), 7.08 (t, J = 8.0 Hz, 4H). F NMR (470 MHz, CDCl3) δ -61.74 (s, 3F). C

NMR (126 MHz, CDCl3) δ 160.5, 155.7, 130.1, 127.1 (q, J = 3.7 Hz), 124.9 (q, J = 32.6

Hz), 124.5, 124.2 (q, J = 271.4 Hz), 119.9, 117.9. GC-MS m/z 238 (M+).

1,2-Dimethoxy-4-(trifluoromethyl)benzene57

1 H NMR (500 MHz, CDCl3) δ 7.24 (dd, J = 8.4, 1.0 Hz, 1H), 7.10 (d, J = 1.9 Hz, 1H),

19 6.94 (d, J = 8.4 Hz, 1H), 3.95 (d, J = 1.4 Hz, 6H). F NMR (470 MHz, CDCl3) δ -61.54

13 (s, 3F). C NMR (126 MHz, CDCl3) δ 151.6, 149.1, 124.3 (q, J = 271.3 Hz), 122.9 (q, J

= 32.7 Hz), 118.4 (q, J = 4.2 Hz), 110.6, 108.0 (q, J = 3.4 Hz), 56.1, 56.0. GC-MS m/z

206 (M+).

4-Trifluoromethylanisole52

1 H NMR (500 MHz, CDCl3) δ 7.58 (d, J = 8.5 Hz, 2H), 6.99 (d, J = 8.5 Hz, 2H), 3.88 (s,

19 13 3H). F NMR (470 MHz, CDCl3) δ -61.50 (s, 3F). C NMR (126 MHz, CDCl3) δ 162.0, 134

126.9 (q, J = 3.8 Hz), 124.5 (q, J = 270.9 Hz), 122.9 (q, J = 32.7 Hz), 114.0, 55.5. GC-

MS m/z 176 (M+).

Methyl 3-(trifluoromethyl)benzoate57

CF3

MeOOC

1 H NMR (400 MHz, CDCl3) δ 8.33 (s, 1H), 8.25 (d, J = 7.8 Hz, 1H), 7.84 (d, J = 7.8 Hz,

19 1H), 7.61 (t, J = 7.8 Hz, 1H), 3.98 (s, 3H). F NMR (376 MHz, CDCl3) δ -62.86 (s, 3F).

13 C NMR (101 MHz, CDCl3) δ 165.8, 132.8 (q, J = 1.1 Hz), 131.1 (q, J = 33.0 Hz),

131.0, 129.4 (q, J = 3.7 Hz), 129.0, 126.5 (q, J = 3.9 Hz), 123.7 (q, J = 272.3 Hz), 52.5.

GC-MS m/z 204 (M+).

Ethyl 3-(trifluoromethyl)benzoate58

1 H NMR (400 MHz, CDCl3) δ 8.33 (s, 1H), 8.25 (d, J = 7.8 Hz, 1H), 7.83 (d, J = 7.8 Hz,

1H), 7.61 (t, J = 7.8 Hz, 1H), 4.44 (q, J = 7.1 Hz, 2H), 1.44 (t, J = 7.1 Hz, 3H). 19F NMR

13 (376 MHz, CDCl3) δ -62.83 (s, 3F). C NMR (101 MHz, CDCl3) δ 165.3, 132.8 (q, J =

1.2 Hz), 131.4, 131.0 (q, J = 32.9 Hz), 129.3 (q, J = 3.7 Hz), 129.0, 126.5 (q, J = 3.9 Hz),

123.7 (q, J = 272.4 Hz), 61.5, 14.2. GC-MS m/z 218 (M+). 135

1-(4-(Trifluoromethyl)phenyl)ethanone25

1 H NMR (400 MHz, CDCl3) δ 8.08 (d, J = 8.0 Hz, 2H), 7.75 (d, J = 8.0 Hz, 2H), 2.67 (s,

19 13 3H). F NMR (376 MHz, CDCl3) δ -63.15 (s, 3F). C NMR (101 MHz, CDCl3) δ 197.0,

139.7 (q, J = 1.1 Hz), 134.4 (q, J = 32.7 Hz), 128.6, 125.7 (q, J = 3.8 Hz), 123.6 (q, J =

272.6 Hz), 26.8. GC-MS m/z 188 (M+).

4-(Trifluoromethyl)benzaldehyde59

1 H NMR (400 MHz, CDCl3) δ 10.13 (s, 1H), 8.03 (d, J = 7.8 Hz, 2H), 7.83 (d, J = 7.8

19 13 Hz, 2H). F NMR (376 MHz, CDCl3) δ -63.20 (s, 3F). C NMR (101 MHz, CDCl3) δ

191.1, 138.7 (q, J = 1.2 Hz), 135.6 (q, J = 32.7 Hz), 129.9, 126.1 (q, J = 3.8 Hz), 123.4

(q, J = 272.9 Hz). GC-MS m/z 174 (M+).

1-Chloro-4-(trifluoromethyl)benzene57

136

1 19 H NMR (500 MHz, CDCl3) δ 7.59 (d, J = 8.3 Hz, 2H), 7.49 (d, J = 8.3 Hz, 2H). F

13 NMR (470 MHz, CDCl3) δ -62.63 (s, 3F). C NMR (126 MHz, CDCl3) δ 138.1, 129.1,

129.0 (q, J = 33.3 Hz), 126.8 (q, J = 3.7 Hz), 123.8 (q, J = 272.1 Hz). GC-MS m/z 180

(M+).

2.2.4 Proposed mechanism copper-catalyzed electrophilic trifluoromethylation of organometallic compounds

N Cu L N RM RCF 3 A

CF3 LM LM N Cu R N B

O O R: R' S Ar M: BF3KorNa Ar

Scheme 2.4 A possible mechanism for copper-catalyzed electrophilic trifluoromethylation of organometallic compounds.

137

We proposed a mechanism for the copper-catalyzed electrophilic trifluoromethylation of organometallic compounds which include the alkynyltrifluoroborates, sodium arylsulfinate, and potassium aryltrifluoroborates as shown in Scheme 2.4. Ligation of copper source with nitrogen-containing ligand forms the intermediate A in situ.

Subsequently, it will undergo the transmetallation process with the organometallic

+ compounds to form intermediate B. Nucleophilic attack of the R part of B at the CF3 moiety is proposed to occur next to form the desired product and the catalytic species complex A.

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Chapter 3

Exploiting Cu/Cu2O Nanowires with Novel Catalytic Reactivity:

Application for C-S Bond Cross-Coupling Reaction and CuAAC

Reaction 3.1 Introduction

The catalysis of nanostructured materials is one of the most appealing for the organic transformations, particularly due to the goals of ‘green and sustainable catalysis’.1 The nanocatalysts are nanoscale materials which have at least one nanoscale dimension. The discovery of the transition metal catalyzed methodology has been a considerable advance for organic chemistry. However, the issues of recovery and pollution of catalysts and ligands were still not solved which are extremely important for the pharmaceutical industry. The nano-sized catalysts can be simply separated from the reaction mixture because of their insolubility and thus they can be used recycled. The amount of metal remaining in solution is in the ppm range. Notably, because of the high reactivities of nano-sized metal catalysts, the use of ligands can be avoided and the catalysts loadings can be reduced greatly.2

As a result of these reasons, nanocatalysts show better reactivity than the conventional catalysts and have wider applications in many fields.3

On the other hand, much advances have been made in the synthesis and the catalytic applications of nanostructured materials in recent years. A variety of organic transformations have been achieved using all kinds of nanostructured catalysts (Scheme

3.1). The catalytic performance, selectivity, and reusability of nanostructured materials rely on the size, shape, composition, as well as their interaction with the support.

In general, transition metal nanoparticles (MNP) are thermodynamically unstable, so stabilizers with the aim of preventing aggregation of the nanoparticles is necessary. A 147 wide range of heterogeneous nanocatalysts have been designed and fabricated typically employing metals such as gold, palladium, platinum, silver or copper on various high surface area support materials including carbon,4 silica,5 alumina,6 titanium dioxide,7 and zeolites (Scheme 3.1).

148

OH Pd nanocrystal +H2 (3 bar) o H2O, 60 C OH

Pd NPs/SBA-15 R Br + B(OH)2 R EtOH/H2O(1:3) o K2CO3,85 C

Pt@Fe2O3 nanowires O

o CH3CN, 70 C H O2(1 bar), 24h

Pt NPs/alumina O room temperature H OH O O R +H2 (70 bar) R O O 75-80% ee R=Et, Me HO N

Au NPs/MoOx

K2CO3,CH3CN OH o 80 C, O2 (1bar) O R1 R2 R1 R2

Ag NPs@CeO2 o NO2 Dodecane, 110 C NH2 + H2 (6 bar)

Fe3O4/Pd NPs O O X Toluene, NaOtBu, 80oC + Ph N N Ph

Ph Ph 33-85% ee OH HO

Scheme 3.1 Selected examples of the metal based nanocatalysts for the organic transformations. 149

However, with the aim to cost effective, copper catalytic system has been emerging alternative with similar efficiency to the above mentioned metals, particularly copper nanoparticles (NPs) in the form of metal or metal oxides have been widely developed for the various organic transformations under ligand-free condition.8

I SH Cu NPs (20%) S R1 + R2 R1 R2 (1) K2CO3,DMF MW, 120oC, 5-7 min

X OH Cu NPs (10%) O R1 + R2 R1 R2 (2) Cs2CO3,CH3CN 50-60oC X B(OH) 2 Cu/Pd nanocluster(2%) R1 + R2 (3) o 1 2 K2CO3, DMF, 110 C R R

I Cu bronze NPs (3%) R1 + R1 (4) CO2Bu TBAB, TBAA, 130oC CO2Bu PhSeSePh I Br Cu NPs (20%) SePh SePh R or R R or R (5) Zn, H2O, reflux

Scheme 3.2 Typical protocols of the Cu nanostructured material catalyzed transformations under the ligands free condition.

Ranu and co-workers have developed a procedure for the reaction of aryl iodides with thiophenols and alkanethiols using Cu NPs as catalyst without the addition of ligand.9 A range of function groups can be tolerated and the desired products were afforded in excellent yields. A reasonable radical mechanism has been proposed (Scheme 3.2, Eq.1). 150

Recyclable Cu-nanoparticles catalyzed O-arylation of phenols with aryl halides has been reported by Kidwaia and co-workers.10 This catalytic system showed superior results such as recyclability, additives or cofactors free, lower catalyst loading, broader substrate

X OH O Cu2O nanocubes R1 + R2 R1 R2 (1) Cs2CO3,THF 150oC I Cu2O NPs (10%) 1 + 1 R R (2) CO2Bu TMAB,DMF,120oC CO2Bu R1 O R2 R1 CuO NPs(5%) + R2 o (3) CH2Cl2,60 C NH2 N

X CuO NPs (2%) SePh R + PhSeSePh R (4) KOH, DMSO 110oC

I SH CuO NPs (1.26%) S R1 + R2 R1 R2 (5) KOH, DMSO, 80oC

R1 N N CuO NPs (1.26%) R1 N + 2 (6) N N N R o THF, H2O, 60 C R2

Scheme 3.3 Selected protocols of the Cu(I) and Cu(II) oxide nanostructured material catalyzed transformations under the ligands free condition.

compatibility, and shorter reaction times (Scheme 3.2, Eq.2). The system of multi- metallic nanocluster improved the catalytic performance of Suzuki cross-coupling because it’s structure has been dramatically changed after the incorporation of different 151 metals as reported by Thathagar and co-workers (Scheme 3.2, Eq.3).11 Calo and co- workers have developed the Heck type reaction using nano Cu-bronze as a catalyst in ionic liquid.12 These NPs are very stable and easily recycled and they showed the prospect of an alternative to noble metal catalysts (Scheme 3.2, Eq.4). Saha and co- workers have reported a powerful process for the preparation of aryl- and vinyl-selenides employing Cu NPs from aryl iodide/vinyl bromide with diphenyl selenide in the presence

13 of zinc and H2O. The catalyst can be recycled and reused for four times without much loss the reactivity (Scheme 3.2, Eq.5).

Cu in the form of oxides has drawn much more attention due to its high air and thermal stability. Both Cu(I) and Cu(II) oxides have been regarded as powerful catalysts for many organic reactions.

Kim and co-workers have reported the reaction of aryl halides with phenols using

14 thermal and air-stable uniform Cu2O nanocubes. This process is simple and shows the power of recyclability of the catalyst (Scheme 3.3, Eq.1). Peng and co-workers have studied a ligand-free Cu-catalyzed Heck reaction.15 A variety of aryl iodides and olefins can be applied in this protocol. Notably, a set of the respective E-internal olefins were afforded selectively in moderate to good yields (Scheme 3.3, Eq.2). Nezhad and co- workers reported the one-pot Friedlander quinoline synthesis by using CuO NPs as an efficient and reusable catalyst.16 The current protocol showed superior properties due to the safe, nonvolatile, noncorrosive catalyst and the easy recovery of catalyst. The desired products are afforded generally in excellent yields under mild reaction conditions

(Scheme 3.3, Eq.3). Reddy and co-worker reported a novel process for the cross-coupling 152 of aryl halides with diaryl diselenides by employing a recyclable CuO NPs as a catalyst.17

The catalyst can be simply recovered and reused (Scheme 3.3, Eq.4). Punniyamurthy and co-workers have reported a pretty efficient C-S cross-coupling reaction of aryl and alkyl thiols with iodobenzene by employing inexpensive, and air stable CuO nanoparticles as a catalyst (Scheme 3.3, Eq.5).18 Song and co-workers reported an excellent example of

Huisgen cycloaddition reaction of azides and acetylenes in the presence of a recyclable

CuO NPs as a catalyst.19 This reaction can be conducted under open flask and a variety of functional groups are compatible with this procedure. Notably, the catalytic activity of Cu species can be significantly improved by controlling the particle size (Scheme 3.3, Eq.6).

Although the Cu based NPs has been found to be very effective for numerous catalytic reactions, there are still several challenges in the area of Cu based nanocatalysis that need to be resolved, such as the loss of catalytic activity because of sintering and leaching of soluble species into the reaction systems. The design and development of novel nanostructured materials with the aim to improving the efficacy of nanocatalysts and to addressing the related challenges are still highly desirable.

3.2 Results and discussion

3.2.1 Efficient C-S cross-coupling reactions catalyzed by novel core-shell structured

20 Cu/Cu2O nanowires

The popularity of C-S bonds in various biologically and pharmaceutically active compounds and polymeric materials have led C-S coupling to become more attractive in organic synthesis.21 The ligand-assisted homogeneous transition metals such as 153 palladium, nickel, and copper et al could catalyze such coupling reaction under relatively mild reaction condition.22 However, the presence of the ligands often suffer from their toxic and boring process for the synthesis, and thus limit their utilization in large-scale processes. As a consequence, the development of alternative catalytic systems with relatively inexpensive catalysts, mild reaction conditions, low catalyst loadings, or ligand-free are still highly desirable.

On the other hand, nanostructured materials have been employed broadly as catalysts due to their high catalytic reactivity.1a, 23 More importantly, they can fulfill these above mentioned conditions. Recently, Cu, Cu2O, and CuO nanoparticles as heterogeneous catalysts have been studied and afforded a green and environmentally friendly approach to C-S cross-coupling reactions, exhibiting their advantages in catalytic efficiency, product separation/purification, and recyclability.24 However, to date, the present Cu- based nanostructured catalysts have been dominated by granular nanoparticles with particle size in the range of 5-60 nm.24 Herein, we report that readily available and recyclable core-shell structured Cu/Cu2O nanowires catalyze the C-S formation reaction of aryl and alkyl thiols with aryl iodide. To the best of our knowledge, this reaction is the first case of the use of one-dimensional (1D) copper nanowires for the catalysis of C-S bond cross-coupling.

The overall procedure for the preparation of core-shell Cu/Cu2O nanowires is illustrated in Fig. 1A. Initially, Cu foam was heated at 440°C in the forming gas (20% O2 in N2) to produce CuO nanowires, which acted as sacrificial templates for the subsequent phase transformation. Scanning electron microscopy (SEM) investigation showed that dense straight CuO nanowires were anchored on the three-dimensional (3D) struts (Fig. 154

1B), preserving the origin spatial configuration derived from Cu foam. The size distribution of nanowires was relatively uniform possessing the diameter in the range of

40-60 nm and the length of 3-10 μm (Figure 1C). The subsequent reduction/passivation processes resulted in the core-shell Cu/Cu2O nanowires.

Figure 3.1 (A) Schematic illustration showing the general procedure for the preparation of Cu/Cu2O nanowires; SEM images of (B), (C) CuO nanowires, and (D), (E) Cu/Cu2O.

155

From high-resolution transmission electron microscopy (HRTEM) image (Fig. 2A), the CuO nanowires were found to be dominated by monoclinic phase of CuO crystal, with the lattice spacing of 2.52 Å corresponding to CuO [11ī] plane. The electron energy- loss spectroscopy (EELS) curve of point 1 in the center of CuO nanowire also exhibited the characteristic peak of CuO signal (Fig. 2C, E).25 A large number of nanowires were imaged randomly and the results showed all nanowires were in a cupric oxide phase with no exception. Fig. 2B reveals that the Cu/Cu2O nanowire possessed a core-shell structure, where the shell with a layer thickness of about 3 nm covered the whole core. The lattice spacing of the shell was 2.47 Å, which corresponded to the Cu2O [111] fringe; the spacing of 1.81 Å in the core of the nanowire was consistent with the Cu [200] plane. The

EELS spectra, whose information originated from point 2 and 3, indicated the characteristic signals of metallic copper and cuprous oxide, respectively (Fig. 2D, E), confirming the core-shell structure of Cu/Cu2O nanowires. The formation of Cu2O shell is considered to arise from the passivation of metallic Cu. X-ray diffraction (XRD) patterns of blank Cu foam in Figure 3A-a displayed the diffraction peaks of metallic Cu

[111] and [200] planes (JCPDS 04-0836, marked with squares), respectively.

156

Figure 3.2 HRTEM/TEM images of individual (A), (C) CuO nanowire and (B), (D)

Cu/Cu2O nanowire; (E) The EELS spectra 1, 2 and 3 correspond to the areas marked with circles in (C) and (D), respectively.

157

Figure 3.3 (A) XRD patterns and (B) Raman spectra of (a) blank Cu foam, (b) CuO nanowires, and (c) Cu/Cu2O nanowires.

For the sample CuO nanowires (Figure 3A-b), besides the characteristic peaks of CuO

(JCPDS 48-1548, marked with diamonds), Cu and Cu2O peaks (JCPDS 05-0667, marked with triangles) were also detected. Since only CuO phase was observed in the nanowires by HRTEM, the phases Cu and Cu2O were suggested to be from the substrate, in agreement with the results reported previously.26 Figure 3A-c shows that both Cu and

Cu2O phases were present in the sample Cu/Cu2O nanowires. The most intense diffraction peak [111] of Cu2O was discernible and broadened, suggesting the presence of nano-sized Cu2O layer in Cu/Cu2O nanowires, which was consistent with HRTEM observation. The compositions of blank Cu foam, CuO nanowires and Cu/Cu2O nanowires were further studied by Raman spectroscopy. From Figure 3B-a, it can be 158 seen that there showed no Raman peak for blank Cu foam. Both Cu2O and CuO coexisted in the sample CuO nanowires (Figure 3B-b), whereas only Cu2O peaks were found for

27 Cu/Cu2O nanowires (Figure 3B-c), which agreed well with the XRD results.

With this novel core-shell structured Cu/Cu2O nanowires in hand, the reaciton of 4- iodotoluene and 1-octanethiol was chosen as a model reaciton to test their catalytic activity as part of our continuous efforts in the area of C-S bond cross-coupling.28

Table 3.1 The C-S cross-coupling over different Cu-based catalysts.

a Reaction conditions: loading amount of active components for Cu-based catalyst

(0.0072 mmol, 0.72 mol%), 4-iodotoluene (1.0 mmol), 1-octanethiol (1.2 mmol), Cs2CO3

(1.5 mmol) in 4.0 mL DMSO, at 110 °C for 12 h. b Surface area (m2/g): Cu foam: 0.2;

c CuO nanowires: 40.2; Cu/Cu2O nanowires: 41.1. Isolated yield.

Initially, with the aim of further insight into the reaction catalyzed by nanowires, both Cu/Cu2O nanowires and CuO nanowire were subjected to the C-S coupling reaction and compared with the copper foam employing Cs2CO3 as the base and 159

DMSO as the solvent at 110°C. The control experiment showed that low yield was obtained over blank Cu foam while the lower activities may arise from its low specific surface area (Table 3.1, entry 1). Notably, the catalytic activities were highly depended on the components of the catalysts. Core-shell structured Cu/Cu2O nanowires (Table 3.1, entries 3) afforded the desired product in 92 % yields, which are much higher than single-component CuO nanowires (Table 3.1, entries 2). It is generally proposed that Ullmann-type cross-coupling reactions may occur via oxidative addition/reductive elimination involving Cu(I)/Cu(III) catalytic cycles.29

The possible process is oxidative addition of aryl halide to Cu(I) complex forms

Cu(III) intermediate, which conducts the reaction with nucleophile through reductive elimination to produce thiolation product and release Cu(I) species.29 As a result, cuprous catalysts show superior activity over counterpart species in C-S coupling reaction. Furthermore, the higher activity of Cu/Cu2O nanowires is presumably attributed to the unique spatial configuration. The Cu2O shells supported by Cu cores remain independent extension from 3D foam-like substrate, which make these

Cu/Cu2O nanowires more accessible to the reactant molecules. On the other hand, for

Cu/Cu2O core-shell structured catalysts, the Cu core as electron reservoir facilitates the formation and transformation of Cu(III) intermediate,30 resulting in high activities in the C-S cross-coupling reactions. Therefore, profited from the synergetic effect of the special core-shell structures and their advanced spatial configuration, Cu/Cu2O nanowires showed the best catalytic activity compared to the single-component of

CuO nanowire catalysts.

Next, we investigated the substrate scopes with respect to aryl iodides and thiols 160 under the optimal reaction conditions. It was found that this protocol was not sentive to the elctoron properties of the substrates in which both electron rich and electron poor substituents could be tolerated (Table 3.2, entries 1-4). It was also observed that cross-coupling reactions of fluro- and chloro-substituted aryl iodides proceeded exclusively at the iodo- substituted position (Table 3.2, entries 2 and 3). Sterically hindered ortho- substituents did not hamper the arylation reaction and the corresponding thioethers were isolated with good yields (Table 3.2, entries 6, and 8).

Even more sterically hindered substrate such as 2- iodo-1,3,5-trimethylbenzene was also proved to be good substrates (Table 3.2, entry 8). In the case of aryl thiols, the presence of electron rich and electron deficient groups in the phenyl did not cause significant changes in yields (Table 3.2, entries 9-12). Introduction of the naphthalene into the sulfide was also achieved with naphthalenethiol (Table 3.2, entry 12). The reaction could be scaled up to a gram scale with an excellent yield

(Table 3.2, entry 4).

Table 3.2 Cu/Cu2O nanowires catalyzing the coupling reactions of aryl iodides with thiols.

161

162

Table 3.3 Recycling of Cu/Cu2O nanowires for the reaction of 4-iodotoluene and 1- octanethiol.

Run 1st 2nd 3rd 4th 5th

Yield [%]b 92 99 99 98 95 aThe recovered catalyst was used under the same reaction conditions with those for the first run. bIsolated yield.

Figure 3.4 TEM images of the catalyst Cu/Cu2O nanowires after reactions. A) after the first run. B) after the fifth run.

The Cu/Cu2O nanowires catalysts could be conveniently recycled and reused. The catalyst was recovered by simple centrifugation and reused for the reaction of 4- iodotoluene and 1-octanethiol. The results in Table 3.3 showed that the catalyst was 163 recycled over five runs without loss of activities. It is noteworthy that the catalytic activities increased from 92 % yield in the first run to 99 % in the second run and were then kept stable in the following runs (99-95 %). The TEM image of the catalyst after the first run showed that Cu2O layer become hump shell along the core from initial uniform layer (Figure 3.4). This implies that favorable changes of the shape of active shells occurred in the reaction environment, resulting in the increased activity with respect to the fresh catalyst. After the fifth runs, the morphology of the catalyst was found to be almost the same to that after the first run, indicative of the stability of the active sites during multiple catalytic trials (Figure 3.4).

In summary, we have studied that a novel, recyclable Cu/Cu2O nanowires could be applied as a highly reactive catalysts for the cross-coupling reaction between aryl iodides and thiols under ligand-free conditions. The catalyst can be separated easily and recycled for five times without loss of catalytic activity.

3.2.1.1 Experimental

3.2.1.1.1 General

Copper foam was purchased from Lyrun Co. (purity > 99.9%). Cu foam was treated with methanol, isopropanol, and deionized water in turn and then dried under Ar atmosphere and stored in glove-box for use. Field-emission scanning electron microscopy

(SEM) pictures were taken by a FEI Quanta 600 FEG, and the acceleration voltage was 5 kV. High-resolution transmission electron microscopy (HRTEM) images were obtained using a Titan ST microscope (FEI Co.) operating at 300 kV. The electron energy-loss spectroscopy (EELS) analyses were carried out in this microscope with 150 µm C2 164 aperture, spot size 6, 29.6 mm camera length, 5 mm entrance aperture (collection angle β

= 54 mrad) and 1 s collection time. XRD was performed with Cu Ka radiation (λ =

1.54056 Å) on a Bruker D8 X-ray diffractometer. Raman spectroscopy measurements were carried out on a Horiba Aramis confocal microprobe Raman instrument with He-Ne laser (λ = 632.8 nm) at ~ 0.5 mW incident power.

3.2.1.1.2 Preparation and Characterization of Cu-based catalysts

Preparing CuO nanowires: The as-cleaned Cu foam was heated from room

-1 temperature to 440 °C (heating rate 2 °C min ) in the forming gas (20% O2 in N2) with flow rate of 5 ml min-1 and was kept at this temperature for 3 h. After cooling down to room temperature in air, as-obtained CuO nanowires were stored in glovebox for use.

Preparing Cu/Cu2O nanowires: Using CuO nanowires as initial materials, they were

-1 heated from room temperature to 110 °C (heating rate 0.4 °C min ) in pure H2 (purity

99.999%) with flow rate of 200 ml min-1 and were kept at this temperature for 3 h.

After cooling down to room temperature in H2, as-reduced sample was exposed in air for 15 min to obtain Cu/Cu2O nanowires, which were stored in glove-box for use. 165

3.2.1.1.3 Typical procedure for the C-S bond cross-coupling in the presence of a core- shell structured Cu/Cu2O nanowires

A 15 mL sealed tube equipped with a magnetic stir bar was charged with base (1.5

-3 mmol). Cu2O nanowires on copper foam (7.2 × 10 mmol), 1-octanethiol (1.2 mmol), 4- iodotoluene (1.00 mmol) and DMSO (4.0 mL) were added into the sealed tube, and the it was stirring at 110 °C. After filtration, extraction, washing by water and dried over magnesium sulfate, the target product was isolated by column chromatography.

3.2.1.1.4 General procedure of the recycle process for the C-S bond cross-coupling reaction

After each cycle, the reaction mixture was allowed to cool down to ambient temperature, and the catalyst was recovered by simple centrifugation followed by decantation, and then washed by ethyl acetate. The same operation with ethyl acetate was repeated five times. The recovered catalyst was used directly in the next cycle and the reaction was performed with fresh solvent and reactants under the identical conditions.

4-Methylphenyl octyl sulfide31

1 H NMR (400MHz, CDCl3): δ ppm 7.22 (d, J = 8.4 Hz, 2 H), 7.07 (d, J = 8.4 Hz, 2 H),

2.85 (t, J = 7.2 Hz, 2 H), 2.30 (s, 3 H), 1.63-1.23 (m, 12 H), 0.86 (t, J = 6.8 Hz, 3 H). 13C 166

NMR (101 MHz, CDCl3): δ ppm 135.8, 133.2, 129.8, 129.6, 34.4, 31.9, 29.3, 29.2, 29.1,

28.8, 22.8, 21.0, 14.1.

Octyl(3-(trifluoromethyl)phenyl)sulfane32

1 H NMR (400 MHz, CDCl3): δ ppm 7.47-7.28 (m, 3H), 7.19 (s, 1H), 2.90 (t, J = 7.6 Hz,

13 2 H), 1.68-1.15 (m, 12H), 0.81 (t, J = 6.8, 3H). C NMR (101 MHz, CDCl3): δ ppm

137.1, 131.8, 129.9, 126.8, 126.7, 125.2, 122.5, 39.2, 33.2, 31.8, 29.2, 28.9, 28.6, 22.6,

19 14.1. F NMR (377 MHz, CDCl3): δ ppm -62.8.

(4-Fluorophenyl)(octyl)sulfane33

1 H NMR (400 MHz, CDCl3): δ ppm 7.19 (t, J = 3.2, 2H), 7.14-7.07 (m, 2H), 2.90 (t, J =

13 7.6 Hz, 2 H), 1.68-1.20 (m, 12H), 0.81 (t, J = 6.8, 3H). C NMR (101 MHz, CDCl3): δ ppm 162.8, 160.4, 137.7, 131.9, 130.3, 115.9, 35.0, 33.2, 31.8, 29.2, 29.1, 28.8, 22.6,

19 14.1. F NMR (377 MHz, CDCl3): δ ppm -116.2.

(3-Chlorophenyl)(octyl)sulfane34 167

1 H NMR (400 MHz, CDCl3): δ ppm 7.19 (t, J = 3.2, 1H), 7.14-7.07 (m, 2H), 7.04 (dt, J =

7.0, 2.1, 1H), 2.90 (t, J = 7.6 Hz, 2H), 1.63-1.13 (m, 12H), 0.81 (t, J = 6.8, 3H). 13C NMR

(101 MHz, CDCl3): δ ppm 139.5, 134.8, 129.9, 127.9, 126.4, 125.5, 39.2, 33.2, 31.8,

31.7, 29.1, 28.8, 22.6, 14.1.

(4-Nitrophenyl)(octyl)sulfane 33

1 H NMR (400 MHz, CDCl3): δ ppm 8.14-7.96 (m, 2H), 7.33-7.15 (m, 2H), 3.02-2.83 (m,

13 2H), 1.71-1.11 (m, 12H), 0.81 (t, J = 6.8, 3H). C NMR (101 MHz, CDCl3): δ ppm

148.2, 144.8, 127.0, 126.9, 126.0, 123.9, 39.2, 31.9, 31.7, 29.2, 29.0, 28.5, 22.6, 14.1.

Octyl(phenyl)sulfane 31

1 H NMR (400 MHz, CDCl3): δ ppm 7.25-7.20 (m, 5H), 2.82 (t, J = 8.0 Hz, 2H), 1.61-

13 1.12 (m, 12H), 0.80 (t, J = 6.8, 3H). C NMR (101 MHz, CDCl3): δ ppm 137.1, 128.9,

128.8, 125.6, 33.6, 31.8, 29.3, 29.2, 28.9, 22.7, 14.1. 168

Octyl(o-tolyl)sulfane 33

1 H NMR (400 MHz, CDCl3): δ ppm 7.20-6.94 (m, 4H), 2.80 (t, J = 7.2 Hz, 2 H), 2.29 (s,

13 3H), 1.63-1.13 (m, 12H), 0.80 (t, J = 6.8, 3H). C NMR (101 MHz, CDCl3): δ ppm

137.2, 136.5, 130.0, 127.3, 126.3, 125.2, 39.3, 32.8, 31.8, 29.2, 29.0, 28.6, 22.7, 20.3,

14.1.

(3,5-Dimethylphenyl)(octyl)sulfane 33

1 H NMR (400 MHz, CDCl3): δ ppm 6.83 (s, 3H), 2.63-2.56 (m, 3H), 2.55-2.48 (m, 3H),

2.42 (s, 1H), 2.17 (s, 1H), 1.63-1.12 (m, 12H), 0.81 (t, J = 6.8, 3H). 13C NMR (101 MHz,

CDCl3): δ ppm 142.9, 137.7, 130.7, 128.9, 36.6, 31.6, 30.0, 29.3, 29.0, 28.6, 22.7, 22.0,

20.9, 14.1.

Mesityl(octyl)sulfane 169

1 H NMR (400 MHz, CDCl3): δ ppm 6.83 (s, 2H), 2.63-2.56 (m, 3H), 2.55-2.48 (m, 3H),

2.42 (s, 3H), 2.17 (s, 2H), 1.62-1.12 (m, 12 H), 0.81 (t, J = 6.8, 3H). 13C NMR (101 MHz,

CDCl3): δ ppm 142.9, 137.7, 130.7, 128.9, 39.3, 35.6, 31.9, 30.0, 29.2, 29.0, 28.6, 22.7,

22.0, 21.0, 14.1. HRMS: calculated for C17H28S: 264.04648; found: 264.04496.

(2-Methoxyphenyl)(p-tolyl)sulfane 35

1 H NMR (500 MHz, CDCl3): δ ppm 7.33 (d, J = 7.7 Hz, 2 H), 7.19-7.15 (m, 3 H), 6.93

(d, J = 7.7 Hz, 1 H), 6.88 (d, J = 7.6 Hz, 1 H), 6.84 (t, J = 8.1 Hz, 1 H), 3.90 (s, 3 H), 2.36

13 (s, 3 H). C NMR (125 MHz, CDCl3): δ ppm 156.51, 137.89, 133.13, 130.22, 129.80,

127.47, 125.79, 121.28, 110.62, 55.96, 21.30.

4-(p-Tolylthio)aniline 36

170

1 H NMR (400 MHz, CDCl3): δ ppm 7.24-7.16 (m, 2H), 6.99 (dd, J = 19.7, 8.2, 4H), 6.58

13 (m, 2H), 3.68 (s, 2H), 2.22 (s, 3H). C NMR (100MHz, CDCl3): δ ppm 146.7, 135.6,

135.5, 135.3, 129.7, 128.4, 121.9, 115.8, 21.0.

(2,4-Difluorophenyl)(p-tolyl)sulfane

1 H NMR (500 MHz, CDCl3): δ ppm 7.30-7.24 (m, 3 H), 7.15-7.13 (m, 2 H), 6.90-6.83

13 (m, 2 H), 2.35 (s, 3 H). C NMR (125 MHz, CDCl3): δ ppm 163.75 (d, J = 11.15 Hz),

162.44 (d, J = 12.29 Hz), 161.76 (d, J = 10.68 Hz), 160.45 (d, J = 11.86 Hz), 137.71 (s),

134.61 (dd, J = 9.38 Hz), 131.23 (s), 130.61 (s), 130.24 (s), 118.87 (dd, J = 18.27 Hz),

112.16 (dd, J = 21.64 Hz), 104.69 (t, J = 26.53 Hz), 21.23 (s). 19F NMR (377 MHz,

CDCl3): δ ppm -103.92 (m, 1F), -110.08 (m, 1F). HRMS: calculated for C13H10F2S:

236.04713; found: 236.04589.

Naphthalen-2-yl(p-tolyl)sulfane 37

1 H NMR (500 MHz, CDCl3): δ ppm 7.87-7.85 (m, 2 H), 7.82-7.77 (m, 2 H), 7.55-7.52

(m, 2 H), 7.48-7.44 (m, 3 H), 7.23 (d, J = 7.85 Hz, 2 H), 2.44 (s, 3 H). 13C NMR (125 171

MHz, CDCl3): δ ppm 137.65, 134.42, 133.82, 132.20, 132.05, 131.42, 130.20, 128.77,

128.39, 127.93, 127.79, 127.35, 126.61, 125.98, 21.25.

3.2.2 Azide-alkyne cycloaddition reaction in water catalyzed by recoverable copper(I) oxide nanowires20

The non-catalyzed azide/alkyne cycloaddition reaction known as the Huisgen reaction has been reported by Rolf Huisgen for the synthesis of 1,2,3-triazoles with the formation of a mixture of 1,4 and 1,5-disubstitution products.38

Cu(I) catalyzed azide/alkyne cycloaddition (CuAAC) has drawn much attention due to it’s application in the quite efficient construction of the corresponding 1,4-disubstituted

[1,2,3]-triazoles as a sole regioisomer.39 This reaction run rapidly under very mild conditions, tolerates a variety of functional groups, and affords high yields.

Consequently, various applications of the CuAAC have been demonstrated in the fields of organic synthesis, polymer chemistry, chemical biology, and medicinal chemistry since it’s discovery (Scheme 3.4).39c, 40

The approaches to copper catalyst generation were summarized into two types

(Scheme 3.4). One is the reduction of copper(II) sulfate in situ by sodium ascorbate. This method represents the most reliable way for the synthesis of the triazoles due to their great simplicity. The other method is the employment of copper(I) salt (CuI, CuBr,

[Cu(MeCN)4]PF6) along with a greatly coordinating, copper(I)-stabilizing ligand, and an amine base (2,6-lutidine, triethylamine, DIPEA, or pyridine) for reactivity "tuning".

However, the production of undesired oxidative coupling side products, for example, diacetylenes, was often observed with the copper(I) salt process, and thus oxygen 172 exclusion was found to be necessary to achieve clean conversion to the desired 1,2,3- triazole product.

Nowadays, it is accepted that the CuAAC reaction is catalyzed via the Cu(I) species.

The active Cu(I) species are often formed in situ from a copper(II) salt and a reducing agent (most usually sodium ascorbate). Furthermore, the addition of ligands is shown not only to protect Cu(I) centers from oxidation but also to greatly enhance their activity.41

However, the existence of the ligands often limited with their toxic and tedious procedure for the preparation, and thus hamper their applications in large-scale processes, especially given the chemical and pharmaceutical manufacturing processes.

Thus, the development of alternative catalytic systems that avoid the use of ligand are necessary.

Scheme 3.4 Huisgen reaction and Cu(I) catalyzed azide/alkyne cycloaddition (CuAAC).

173

Scheme 3.5 Nanostructured copper catalyzed azide/alkyne cycloaddition (CuAAC).

To improve the recovery and decrease the toxic Cu and ligands contaminates, an alternative approach that overcomes the problems of homogeneous catalysis is to develop the heterogeneous catalyst. On the other hand, nanostructured materials as the heterogeneous catalysts have been widely used in organic synthesis due to their high catalytic reactivity, ligand-free condition and high reusability.1a, 23 Among them,

Cu nanoparticles (CuNPs) immobilized on a variety of supports, such as activated

42 43 44 45 carbon, Fe3N@SiO2, polyvinylpyrrolidine (PVP), and Al2O3, et al have been successfully used as catalysts for CuAAC reactions. An important advantage of the supported catalysts is that they can be easily recycled. However, unsupported CuNPs often result in aggregation during the reaction, which lead to deactivation and loss of reusability. Based on these concepts in mind and our previous work,46 herein, we report that the core-shell structured nanowires can offer high catalytic activities with reusability for click reactions in water without the addition of ligand, base or support

(Scheme 3.5). To our best knowledge, this reaction is the first example of the use of one-dimensional (1D) copper nanowires for the catalysis of CuAAC reactions. 174

The reaciton of phenylacetylene and benzyl azide in water in the presence of copper based catalysts was chosen as a model reaciton to test the catalytic activity

(Table 3.4). The control experiment showed that only trace amount of desired product can be afforded over blank Cu foam (Table 3.4, entry 1). CuO nanowire was also prepared and subjected to the current reaction, but it showed poor reactivity towards

CuAAC reaction under the reaction condition

Table 3.4 Nanostructured copper catalyzed azide/alkyne cycloaddition (CuAAC).

N N N N Copper-based catalyst + 3 Distilled Water

1a 2a 3a

Entry Catalystb Yield (%)c

1 Cu foam trace

2 CuO nanowires 5%

3 Cu/Cu2O nanowires 98%

a Reagents and reaction conditions: 1a (0.5 mmol), 2a (0.5 mmol), and the copper based catalyst (loading amount of active components for Cu-based catalyst equals 0.5 mol%), in water (2 mL) was stirred. b Surfacearea(m2/g): Cu foam: 0.2; CuO nanowires: 40.2; c Cu/Cu2O nanowires: 41.1. Isolated yields.

(Table 3.4, entry 2). To our delight, when employing the core-shell structured

Cu/Cu2O nanowires as the catalyt, the CuAAC reaction could be completed in 2 hours with excellent yield. It is interesting to note that the catalytic activities were highly depended on the components of the catalysts rather than the surface area (Table 3.4).

The remarkable activity of Cu/Cu2O nanowires is probably due to the unique spatial 175 configuration. The Cu2O shells supported by Cu cores remain independent extension from 3D foam-like substrate, which make these Cu/Cu2O nanowires more accessible to the reactant molecules. Thus, benefited from the synergetic effect of the special core-shell structures and their advanced spatial configuration, Cu/Cu2O nanowires exhibited the superior reactivity to the single-component of CuO nanowire catalysts.

176

Table 3.5 Cu/Cu2O nanowires catalyzed CuAAC reaction of benzyl azide with various alkynes in water.

177

The remarkable reactivity of Cu/Cu2O nanowires led us to explore the substrate scopes of the CuAAC reactions. Initially, CuAAC reaction between benzyl azide and different alkynes was tested in the presence of 0.5 mol% Cu/Cu2O nanowires as a catalyst. Cycloaddition with electron-rich (m-CH3, o-OCH3) phenylacetylenes worked well to give the corresponding 1,2,3-triazoles in almost quantitative yield (Table 3.5, entries 2 and 3). The electron-poor alkynes were also excellent substrates for the

Cu/Cu2O nanowires catalyzed cycloaddition (Table 3.5, entries 4 and 5). The halogen atoms, such as Br and Cl, could be tolerated under current reaction condtions which allows for further functionalization (Table 3.5, entries 6-8). Notably, since the reaction is also with low catalyst loadings, the multi-gram scale reaction was carried out. It was found that this raction could be scaled up with an excellent yield (Table

3.5, entry 6). It was shown that reactivity of aliphatic terminal acetylenes toward azides was also remarkably high and afforded the desired product in excellent yield

(Table 3.5, entry 9). We successfully spreaded this protocol to heteroatom-containing aromatic terminal alkynes, with the excellent yield of the target product being 97%, although, compared to the aromatic acetylenes, heteroatom-containing aromatic terminal alkynes required more time (Table 3.5, entry 10). When the polycyclic aromatic termianal alkyne was used, the experiments were carried out smoothly to completion in 2 hours at room temperature, and the corresponding triazoles were obtained in excellent yields (Table 3.5, entry 11).

To gereralize this method, the substrate scope of organic azides was further investigate (Table 3.6). The results indicated that both aromatic and aliphatic azide could be employed in this protocol. 1-Naphthyl, and phenyl azides were also 178 effectively clicked with phenylacetylene in the presence of 0.5 mol% Cu/Cu2O nanowires as the catalysts and the corresponding triazoles were afforded in excellent yields (Table 3.5, entry 1 and 2). Furthermore, the catalyst also proved to be applicable for the cycloaddition of methyl or 2-methoxy substituted aromatic azides, and the desired products were formed in excellent yields (Table 3.5, entries 3-5). It is significant to note that even sterically hindered aryl or alphatic azides bearing ortho substituents could be proceed smoothly and gave the target products in excellent yields (Table 3.5, entries 6-7). This evidently shows the advantage of using Cu/Cu2O nanowires as the catalysts.

179

Table 3.6 Cu/Cu2O nanowires catalyzed CuAAC reaction of phenylacetylenes with various azides in water.

Cu2O/Cu nanowires(0.5%) N N Ph + RN Ph 3 N Distilled Water R

Entry Azide Product Yield(%)b

N N N 1 N3 97%

N N N 2 99% N3

N N N 3 N3 97%

N N N 4 96% N3

N N N OCH3 5 H3CO N3 98%

N N N 6 N3 98%

N N N 3 N 7 98%

a Reagents and reaction conditions: alkyne (0.5 mmol), azide (0.5 mmol), and catalyst in water (2 o mL)werestirredfor2hat60 C. 180

Scheme 3.6 Cu/Cu2O nanowires catalyzed one pot process for the synthesis of triazole.

As shown in Scheme 3.6, one case of one-pot process involving the formation of the organic azide in situ from the benzyl bromide with sodium azide reaction was carried out successfully. Under the above-mentioned reaction conditions, the corresponding product could be afforded in excellet yield. Such a one-pot method is considered to be useful because organic azides are usually unstable to heat and light.

Consequently, a methodology that avoids the isolation of organic azides is desirable.

Table 3.7 Recyclability of the Cu/Cu2O nanowires catalytic system.

As a further extension of this work, the core-shell structured Cu/Cu2O nanowires catalyst was recovered by simple centrifugation and reused after the reaction. As can 181 be seen in Table 3.7, The core-shell structured Cu/Cu2O nanowires catalyst exhibited a high reusability. It can be recycled for ten times without significant loss of activity.

Moreover, TEM images of the recycled catalyst after ten runs showed that Cu2O layer of the structure of Cu/Cu2O nanowires become hump shell along the core, instead of the initial uniform layer structure (Figure 3.5). This indicates that hump shell along the core shape could also work well under current reaction environment, resulting in the comparable activity with the fresh catalyst.

th Figure 3.5 TEM images of the catalyst Cu/Cu2O nanowires after reactions of the 10 run.

182

80000 08/10/2012 932.5

70000 Cu 2p Cu Foam 60000

50000 952.3 40000

Intensity (CPS) 30000

20000

10000

980 970 960 950 940 930 920 Binding energy (eV)

Figure 3.6 XPS spectrum of the fresh prepared Cu/Cu2O nanowires.

80000 08/10/2012 932.5 70000 Cu 2p 60000 Cu Powder

50000

952.3 40000 Intensity (CPS) 30000

20000

10000 980 970 960 950 940 930 920 Binding energy (eV)

Figure 3.7 XPS spectrum of the the catalyst Cu/Cu2O nanowires after reactions of the

10th run.

XPS characterization was done for the catalysts before reaction and after reaction

th of 10 run. From the XPS spectrum of Cu2O/Cu nanowires before reaction, it could be seen clearly that only intense Cu(I) peaks present in which Cu2P3/2 peak locates at

932.5 ev, and Cu2P1/2 peak locates at 952.3 ev. Meanwhile, O1s locates at 530.4 ev. 183

Both of the Cu(I) signal and the oxygen signal are completely same as those of Cu (I) and O in standard Cu2O XPS spectrum (Figure 3.6).

After reactions of the 10th run, the copper peaks and the main peak of oxygen are the same as those of fresh catalyst, which indicates that the chemical compositions are identical to that of fresh catalyst. Thus, Cu2O is stable in the whole recycled reactions. Another oxygen peak of 532.4 ev may be corresponding to the remained reagents or products (Figure 3.7).

In conclusion, we have described a novel catalytic system that effectively catalyzed the cycloaddition of terminal alkynes and azides in water based on core-shell structured Cu/Cu2O nanowires. The cycloaddition reaction demonstrated, for the first time, that one-dimensional (1D) copper nanowires can be applied for the click reaction. The reaction also showed several advantages, such as high reusability, without the addition of support, ligand or base and a very low catalyst loading of 0.5 mol%.

Further research to extend the substrate scope and other related transformations are currently underway in our laboratories.

3.2.2.1 Experimental

3.2.2.1.1 General

Core-shell structured Cu/Cu2O nanowires was prepared according to the method above mentined. Field-emission scanning electron microscopy (SEM) pictures were taken by a

FEI Quanta 600 FEG, and the acceleration voltage was 5 kV. High-resolution transmission electron microscopy (HRTEM) images were obtained using a Titan ST microscope (FEI Co.) operating at 300 kV. The electron energy-loss spectroscopy 184

(EELS) analyses were carried out in this microscope with 150 µm C2 aperture, spot size

6, 29.6 mm camera length, 5 mm entrance aperture (collection angle β = 54 mrad) and 1 s collection time. XRD was performed with Cu Ka radiation (λ = 1.54056 Å) on a Bruker

D8 X-ray diffractometer. Raman spectroscopy measurements were carried out on a

Horiba Aramis confocal microprobe Raman instrument with He-Ne laser (λ = 632.8 nm) at ~ 0.5 mW incident power. The XPS spectra were obtained from AMICUS/ESCA 3400

KRATOS using Mg anodes at 12 kV and 10 mA. A prominent maximum peak of carbon

1s at 284.8 eV was used as a reference to calibrate the XPS spectrum.

3.2.2.1.2 Typical procedure for the core-shell structured Cu/Cu2O nanowires-catalyzed click reactions

To a solution of Cu/Cu2O nanowires (0.5 mol%) in 2 mL distilled water, phenylacetylene (0.5 mmol) and benzyl azide (0.5 mmol) were injected dropwise under Ar. Reaction was monitored by TLC. After completion of the reaction, the mixture was passed through a celite pad and the product was extracted from water with CH2Cl2, dried over Na2SO4. A crude solid product was obtained which was later 185 purified by column chromatography.

3.2.2.1.3 Typical procedure for the core-shell structured Cu/Cu2O nanowires-catalyzed click reactions

To a solution of Cu/Cu2O nanowires (0.5 mol%) in 2 mL distilled water, phenylacetylene (0.5 mmol) and benzyl bromide (0.5 mmol) were injected dropwise under Ar. Then the powder sodium azide was added into the solution in one portion.

Reaction was monitored by TLC. After completion of the reaction, the mixture was passed through a celite pad and the product was extracted from water with CH2Cl2, dried over Na2SO4. A crude solid product was obtained which was later purified by column chromatography.

3.2.2.1.4 General procedure of the recycle process for the core-shell structured Cu/Cu2O nanowires-catalyzed click reactions

After each cycle, the catalyst was recovered by simple centrifugation followed by decantation, and then washed by dichloromethane. The same operation with dichloromethane was repeated five times. The recovered catalyst was used directly in the next cycle and the reaction was performed with fresh solvent and reactants under the identical conditions.

1-Benzyl-4-phenyl-1H-1,2,3-triazole48

186

1 H NMR (500 MHz, CDCl3) δ 7.82 (d, J = 6.9 Hz, 2H), 7.69 (s, 1H), 7.42-7.30 (m, 7H),

13 5.56 (s, 2H). C NMR (125 MHz, CDCl3) δ 148.19, 134.74, 130.55, 129.17, 128.85,

128.79, 128.20, 128.07, 125.70, 119.66, 54.20.

1-Benzyl-4-(3-methylphenyl)-1H-1,2,3-triazole49

1 H NMR (500 MHz, CDCl3) δ 7.67-7.66 (m, 2H), 7.59-7.57 (m, 1H), 7.40-7.39 (m, 3H),

7.33-7.28 (m, 3H), 7.15-7.14 (m, 1H), 5.59 (s, 2H), 2.39 (s, 3H). 13C NMR (125 MHz,

CDCl3): δ 148.46, 138.61, 134.81, 130.47, 129.26, 129.05, 128.89, 128.81, 128.17,

126.47, 122.87, 119.58, 54.32, 21.54.

1-Benzyl-4-(4-methoxyphenyl)-1H-1,2,3-triazole49

1 H NMR (500 MHz, CDCl3) δ 7.72 (d, J = 8.6 Hz, 2H), 7.58 (s, 1H), 7.39-7.26 (m, 5H),

13 6.93 (d, J = 8.4 Hz, 2H), 5.56 (s, 2H), 3.83 (s, 3H). C NMR (125 MHz, CDCl3): δ

159.68, 148.23, 134.88, 129.27, 128.88, 128.18, 127.11, 123.36, 118.81, 114.30, 55.44,

54.32. 187

2-(1-benzyl-1H-1,2,3-triazol-4-yl)pyridine50

1 H NMR (500 MHz, CDCl3) δ 8.52 (d, J = 4.0 Hz, 1H), 8.16 (d, J = 8.0 Hz, 1H), 8.04 (s,

1H), 7.76 (d, J = 7.9 Hz, 1H), 7.37-7.31 (m, 5H), 7.21-7.19 (m, 1H), 5.57 (s, 2H). 13C

NMR (125 MHz, CDCl3): δ 150.28, 149.43, 148.81, 137.07, 134.40, 129.29, 128.97,

128.44, 123.01, 122.03, 120.35, 54.50.

1-Benzyl-4-(4-(trifluoromethyl)phenyl)-1H-1,2,3-triazole51

1 H NMR (500 MHz, CDCl3) δ 7.91 (m, 2H), 7.74 (s, 1H), 7.65 (m, 2H), 7.41-7.32 (m,

13 5H), 5.60 (s, 2H). C NMR (125 MHz, CDCl3) δ 146.98, 134.48, 134.06, 130.12 (q, J =

32.1 Hz), 129.39, 129.10, 128.28, 125.92, 125.28, 123.11, 120.36, 54.51. 19F NMR (377

MHz, CDCl3): δ -62.61.

1-Benzyl-4-(4-fluorophenyl)-1H-1,2,3-triazole49

188

1 H NMR (500 MHz, CDCl3) δ 7.76 (t, J = 6.9 Hz, 2H), 7.62 (s, 1H), 7.39-7.26 (m, 4H),

13 7.08 (t, J = 8.5 Hz, 2H), 5.57 (s, 2H). C NMR (125 MHz, CDCl3) δ 163.72, 161.76,

147.48, 134.68, 129.30, 128.96, 128.20, 127.52 (d, J = 7.9 Hz), 126.84 (d, J = 3.0 Hz),

19 119.36, 115.9, 115.8, 54.37. F NMR (377 MHz, CDCl3): δ -113.56.

1-Benzyl-4-(4’-bromophenyl)-1H-1,2,3-triazole52

1 H NMR (500 MHz, CDCl3) δ 7.70 (s, 1H), 7.66-7.65 (m, 2H), 7.50-7.49 (m, 2H), 7.37

13 (s, 3H), 7.30-7.29 (m, 2H), 5.54 (s, 2H). C NMR (125 MHz, CDCl3) δ 147.09, 134.52,

131.92, 129.49, 129.19, 128.86, 128.09, 127.19, 121.99, 119.77, 54.25.

1-Benzyl-4-(4’-chlorophenyl)-1H-1,2,3-triazole52

1 H NMR (500 MHz, CDCl3) δ 7.72 (d, J = 8.3 Hz, 2H), 7.65 (s, 1H), 7.40-7.11 (m, 7H), 189

13 5.57 (s, 2H). C NMR (125 MHz, CDCl3) δ 147.29, 134.59, 133.98, 129.32, 129.12,

129.00, 128.23, 127.03, 119.64, 54.41.

1-Benzyl-4-(3-chlorophenyl)-1H-1,2,3-triazole49

1 H NMR (500 MHz, CDCl3) δ 7.80 (s, 1H), 7.69 (s, 2H), 7.41-7.28 (m, 7H), 5.58 (s, 2H).

13 C NMR (125 MHz, CDCl3) δ 147.03, 134.83, 134.54, 132.37, 130.22, 129.33, 129.01,

128.23, 12582, 123.84, 119.99, 54.42.

1,4-dibenzyl-1,2,3-triazole53

1 H NMR (500 MHz, CDCl3) δ 7.48-7.47 (m, 3H), 7.43-7.25 (m, 8H), 5.57 (s, 2H), 4.20

13 (s, 2H). C NMR (125 MHz, CDCl3) δ 148.02, 138.99, 134.81, 129.02, 128.67, 128.59,

127.92, 126.45, 121.42, 53.97, 32.25.

1-benzyl-4-(phenanthren-9-yl)-1H-1,2,3-triazole54

190

1 H NMR (500 MHz, CDCl3) δ 8.75 (d, J = 8.3 Hz, 1H), 8.68 (d, J = 8.5 Hz, 1H), 8.38 (d,

J = 8.2 Hz, 1H), 7.96 (s, 1H), 7.87 (d, J = 7.3 Hz, 1H), 7.77 (s, 1H), 7.69-7.65 (m, 2H),

13 7.62-7.58 (m, 2H), 7.43-7.37 (m, 5H), 5.66 (s, 2H). C NMR (125 MHz, CDCl3) δ

147.40, 134.77, 131.36, 130.78, 130.48, 130.17, 129.34, 128.97, 128.50, 128.30, 127.22,

127.04, 126.99, 126.81, 126.26, 123.09, 122.83, 122.66, 54.44.

55 1,4-Diphenyl-1H-1,2,3-triazol

1 H NMR (500 MHz, CDCl3) δ 8.20 (s, 1H), 7.93 (m, 2H), 7.81 (m, 2H), 7.55 (t, J = 7.5

13 Hz, 2H), 7.47 (m, 3H), 7.37 (t, J = 7.7 Hz, 1H). C NMR (125 MHz, CDCl3) δ 148.03,

136.67, 129.84, 129.43, 128.57, 128.43, 128.08, 125.47, 120.16, 117.25.

1-(Naphthalen-1-yl)-4-phenyl-1H-1,2,3-triazole56

191

1 H NMR (500 MHz, CDCl3) δ 8.13 (s, 1H), 8.01-7.94 (m, 4H), 7.70 (d, J = 8.3 Hz, 1H),

7.60-7.51 (m, 4H), 7.47 (t, J = 7.5 Hz, 2H), 7.37 (t, J = 7.7 Hz, 1H). 13C NMR (125 MHz,

CDCl3) δ 147.71, 134.13, 133.64, 130.46, 130.27, 128.99, 128.51, 128.44, 128.31,

127.93, 127.12, 125.86, 125.03, 123.56, 122.38, 122.35.

4-Phenyl-1-p-tolyl-1H-1,2,3-triazole56

1 H NMR (500 MHz, CDCl3) δ 8.16 (s, 1H), 7.92 (d, J = 7.9 Hz, 2H), 7.66 (d, J = 8.1 Hz,

2H), 7.46 (t, J = 7.6 Hz, 2H), 7.38-7.32 (m, 3H), 2.43 (s, 3H). 13C NMR (125 MHz,

CDCl3) δ 148.37, 139.02, 134.87, 130.43, 130.39, 129.03, 128.48, 125.94, 120.54,

117.76, 21.26.

4-Phenyl-1-m-tolyl-1H-1,2,3-triazole57

N N N

192

1 H NMR (500 MHz, CDCl3) δ 8.20 (s, 1H), 7.92 (d, J = 7.9 Hz, 2H), 7.63 (s, 1H), 7.57

(d, J = 8.0 Hz, 1H), 7.46 (t, J = 7.6 Hz, 2H), 7.43-7.36 (m, 2H), 7.26 (d, J = 7.9 Hz, 1H),

13 2.46 (s, 3H). C NMR (125 MHz, CDCl3) δ 148.35, 140.09, 137.03, 130.35, 129.62,

129.61, 128.99, 128.47, 125.90, 121.24, 117.79, 117.64, 21.53.

1-(4-Methoxyphenyl)-4-phenyl-1H-1,2,3-triazole58

1 H NMR (500 MHz, CDCl3) δ 8.11 (s, 1H), 7.90 (d, J = 7.9 Hz, 2H), 7.67 (d, J = 8.9 Hz,

2H), 7.45 (t, J = 7.7 Hz, 2H), 7.36 (t, J = 7.4 Hz, 1H), 7.02 (d, J = 8.9 Hz, 2H), 3.87 (s,

13 3H). C NMR (125 MHz, CDCl3) δ 159.91, 148.30, 130.59, 130.45, 129.02, 128.45,

125.91, 122.28, 117.97, 114.88, 55.75.

1-(2,6-xylyl)-4-phenyl-1,2,3-triazole59

1 H NMR (500 MHz, CDCl3) δ 7.93 (d, J = 8.1 Hz, 2H), 7.87 (s, 1H), 7.47 (t, J = 7.7 Hz, 193

2H), 7.39-7.32 (m, 2H), 7.20 (d, J = 7.7 Hz, 2H), 2.06 (s, 6H). 13C NMR (125 MHz,

CDCl3) δ 147.75, 136.02, 135.60, 130.48, 130.19, 129.06, 128.59, 128.45, 125.84,

121.41, 17.56.

1-(Adamant-1-yl)-4-phenyl-1H-1,2,3-triazole49

1 H NMR (500 MHz, CDCl3) δ 7.84-7.83 (m, 2H), 7.42 (t, J = 7.7 Hz, 2H), 7.31 (t, J = 7.4

13 Hz, 1H), 2.29 (s, 9H), 1.81 (s, 6H). C NMR (125 MHz, CDCl3) δ 146.36, 130.69,

128.40, 127.48, 125.22, 115.68, 59.22, 42.63, 35.54, 29.07.

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APPENDICES

1H NMR, 13C NMR, 19F NMR Data of Some Selected Examples

204

CF3

1H NMR

19F NMR

205

CF3

H3C

1H NMR

13C NMR

206

19F NMR

Et CF3

1H NMR

207

13C NMR 147.69 132.49 128.24 115.99 115.65 113.95 87.06 87.01 86.96 86.91 28.98 15.15

210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 -10 f1 (ppm)

19F NMR

-51.77

40 30 20 10 0 -10 -20 -30 -40 -50 -60 -70 -80 -90 -110 -130 -150 -170 -190 -210 -230 f1 (ppm) 208

n-Pr CF3

1H NMR

13C NMR 146.18 132.39 128.82 115.99 115.66 113.95 87.08 87.03 86.97 86.92 38.06 24.19 13.69

209

19F NMR

n-Bu CF3

1H NMR

210

13C NMR 146.43 132.40 128.77 116.00 115.63 113.96 87.08 87.03 86.98 86.92 35.73 33.22 22.28 13.87

210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 -10 f1 (ppm)

19F NMR

-51.77

211

CF3

1H NMR

13C NMR

212

19F NMR

H3CO CF3

1H NMR

213

13C NMR

19F NMR

214

PhO CF3

1H NMR

13C NMR

215

19F NMR

CF3

1H NMR

216

13C NMR

19F NMR

217

Br CF3

1H NMR

13C NMR

218

19F NMR

CF3

H2N

1H NMR

219

13C NMR 146.52 129.62 122.63 122.62 118.14 117.63 115.92 87.03 86.98 86.93 86.88 75.65 75.24 74.82 74.40

19F NMR

220

SO CF 2 3

1H NMR

8.2 8.1 8.0 7.9 7.8 7.7 7.6 f1 (ppm)

16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 0 -1 -2 -3 -4 f1 (ppm)

13C NMR

221

19F NMR

CN SO2CF3

1H NMR

222

19F NMR

-77.669

13C NMR

223

O2N SO 2CF3

19F NMR

40 30 20 10 0 -10 -30 -50 -70 -90 -110 -130 -150 -170 -190 -210 -230 f1 (ppm)

1H NMR 4 7 8.913 8.74 8.72 8.418 8.403 7.973 3.94 4.04 4.05 2.97

224

13C NMR

SO2CF3

19F NMR

225

1H NMR

13C NMR

226

SO2CF 3

19F NMR

1H NMR

227

13C NMR

SO2CF3

SO 2CF3 N

19F NMR

40 30 20 10 0 -10 -30 -50 -70 -90 -110 -130 -150 -170 -190 -210 -230 f1 (ppm)

228

1H NMR

13C NMR

229

SO2CF3

19F NMR

1H NMR

230

13C NMR

CF3

MeO

1H NMR

231

19F NMR

13C NMR

232

CF3

BnO

1H NMR

19F NMR

233

13C NMR

S CH2(CH2)6CH3

1H NMR

234

13C NMR

F F

1H NMR

235

13C NMR

19F NMR

236

N N N

1H NMR

13C NMR

237

N N N

1H NMR

13C NMR

238

N N N

1H NMR

13C NMR

239

N N N

1H NMR

13C NMR

240

N N N OCH3

1H NMR

13C NMR

241

N N N

1H NMR

13C NMR

242

N N N

1H NMR

13C NMR