Introducing fluorine and trifluoromethyl group into organic compounds under heterogeneous transition metal catalysis

Herein, we developed the first heterogeneous catalyzed fluorination of aliphatic acids and the first heterogeneous catalyzed trifluoromethylation of boronic acids using the successfully

VIETNAM NATIONAL UNIVERSITY - HO CHI MINH CITY

HO CHI MINH UNIVERSITY OF TECHNOLOGY

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NGUYỄN VĂN TÚ

INTRODUCING FLUORINE AND TRIFLUOROMETHYL GROUP INTO ORGANIC COMPOUNDS UNDER HETEROGENEOUS TRANSITION METAL CATALYSIS

PhD THESIS

HO CHI MINH CITY, 2018

VIETNAM NATIONAL UNIVERSITY - HO CHI MINH CITY

HO CHI MINH UNIVERSITY OF TECHNOLOGY

&&*&&

NGUYỄN VĂN TÚ

INTRODUCING FLUORINE AND TRIFLUOROMETHYL GROUP INTO ORGANIC COMPOUNDS UNDER HETEROGENEOUS TRANSITION METAL CATALYSIS

Major: Chemical Engineering

Major code: 62.52.03.01

Independent Reviewer No.1: Prof Dr Đinh Thị Ngọ

Independent Reviewer No.2: Assoc Prof Dr Phạm Nguyễn Kim Tuyến Reviewer No.1: Assoc Prof Dr Nguyễn Phương Tùng

Reviewer No.2: Assoc Prof Dr Nguyễn Thị Dung

Reviewer No.3: Assoc Prof Dr Bạch Long Giang

ADVISORS:

1 Prof Dr Phan Thanh Sơn Nam

2 Dr Trương Vũ Thanh

i

DECLARATION OF ORIGINALITY

I hereby declare that this thesis represents my original work under the advice from Dr Trương Vũ Thanh and Prof Dr Phan Thanh Sơn Nam, and that all figures and results obtained in this thesis are absolutely true and have been not yet released ever before

All data, tables, figures and text citations which have been reproduced from any other source, including the internet, have been explicitly acknowledged as such

I am aware that in case of non-compliance, I have to be under any judgement from the scientific committee

Ho Chi Minh City, 2018

Performer

Nguyễn Văn Tú

ii

TÓM TẮT LUẬN ÁN

Các hợp chất chứa một hay nhiều nguyên tử flo trong phân tử có những tính chất đặc biệt được hình thành bởi kích thước nhỏ và độ âm điện cao của flo Sự có mặt của flo trong phân tử hợp chất làm tăng độ âm điện, tính ưa mỡ, độ ổn định sinh học các hợp chất chứa nó và đặc biệt là tăng hoạt tính sinh học của chúng Do vậy, các hợp chất chứa flo được sử dụng ngày càng nhiều trong hóa nông, hóa dược và trong nhiều loại vật liệu Ngoài ra, các hợp chất chứa đồng vị flo 18 (18F) còn được sử dụng rộng rãi trong kỹ thuật Positron Emission Tomography (PET) ứng dụng trong y học Chính vì vậy, nhiều công trình nghiên cứu đã được các nhà khoa học trên thế giới thực hiện để tìm ra các phương pháp khác nhau tổng hợp các hợp chất chứa flo Tuy nhiên, do đặc điểm hoạt tính hóa học mạnh của flo mà các phản ứng tổng hợp đều có những nhược điểm như: sinh ra nhiều sản phẩm phụ, điều kiện phản ứng khắc nghiệt, sử dụng các chất phản ứng và xúc tác đắt tiền hoặc phạm vi chất nền hẹp, v.v Hơn nữa, tất cả các phản ứng trong lĩnh vực hóa học flo đã được công bố trước đây đều sử dụng kim loại chuyển tiếp làm xúc tác đồng thể hoặc được sử dụng như chất phụ trợ trong hệ đồng thể, chưa có công trình nghiên cứu nào được thực hiện trong đó sử dụng kim loại chuyển tiếp làm chất xúc tác dị thể, góp phần vào việc tăng khả năng tái sử dụng và tiết kiệm chi phí (dựa trên tìm hiểu của nhóm nghiên cứu và tìm kiếm trên SciFinder tính đến tháng 8 năm 2018) Với sự phát triển mạnh mẽ từ những ứng dụng của hợp chất hữu cơ kim loại MOFs và hạt nano (nanoparticles), chúng tôi đã nghiên cứu tổng hợp và sử dụng MOFs Cu(INA)2 và hạt nano delafossite AgFeO2 làm xúc tác cho phản ứng gắn nhóm -CF3 (trifluoromethylation)và gắn flo (fluorination) - những phản ứng được nghiên cứu phổ biến hiện nay Kết quả khẳng định sự tổng hợp thành công của MOFs Cu(INA)2 và hạt nano AgFeO2 với những đặc tính trùng khớp với các nghiên cứu trước Việc sử dụng chúng vào các phản ứng flo hóa đã mang lại những kết quả ngoài mong đợi được thể hiện ở hiệu suất phản ứng cho đa số các chất nền khác nhau cho kết quả cao và rất cao Hơn nữa, các xúc tác sử dụng được thu hồi và sử dụng lại nhiều lần mà không có sự giảm đáng kể hiệu suất phản ứng cũng như sự phá vỡ cấu trúc tinh thể của xúc tác Những kết quả trên đã khẳng định sự thành công của đề tài nghiên cứu sử dụng xúc tác dị thể tâm kim loại chuyển tiếp trong lĩnh vực hóa học flo

iii

ABSTRACT

There have not been recorded articles yet, conducting the fluorination of boronic acids and aliphatic acids under the heterogeneous catalysis (according to searching on SciFinder and under our consideration till August 2018) Due to the precious characteristics of fluorinated compounds in the human life, especially in biochemistry, several studies have been investigated to find out different methods for fluorinating organic compounds In spite of the increasing developments in fluorine chemistry, the drawbacks have still remained The use of strong reagents leading to the generation of several isomers, the use of expensive reagents resulting in the enhanced expense, the application of harsh conditions and the limited substrate scope have been the major disadvantages so far Therefore, the novel methods for the transformation of organic frameworks into fluorinated ones are needed Herein, we developed the first heterogeneous catalyzed fluorination of aliphatic acids and the first heterogeneous catalyzed trifluoromethylation of boronic acids using the successfully synthetic catalysts of Cu(INA)2 MOFs and AgFeO2 nanoparticles The characterization of the two mentioned catalysts proved the similarity to the previous materials described in the former studies They were employed in the fluorination and trifluoromethylation reactions Interestingly, they exhibited the unexpected compatibility with the fluorination reactions with the high to excellent yields of the desired products and the wide substrate scope They also showed the high recoverability and reusability as they were recovered and reused several times without significant degradation in product yields The leaching tests showed the stable crystallinity of above catalysts in the reaction mixtures, wherein no enhanced yield was observed by the contribution of leached active species, if any The results from our developments proved the success

in the syntheses of catalyst materials as well as in the fluorination reaction of aliphatic acids and trifluoromethylation of boronic acids under the mild, efficient conditions Our studies will contribute to the fluorine chemistry the novel methods for the fluorination and trifluoromethylation described in this thesis And futher studies will focus on using various transition metal catalysts for fluorinating different organic compounds

iv

ACKNOWLEDGEMENT

First and foremost, I want to send my deep thanks to my advisors namely Doctor Thanh Truong and Prof Nam T S Phan for the thorough, thoughtful guidance with their comprehensive knowledge and their financial support, contributing to the success

of this thesis Working with them is my honor, and I have gained much precious experience for my future work

I also give thanks for the considerate help to teachers in Department of Organic Chemical Engineering and all staffs in the MANAR Lab, who always have given me any aids when needed

Additionally, I want to give thanks to my research group including Mr Quan H Tran,

Mr Toan D Ong, Ms Anh H M Lam, Mr Toan X Vu, Mr Vu T Pham, Mr Tin V

T Nguyen, etc for the valuable support, which helps me complete this thesis

Last but not least, I want to express my limitless gratefulness to all members in my family who have been always beside me in the hardest time Their encouragement and support inspire me the strength and belief in my study and my life

Ho Chi Minh City, 2018

Nguyễn Văn Tú

v

TABLE OF CONTENTS

DECLARATION OF ORIGINALITY i

TÓM TẮT LUẬN ÁN ii

ABSTRACT iii

ACKNOWLEDGEMENT iv

TABLE OF CONTENTS v

LIST OF FIGURES viii

LIST OF SCHEMES x

LIST OF TABLES xiii

LIST OF ABBREVIATIONS xiv

INTRODUCTION 1

Chapter 1 : LITERATURE REVIEW 3

1.1 Introduction of fluorine into organic scaffolds 4

1.1.1 Electrophilic Fluorination 4

1.1.2 Nucleophilic Fluorination 10

1.1.3 Radical Fluorination 15

1.2 Introduction of trifluoromethyl group (CF3 group) into organic compounds 19

1.2.1 Electrophilic trifluoromethylation 21

1.2.2 Nucleophilic trifluoromethylation 26

1.2.3 Radical trilfuoromethylation 32

1.3 Metal organic frameworks (MOFs), delafossite-type oxides and nanoparticles in organic syntheses 36

1.3.1 MOFs in organic chemistry 36

1.3.2 Silver-Ferrite Nanoparticles AgFeO2 38

1.4 Aim and objectives 39

Chapter 2 : EXPERIMENTAL 41

2.1 Materials and instrumentation 41

vi

2.2 Preparation of metal organic framework Cu(INA)2 44

2.3 Preparation of Delafossite-type oxide AgFeO2 nanoparticles 45

2.4 Catalytic studies 46

2.4.1 Copper-catalyzed trifluoromethylation of aryl boronic acids using MOFs Cu(INA)2 as catalyst (reaction 1) 46

2.4.1.1 General procedure 46

2.4.1.2 Determination of GC yield 47

2.4.2 Silver-catalyzed fluorination of aliphatic acids using AgFeO2 as catalyst (reaction 2) 48

2.4.2.1 General procedure 48

2.4.2.2 Determination of GC yield 49

Chapter 3 : RESULTS AND DISCUSSION 51

3.1 Catalyst synthesis and characterization of Cu(INA)2 51

3.2 Characterization of Delafossite-type oxide AgFeO2 (silver-ferrite oxide) 55

3.3 Catalytic studies 58

3.3.1 Copper-catalyzed trifluoromethylation of aryl boronic acids using MOFs Cu(INA)2 as catalyst 58

3.3.1.1 Introduction 58

3.3.1.2 Effect of catalyst loading on reaction yield 60

3.3.1.3 Effect of fluoride anion sources on reaction yield 61

3.3.1.4 Effect of temperature on reaction yield 62

3.3.1.5 Effect of reactant molar ratio on reaction yield 63

3.3.1.6 Effect of ligand amount on reaction yield 64

3.3.1.7 Effect of solvent on reaction yield 65

3.3.1.8 Effect of reaction environment and oxidant on reaction yield 67

3.3.1.9 Leaching Test 68

3.3.1.10 Reaction with different copper-based catalysts 69

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3.3.1.11 Catalyst recycling studies 72

3.3.1.12 Substrate scope studies 75

3.3.1.12 Conclusions 77

3.3.2 Silver-catalyzed fluorination of aliphatic acids using AgFeO2 as catalyst 77

3.3.2.1 Introduction 77

3.3.2.2 Effect of SelectFluor equivalent on reaction yield 80

3.3.2.3 Effect of catalyst loading on reaction yield 81

3.3.2.4 Effect of different solvents on reaction yield 82

3.3.2.5 Effect of volume ratio of acetone to water on reaction yield 83

3.3.2.6 Effect of the concentration of reactant on reaction yield 85

3.3.2.7 Effect of temperature on reaction yield 86

3.3.2.8 Leaching Test 87

3.3.2.9 Reaction with different silver- and other metals-based catalysts 88

3.3.2.10 Catalyst recycling studies 90

3.3.2.11 Substrate scope studies 92

3.3.2.12 Initial study for the feasible pathway of the reaction 95

3.3.2.13 Conclusion 96

CONCLUSIONS 97

REFERENCES 99

LIST OF PUBLICATIONS 116

APPENDICES 117

viii

LIST OF FIGURES

Figure 1.1 Some popular drugs containing fluorines [9] 3

Figure 1.2 Naturally occuring fluorinated compounds [10] 4

Figure 1.3 Some common N-fluoro reagent classes as fluorine sources [14-17] 5

Figure 1.4 Some nucleophilic fluorinating reagents used in fluorination reactions [5] 11

Figure 1.5 Hypervalent iodine perfluoroalkyl reagents [63-67] 21

Figure 1.6 Different forms of Yagupolski-Umemoto reagents used in trifluoromethylation of organic compounds [65] 25

Figure 1.7 View of the crystal structure of Cu(INA)2 [147] 37

Figure 1.8 Delafossite-type crystal structure of AgFeO2 Unit-cell of (a) 3R polytype and (b) 2H polytype [159] 38

Figure 2.1 Calibration curve for determining GC yield of 4-trifluoromethyl anisole 48 Figure 2.2 Calibration curve for determining GC yield of (2-fluoroethane-1,1-diyl)dibenzene 50

Figure 3.1 XRD patterns of (a) the synthesized Cu(INA)2; 51

Figure 3.2 FT–IR spectra of the Cu(INA)2 (a) and isonicotinic acid HINA (b) 52

Figure 3.3 SEM micrograph of the Cu(INA)2 53

Figure 3.4 TGA result of the Cu(INA)2 54

Figure 3.5 XRD patterns of the synthesized AgFeO2 (a); 55

Figure 3.6 SEM and TEM images of AgFeO2 nanoparticles 56

Figure 3.7 TGA profile of AgFeO2 nanoparticles 57

Figure 3.8 Effect of catalyst loading on reaction yield 61

Figure 3.9 Effect of fluoride ion sources on reaction yield 62

Figure 3.10 Reaction yields at different temperature 63

Figure 3.11 The reaction yields under various equivalent of TMSCF3 64

Figure 3.12 Reaction yields obtained under various amount of 1,10-phenanthroline 65 Figure 3.13 Leaching Test 69

Figure 3.14 Catalyst recycling studies 73

Figure 3.15 FT-IR spectra of the fresh (a) and reused (b) Cu(INA)2 catalyst 74

ix

Figure 3.16 X-ray powder diffractograms of the fresh (a) and reused (b) Cu(INA)2

catalyst 74

Figure 3.17 Reaction yields with different amount of SelectFluor as fluorine reagent 80

Figure 3.18 Effect of various catalyst loadings of AgFeO2 on reaction yield 81

Figure 3.19 Reaction yields obtained with different solvents 83

Figure 3.20 The effect of volume ratio of acetone to water on reaction yield 84

Figure 3.21 Reaction yields under various concentrations of reactant 85

Figure 3.22 Reaction yields obtained at various temperature 86

Figure 3.23 Leaching Test 88

Figure 3.24 Catalyst recycling studies 91

Figure 3.25 The XRD spectra of (a) the fresh AgFeO2 and (b) the recovered AgFeO2 92

x

LIST OF SCHEMES

Scheme 1.1 Electrophilic fluorination of aryl boronic acids and trifluoroborates [18] 5

Scheme 1.2 Fluorination of aryl Grignard reagents [19-21] 6

Scheme 1.3 Transition metal catalyzed fluorinations with directing groups [22, 23] 6

Scheme 1.4 Fluorination of aryl stannanes, boronic acids and silanes [24-26] 7

Scheme 1.5 Pd-catalyzed Aminofluorination of Unactivated Alkenes [27, 28] 7

Scheme 1.6 Two steps for fluorination of ketones with N-fluoro reagent of SelectFluor [34] 8

Scheme 1.7 Fluorination of ketones with N-fluoro reagent SelectFluor [35] 8

Scheme 1.8 Transition metal catalyst for aliphatic C-F bond formation [22] 9

Scheme 1.9 Ion (II) catalyzed fluorination of benzylic substrates [37] 9

Scheme 1.10 Fluorination of carboxylic acids using fluorine as reagent [38] 10

Scheme 1.11 Nucleophilic fluorination using DAST as fluorinating reagent [39] 12

Scheme 1.12 The aryl fluoride formation via palladium-catalyzed fluorination [40] 13 Scheme 1.13 Copper-catalyzed aryl-F formation with AgF [42] 13

Scheme 1.14 Fluorination of Aryl Iodides with (tBuCN)2CuOTf and AgF [43] 14

Scheme 1.15 The C-F bond formation from cyclic allylic chlorides using Pd(0) as catalyst [44] 14

Scheme 1.16 Iridium-catalyzed fluorination of organic halides [45] 15

Scheme 1.17 Manganese catalyzed nucleophilic fluorination of C(sp3)-H bond [46] 15 Scheme 1.18 The radical fluorination pathway [47] 16

Scheme 1.19 The fluorodecarboxylation of aliphatic acids under XeF2 [50-53] 16

Scheme 1.20 Photo-fluorodecarboxylation of 2-aryloxy and 2-aryl carboxylic acids [55] 16

Scheme 1.21 Radical mechanism of photo-decarboxylation of carboxylic acids [55] 17 Scheme 1.22 Fluorodecarboxylation of aliphatic acids with silver as catalyst [56] 18

Scheme 1.23 Three pathways hypothesized for the formation of alkyl radical [57] 18

Scheme 1.24 The difference between methyl group and trifluoromethyl group [58-60] 20

xi

Scheme 1.25 Route via fluoroalkylcopper intermediate by McLoughlin and Thrower

[62] 20

Scheme 1.26 Reactivity of alcohol Togni’s reagent 3 via various examples [65] 22

Scheme 1.27 The low yields in trifluoromethylation of phenols using reagent 2 [73] 23 Scheme 1.28 Reactivity of acid CF3-reagent 2 via various examples [65] 24

Scheme 1.29 Copper (I) catalyzed-allylic trifluoromethylation of unactivated olefins [76] 24

Scheme 1.30 Some specific applications of Umemoto’s reagents 4 and 5 [77-82] 25

Scheme 1.31 Some paths to prepare Ruppert-Prakash reagent [83-86] 26

Scheme 1.32 Methods for trifluoromethylation of aromatics and heteroaromatics [93-110] 27

Scheme 1.33 Plausible pathway of copper catalyzed trifluoromethylation proposed by Quing and Chu [98] 28

Scheme 1.34 Cu-mediated ortho C-H trifluoromethylation of arenes using TMSCF3 [101] 28

Scheme 1.35 Copper mediated oxidative trifluoromethylation of boronic acids developed by Quing and co-workers [102] 29

Scheme 1.36 Reaction pathway proposed for generation of benzotrifluorides [102, 104] 29

Scheme 1.37 Copper catalyzed allylic trifluoromethylation of termial alkenes using TMSCF3 developed by Quing and co-workers [112] 30

Scheme 1.38 Trifluoromethylation of oxindoles catalyzed by palladium [113] 31

Scheme 1.39 Trifluoromethylating into α-position of substrates bearing activated groups [114-116] 32

Scheme 1.40 Two steps to afford α-CF3 ketones compounds [121, 122] 33

Scheme 1.41 Radical oxidative-trifluoromethylation of styrenes [123] 33

Scheme 1.42 The feasible pathway of trifluoromethylation of styrenes [123] 34

Scheme 1.43 Copper-mediated trifluoromethylation of alkenes using Langlois reagent [124] 34

Scheme 1.44 Silver-catalyzed trifluoromethylation of unactivated alkenes [125] 35

Scheme 1.45 Metal-free oxytrifluoromethylation of unactivated alkenes [126] 35

xii

Scheme 1.46 Manganese catalyzed oxytrifluorination proposed by Vicic et al [127] 36Scheme 3.1 Copper-mediated trifluoromethylation of 4-phenoxyphenyl boronic acid 58Scheme 3.2 Proposed mechanism for the copper-mediated oxidative trifluoromethylation of boronic acids 59Scheme 3.3 The trifluoromethylation of 4-methoxyphenylboronic acid with TMSCF3

to produce 4-trifluoromethylanisole using MOF Cu(INA)2 60Scheme 3.4 The decarboxylative fluorination of aliphatic acids reported by Li’s group 78Scheme 3.5 The proposed pathway for the silver catalyzed-fluorination of aliphatic acids investigated by Flowers’ group 79Scheme 3.6 The fluorination of 3,3-diphenylpropionic acid with SelectFluor to afford (2-fluoroethane-1,1-diyl)dibenzene using AgFeO2 nanoparticles as catalyst 79

xiii

LIST OF TABLES

Table 2.1 List of chemicals used for the trifluoromethylation of boronic acids and the

fluorination of aliphatic acids 41

Table 2.2 List of chemicals for Cu(INA)2 MOFs synthesis 45

Table 2.3 List of chemicals for AgFeO2 nanoparticles synthesis 46

Table 3.1 Effect of solvent on forming reaction products 66

Table 3.2 Effect of reaction environment and oxidant on forming reaction products 67 Table 3.3 Catalytic reactivity of other copper-based catalysts under the same conditions 70

Table 3.4 Reaction scope of coupling components 75

Table 3.5 Reaction yields with various catalysts 89 Table 3.6 The substrate scope of the heterogeneous fluorination of aliphatic acids a 93

xiv

LIST OF ABBREVIATIONS

GC: Gas chromatography

GC-MS: Gas chromatography–mass spectrometry

NMR: Nuclear magnetic resonance

RT: Room temperature

DPPA: 3,3-diphenylpropanoic acid (3,3-diphenylpropionic acid) IS: Internal Standard

DCB: 1,2-dichorobenzene

XRD: X-ray powder Diffraction

SEM: Scanning Electron Microscopy

TEM: Transmission Electron Microscopy

TGA: Thermogravimetric Analysis

NIST: National Institute of Standard and Technology

MOFs: Metal Organic Frameworks

Cu(INA)2: Copper isonicotinate (MOFs with ligands of isonicotinic acid) HINA: Isonicotinic acid (the ligand of MOFs Cu(INA)2

TMSCF3: Trifluoromethyltrimethylsilane

PET: Positron Emission Tomography

NFSI: N-Fluorobenzenesulfonimide

DCE: 1,2-Dichloroethane

ISI: Institute for Scientific Information

FT-IR: Fourier Transform Infrared Spectroscopy

ICP-MS: Inductively coupled plasma mass spectrometry

XRF: X-ray fluorescence

INTRODUCTION

The organofluoride compounds are the least common natural ones compared to the other organohalides Most organofluorides found in the earth are insoluble, averting the uptake of bioorganisms [1] However, the fluorine containing groups are of precious characteristics in pharmaceuticals, agrochemicals and materials due to their enhanced electronegativity, lipophilicity, metabolic stability and bioavailability [1-4] Besides, 18F-radiotracers used for Positron Emission Tomography (PET) are remarkably applied to both diagnosis and pharmaceutical development [5] Not until

1970 had fluorinated drugs been prevalent in medicinal chemistry Since then, there has been a significant growth in fluorine chemistry, especially over the last 20 years [6] Until 2002, more than 150 fluorine containing drugs have come to the market, estimably contributed to ca 20-25% of all pharmaceuticals, and even higher in agrochemicals with ca 28% in market Of 31 new drugs licensed in USA in 2002, nine contained fluorine in their scaffolds [1, 6-8] In 2006, Lipitor ® (atorvastatin calcium, which contains one fluorine) and Advair ® (a mixture of fluticasone propionate and salmeterol, which contains three fluorine atoms) are orderly the best- and the second-best-selling pharmaceuticals over the world [9]

In spite of the importance of fluorinated frameworks in actual areas, the number of these compounds in nature are rare [6] Therefore, the investigations to figure out novel strategies to synthesize fluorinated products are needed Of strategies, the developments of simple handling, facile and inexpensive methods have been attracting

a great deal of attention

Almost previous studies employed homogeneous catalysts that could not be recovered and reused after reactions Most of protocols proceeded under harsh or costly conditions owing to the usage of the reagents susceptible to benchtop setup or the expensive reagents, respectively, or both Additionally, the substrate scope and functional group tolerance still remain challenging Further studies, therefore, are required to ameliorate the disadvantages in the former works From above

observations, we propose the thesis: “Introducing fluorine and trifluoromethyl

group into organic compounds under heterogeneous transition metal catalysis”

The purpose of the thesis is to develop the novel and more effective strategies to furnish fluorine containing compounds employing readily, inexpensive and effective methods under heterogeneous transition metal catalysis Moreover, the wide scope and functional group tolerance are also under our consideration From our knowledge, there has been no work utilizing the heterogeneous catalysts to introduce fluorine into organic molecules so far This is an important factor to publish our accomplished studies in ISI journals with high impact factor (IF)

Our studies will contribute to current knowledge of fluorine chemistry the novel methods employing heterogeneous catalysts to introduce fluorine and fluorine containing groups into organomolecules which have not yet been developed ever before Our investigations are also carried out to ameliorate drawbacks in previous studies so far, proving the importance and the practice of our work Furthermore, we establish the new methods for the usage of heterogeneous catalyst in fluorine chemistry that can be restored and recycled many times after reactions, making the methods more inexpensive

Our studies are the first investigations in using heterogeneous transition metal catalysts for introduction of fluorine and fluorine containing groups into organic scaffolds The first time Cu(INA)2 MOFs is employed in the trifluoromethylation of boronic acids, and the first time AgFeO2 nanoparticles is used in the fluorination of aliphatic acids Thus, they make up vitally practical approaches to synthesize the fluorinated products that are necessary in pharmaceuticals, agrochemicals and materials due to unique effects of fluorine and fluorine containing groups on organomolecules Our results may make a turning point in the application of methods using heterogeneous catalysts

in fluorine chemistry

Chapter 1 : LITERATURE REVIEW

Fluorine and fluorinated groups have the strong effects on the properties of organic compounds due to their enhancement of lipophilicity, metabolic stability, bioactivity and binding selectivity Therefore, more and more fluorinated frameworks have been used in medicinal chemistry, even higher in agrochemicals Several fluorinated products have come to the market and have been also the top-selling products over years (Figure 1.1) [9]

Figure 1.1 Some popular drugs containing fluorines [9]

Though the necessity of fluorine containing compounds in pharmaceuticals, agrochemicals, materials and PET, and fluorine is the 13rd most abundant element in the earth’s crust, the availably natural fluorinated compounds are rare (Figure 1.2) [10] As a result, a great number of studies have been done to describe numerous methods for introduction of fluorine and fluorine containing groups into organic frameworks, especially after 1970s Different substrates, reagents, additives, promoters and catalysts have been employed to develop various approaches in the syntheses of fluorine containing scaffolds Of reported works, the attachment of fluorine and trifluoromethyl group is most prevalent and has attracted increasing attention from researchers over the world Generally, more and more effective, inexpensive works

have been conducted to ameliorate the drawbacks of the previous ones However, the regioselectivity, substrate scope and functional group tolerance still remain problematic so far

Figure 1.2 Naturally occurring fluorinated compounds [10]

1.1 Introduction of fluorine into organic scaffolds

Previous studies showed different methods to introduce fluorine into organic molecules using various fluorinating reagents as the fluorine transfer sources In general, there are three ultimate mechanisms of fluorination reactions as following:

1.1.1 Electrophilic Fluorination

The first fluorinating reagent used for fluorination was fluorine gas, the strongest elemental oxidant known [11] Subsequent reagents such as hypofluorites, fluoroxysulfates and perchloryl fluoride were also utilized as fluorine generating sources However, using aforementioned reagents coped with their high reactivity resulting in the difficulty of C-F bond formation [12] Xenon fluoride then exhibited the more stable reactivity than above reagents, but its high oxidizing potential restricted the substrate scope with limited functional group tolerance [13] Continuously, the development of N-fluoro reagent classes including N-fluorobis(phenyl)sulfonimide (NFSI) [14] and related analogs [14, 15], N-fluoropyridinium salts [16], and 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo

[2.2.2]octane bis(tetrafluoroborate) (Selectfluor®, F-TEDA-BF4) [17] became the vital leap in fluorine chemistry due to their air-setup stability, regioselectivity and functional group tolerance (Figure 1.3)

Figure 1.3 Some common N-fluoro reagent classes as fluorine sources [14-17]

Both main group organometallics and transition-metal organometallics can be fluorinated electrophilically to obtain aryl fluorides Compared to the former, the latter could afford aryl fluorides with an enhanced substrate scope as well as wider pathways

of mechanism that help improving the expansion of electrophilic fluorination so far However, the development of stable, direct and functional group tolerant C-F bond formation based upon electrophilic pathways still remains challenging

Scheme 1.1 Electrophilic fluorination of aryl boronic acids and trifluoroborates [18]

Fluorinated arenes could be obtained by the reaction between aryl metal reagents namely aryl-tin , -mercury , -lead , -germanium , -silicon , and -boron and fluorine gas, hypofluorites, fluoroxysulfates, and xenon difluoride High reactivity of reagents, nevertheless, limited the substrate scope, especially the functional group tolerance The generation of N-flouro reagents has overcome the limitations of the high reactivity

of reagents and become the important reagents in fluorination currently Cazorla group conducted the conversion of aryl nucleophiles such as aryl boronic acids and

trifluoroborates into corresponding aryl fluorides in high yield under the facile, mild condition (Scheme 1.1) Such aryl nucleophiles could undergo single electron transfer affording protodemetallation byproducts [18]

Scheme 1.2.Fluorination of aryl Grignard reagents [19-21]

Fluorination of Grignard substrates with N-fluoro reagents generated corresponding adducts but was limited in scope due to the basicity and nucleophilicity of Grignard compounds Undesired protodemetallation byproducts could be reduced by the change

of solvents and reagent equivalent (Scheme 1.2) [19-21]

Scheme 1.3 Transition metal catalyzed fluorinations with directing groups [22, 23]

The earliest transition metal catalyzed aromatic fluorination was conducted via utilizing an ortho-directing group The conversion of C-H bond to C-F bond was obtained, but the broad functional group tolerance was limited due to the necessity of coordinating groups (Scheme 1.3) [22, 23]

Moreover, electrophilic fluorination reactions of aryl stannanes [24], boronic acids [25], and silanes [26] was developed using silver as transition metal catalyst The C-F bond formation was assumed to proceed via the multimetallic, high valent silver

intermediacy generated by the oxidation of silver (I) complexes with oxidant and the adduct was afforded by reductive elimination (Scheme 1.4)

Scheme 1.4 Fluorination of aryl stannanes, boronic acids and silanes [24-26]

Unactivated alkenes were also fluorinated by the use of Palladium as catalyst, which was described by Liu and co-workers Intramolecular aminofluorination of unactivated alkenes gave C-F bond formation in moderate to high yield, whereas the Pd-catalyzed intermolecular fluoroamination of styrenes yielded the corresponding adducts with a limited scope of starting substrate (Scheme 1.5) [27, 28]

Scheme 1.5 Pd-catalyzed Aminofluorination of Unactivated Alkenes [27, 28]

Alternative approach in fluorination reaction is the sp3 C-H bond fluorination Nucleophiles employed in the fluorination reactions of aliphatic compounds were often carbanions in which the first molecules used were carbonyl derivatives The α-fluorination of carbonyl derivatives with strong oxidizing fluorinating reagents, namely gaseous fluorine [29], alkyl hypofluorite [30], perchloryl fluoride [31],

fluoroxysulfate [32], and XeF2 [33] commonly gave desired fluorinated products, but there were a limited substrate scope and byproducts afforded due to the strong oxidizing potential of reagents By contrast, the usage of N-fluoro reagents as less reactive, more functional group tolerant electrophilic fluorinating reagents resulted in the stable, selective fluorination in mild conditions

Scheme 1.6 Two steps for fluorination of ketones with N-fluoro reagent of

SelectFluor [34]

Obviously, Erik Fuglseth group conducted a fluorination of acetophenol derivatives with three routes using various conditions The results showed that route A gave products in moderate to high yields depending upon the electronic properties of substituents In this route, the acetophenones were converted into the corresponding trimethylsilyl enol ethers followed by fluorination with SelectFluor to yield desired fluorinated products (Scheme 1.6) [34]

Scheme 1.7 Fluorination of ketones with N-fluoro reagent SelectFluor [35]

Another specific research was carried out in 2009 by Gaj Stavber group They carried out a direct, regioselective fluorination of various cyclic and acyclic ketones to α-fluoroketones with water as medium and SelectFluor (F-TEDA-BF4) as fluorinating reagent in presence of inexpensive amphiphile sodium dodecyl sulfate (SDS) as a promoter (Scheme 1.7) [35]

The conversion of aliphatic C-H bond to C-F bond still remain challenges so far due to the high electronegativity of elemental fluorine as well as the high hydration energy of

fluoride anion Therefore, the number of articles about the fluorination of aliphatic

C-H bond still remains limited In 2000, Chambers and co-workers conducted the fluorination of saturated systems utilizing fluoride solution and SelectFluor as fluorine sources without catalyst However, the reaction gave corresponding products in low to moderate yield on various substituents [36]

Scheme 1.8 Transition metal catalyst for aliphatic C-F bond formation [22]

The usage of transition metal catalysts has been useful for selective, efficient fluorination of aliphatic C-H bond The first research using transition metal catalyst was proceed by Sanford and co-workers in 2006, which was the palladium-catalyzed fluorination of 8-methylquinoline using the electrophilic N-fluoro reagent This transformation was attributed to occur via the high-valent palladium fluoride intermediates followed by the C-F bond-forming reductive elimination (Scheme 1.8) [22]

Scheme 1.9 Ion (II) catalyzed fluorination of benzylic substrates [37]

Bloom and co-workers utilized inexpensive iron salt, iron (II) acetylacetonate Fe(acac)2 as a transition metal catalyst for the fluorination of benzylic substrates A mild, one pot synthesis of direct conversion of C-H bond to corresponding C-F bond formation gave the fluorinated products in good to excellent yield and in excellent selectivity in the presence of SelectFluor as fluorine source This reaction also exhibited the wide scope with a variety of substituents on benzylic molecules, which has not yet to be reported in the previous literature (Scheme 1.9) [37]

Of presented substrates in the previous studies, carboxylic acids and carboxyl containing compounds have excited a number of researches, presumably due to the discrepancy of boiling point between the fluorodecarboxylative products and corresponding feedstocks The investigations related to fluorination of carboxylic acids appeared before 1960s However, the usage of strongly fluorinated reagents diminished the generation of desired products in situ In 1969, Grakauskas implemented several experiments using various carboxyl compounds ranging from dicarboxylic, monocarboxylic to aqueous alkali salts of monocarboxylic acids in the presence of fluorine as reagent [38] Like previous studies utilizing fluorine, the reactions gave the mixture of several fluorinated isomers and interfered with the isolation due to the close boiling point of products However, the contribution of this work is to elucidate the ionic mechanism of the fluorination of carboxylic acids by fluorine As this work, fluorine would react with carboxylic anions in aqueous solution

to furnish acyl hypofluorites, followed by the decomposition of acyl hypofluorites into alkyl fluorides and carbon dioxide (Scheme 1.10)

Scheme 1.10 Fluorination of carboxylic acids using fluorine as reagent [38]

1.1.2 Nucleophilic Fluorination

In general, nucleophilic fluorination have had a wide application and also been a quite efficient approach for the C-F formation from a large number of organic molecules There are a lot of nucleophilic fluorinating reagents used in fluorination reactions, ranging from earlier reagents such as fluoride ion, tetraalkylamonium fluorides and stable solutions of HF with amines to more fashionalbe nucleophilic fluorinating reagents including diethylaminosulfur trifluoride (DAST), bis(2-methoxyethyl)-

aminosulfur trifluoride (Deoxofluor) and 4-tert-butyl-2,6-dimethylphenylsulfur

trifluoride (Fluolead)

Figure 1.4 Some nucleophilic fluorinating reagents used in fluorination reactions [5]

The usage of fluoride ion faced the challenges of poor solubility associated with the dual reactivity as a nucleophile and a base, which resulted in the unselective reactions and limited substrate scope [5] Therefore, the developments of novel nucleophilic fluorinating reagents have been crucial for the nucleophilic fluorination

To the transition metal catalyzed fluorination, the choice of fluorinating reagents is likely important to proceed since the best outcome may be afforded by the use of a

direct fluoride ion source or by the slow fluoride release in solution from a neutral reagent (Figure 1.4) [5]

Typically, a nucleophilic fluorination of alcohols using Diethylaminosulfur trifluoride (DAST) as reagent was developed The deoxyfluorination occurred via the formation

of alcohol-DAST complexes followed by the electron transfer and the attack of fluoride anion on the C-O bond to generate desired products in good to excellent yield (Scheme 1.11) [39]

Scheme 1.11 Nucleophilic fluorination using DAST as fluorinating reagent [39]

Transition metal catalysis has also attracted a lot of attention from the researching groups due to their reactivity and selectivity catalysis for the both C(sp2)-F and C(sp3)-

F construction in a variety of organic molecules In which, palladium was the first transition metal used for catalyzed nucleophilic fluorination and now is still utilizing for current interests in this approach

The formation of C(sp2)-F bond has encountered the harsh reaction conditions and the requisite of substrates bearing electron-withdrawing groups, which facilitates the nucleophilic substitution (SN) To use transition metal as catalyst for nucleophilic fluorination, the generation of products faces the challenge of high barrier of Ar-F bond formation and transition metal based intermediates generated in the reaction may afford side products in reductive elimination as well [40, 41]

Among transition metals used for nucleophilic fluorination, researchers have turned much attention to palladium as the efficient, selective catalyst for a number of

nucleophilic reactions For example, Watson and co-workers conducted the catalyzed fluorination of aryl halides or sulfonates with a nucleophilic fluorine source

metal-to obtain the corresponding desired products accompanied with functional group tolerance and wide substrate scope This transformation was carried out in the presence of ligand and occurred via the generation of [LPd(II)Ar(F)] complexes (L is a biaryl monophosphine ligand) followed by the reductive elimination to yield aryl fluorides (Scheme 1.12) [40]

Scheme 1.12 The aryl fluoride formation via palladium-catalyzed fluorination [40]

Nucleophilic fluorination of aromatic carbon centers using copper as inexpensive, available catalyst has developed recent years Ribas group used copper as catalyst for the transformation of aryl halides to obtain the aryl-F bond formation in good to excellent yield with the presence of AgF as a nucleophilic fluorine source The reaction was proved to occur via three steps including oxidative addition Cu(I) to Cu(III) complexes into an aryl halides, exchange of halides by fluorine and reductive eliminations to generate desired corresponding products (Scheme 1.13) [42]

Scheme 1.13 Copper-catalyzed aryl-F formation with AgF [42]

Following the study of Ribas group, Fier and co-workers conducted the conversion of aryl iodides into aryl fluoride in the presence of (tBuCN)2CuOTf and AgF in DMF as medium They proved that a diversity of aryl iodides can be fluorinated to obtain desired products by the usage of copper and cyanide complexes Although most products was generated in moderate yield, the functional group tolerance exhibited in this work showed that copper is the suitable catalyst for this transformation (Scheme 1.14) [43]

Scheme 1.14 Fluorination of Aryl Iodides with (tBuCN)2CuOTf and AgF [43]

Nucleophilic fluorination of sp3 carbon centers attracted much attention long time ago, and now are still a challenge in fluorination chemistry Most common reactions conducted to yield desired products employing DAST as fluorine source without the presence of catalysts However, transition metal catalysts have been utilized much recent years for a efficient, selective methodology in nucleophilic way

Scheme 1.15 The C-F bond formation from cyclic allylic chlorides using Pd(0) as

catalyst [44]

The readily enantioselective fluorination of available cyclic allylic chlorides was carried out using Pd(0) as catalyst and Trost bisphosphine ligand with the presence of AgF as fluoride source in THF as medium This transfromation was hypothesized that C-F bond formation could be generated by the nucleophilic attack of fluoride on an electrophilic Pd(II)-allyl intermediate (Scheme 1.15) [44]

Transition metal catalyzed nucleophilic fluorination of benzyl and alkyl halides were performed Iridium(III) complex was synthesized and used to introduce fluorine into organic halides in good yields (Scheme 1.16) [45]

Scheme 1.16 Iridium-catalyzed fluorination of organic halides [45]

Manganese was also reported as catalyst for the oxidative C-H fluorination which was described by Grooves et al They synthesized the MnIII(TMP)Cl complex used as the transition metal catalyst for the conversion of C-H bond to C-F bond in the presence of AgF and TBAF However, this transformation faced the limitation of substrate scope and functional group tolerance as well (Scheme 1.17) [46]

Scheme 1.17 Manganese catalyzed nucleophilic fluorination of C(sp3)-H bond [46]

1.1.3 Radical Fluorination

Radical fluorination of organic molecules has attracted much attention recent years due to its efficiency that showed the compatibility with a variety of functional groups Compared to two kinds of fluorination mentioned above, radical fluorination is of a prominent feature of simple, convenient, and low temperature procedures including no use of exogenous ligands for metal complex formation In this kind of fluorination, C-

F bond formation is generated by the combination between an alkyl radical and radical fluorine source (Scheme 1.18) [47]

Scheme 1.18 The radical fluorination pathway [47]

The radical pathway in fluorination was early uncovered in the studies of Musher [48] and Gregorcic [49], depicting the formation of xenon ester prior to generating the radicals Notable investigations in this way focused on the fluorodecaroxylation of aliphatic acids with xenondifluoride XeF2, where the radical pathway was depicted via the single electron transfer SET in situ [13, 50-53] The side reactions were the rearrangement and cyclization (Scheme 1.19)

Scheme 1.19 The fluorodecarboxylation of aliphatic acids under XeF2 [50-53]

Recent novel approaches in this pathway demonstrated that some N-fluoro reagents might play the role of either fluoride cation (F+) or radical fluorine (F*) That is owing

to the N-F homolytic bond dissociation energy DNF in the certain fluorinated reagent Calculated energies proved the similar homolytic bond dissociation properties in SelectFluor and NFSI that do not depend upon the dielectric feature of the medium [54]

Scheme 1.20 Photo-fluorodecarboxylation of 2-aryloxy and 2-aryl carboxylic acids [55]

To illustrate, a photo-fluorodecarboxylation of 2-aryloxy and 2-aryl carboxylic acids was developed This reaction was conducted under the irradiation of 300nm light in either the mixture of CH3CN and H2O or H2O as solvent and SelectFluor (F-TEDA-

BF4) as radical fluorine source This transformation exhibited the high yield of desired products as well as the wide substrate scope (Scheme 1.20) [55]

The proposed mechanism showed that this reaction occurred via the generation of alkyl radical cation followed by the corporation of atomic fluorine formed by fluorine source (Scheme 1.21) [55]

Scheme 1.21 Radical mechanism of photo-decarboxylation of carboxylic acids [55]

Another specific example of radical fluorination is the silver-catalyzed fluorodecarboxylation of aliphatic acids which proceeded in aqueous solvent and SelectFluor as fluorine transfer source This approach provided a convenient, general, and efficient method for site-specific C(sp3)-F formation Silver nitrate was utilized as transition metal catalyst for this transformation This method was compatible with a variety of aliphatic acids with different substituents on the structure and gave the desired products in high to excellent yield (Scheme 1.22) [56]

Scheme 1.22 Fluorodecarboxylation of aliphatic acids with silver as catalyst [56]

A tentative mechanism of this reaction was also proposed by Li group, in which they assumed that the C-F formation occurred via the silver (II) or silver (III)-mediated decarboxylation [56] However, the following contribution of Patel and co-workers proved the non-existence of the trivalent silver intermediate Ag(III)-F which was attributed to be responsible for the alkyl fluoride formation proposed by Li group According to this study, there were three pathways for the formation of alkyl radical mentioned: 1) the two-electron oxidation of Ag(I) to Ag(III) by SelectFluor, followed

by the oxidation of carboxylic acid by Ag(III) to give an alkyl radical; 2) electron oxidation of Ag(I) to Ag(II) by SelectFluor to afford TEDA-BF4 radical cation which oxidized the carboxylic acid to yield an alkyl radical, Ag(I) herein played

single-as an initiator; 3) the single-electron oxidation of Ag(I) to Ag(II) by SelectFluor to generate TEDA-BF4 radical cation, followed by the oxidation of carboxylic acid by Ag(II) to give alkyl radical (Scheme 1.23) [57]

Scheme 1.23 Three pathways hypothesized for the formation of alkyl radical [57]

By a number of experiments, the plausible mechanism of fluorodecarboxylation of aliphatic acids was cleared In the first hypothesis, Ag(III) are completely capable of oxidizing carboxylic acid to give alkyl radical, but Ag(III) complexes call for specific ligands such as biguanidines, carbaporphyrins, and N-heterocyclic carbenes or its generation occurred under the basic conditions, that generaly means it needs the medium providing enough electron density to stabilize itself Moreover, several investigations proved that reduction of Ag(III) to Ag(I) is typically a one-step, two-electron oxidation Due to above evidences, it is unlikely that Ag(III) complex results

in the formation of alkyl radical

In the second hypothesis, many articles using SelectFluor as a fluorine source proposed the formation of TEDA-BF4 radical cation as an intermediate Experiments conducted to probe the role of TEDA-BF4 radical cation in the generation of alkyl radical through the oxidation reaction of carboxylic acid showed that no desired product was observed, and this outcome proves that TEDA-BF4 radical cation did not join the oxidation to yield alkyl radical

The last pathway was also demonstrated to discover which was responsible for the alkyl radical generation Several experiments were carried out, in which the addition of

Na2S2O8, which oxidized Ag(I) to Ag(II), into the reaction accelerated the reaction rate Furthermore, kinetic studies proved that AgNO3 and Na2S2O8 were consistent with a first order dependence whereas the carboxylic acid and SelectFluor were zero-order dependence The generation of Ag(II) by persulfate accompanied by the zero-order rate dependence on SelectFluor obviously confirmed that Ag(II), not TEDA radical cation, was the oxidant affording the alkyl radical in this reaction

1.2 Introduction of trifluoromethyl group (CF 3 group) into organic compounds

Trifluoromethyl group is significantly different from methyl group over chemical properties To illustrate, the methylation reaction of Grignards is rather facilely done and they can be reacted with ketones to form tertiary alcohols in excellent yields On the contrary, to the same conditions, trifluoromethylation of them furnished low

transformation of unstable Grignards and their reaction with ketones generated low yield trifluoromethylated alcohols due to the concomitant formation of sideproducts (Scheme 1.24) [58-60]

Scheme 1.24 The difference between methyl group and trifluoromethyl group [58-60]

The early trifluoromethylation was developed by Swarts in 1892, which employing SbF5 as fluorine transfer reagent to access benzotrifluoride from benzotrichloride [61] The reaction under the harsh conditions witnessed several sideproducts due to steps to replace chlorides by fluorides In 1968, McLoughlin and Thrower first conducted the fluoroalkylation of iodoaromatic compounds to afford fluoroalkylaromatic ones under the interaction of perfluoroalkylhalides (RfX) as nucleophilic reagent and copper, generating fluoroalkylcopper intermediate [62] The low yield and limited substrate scope are the disadvantages of this method, but the discovery of fluoroalkyl copper intermediate in this transformation became seminal to date (Scheme 1.25)

Scheme 1.25 Route via fluoroalkylcopper intermediate by McLoughlin and Thrower [62]

Previous studies set forth various approaches to introduce the trifluoromethyl group into organomolecules Like methods for fluorination, the developed tools for

trifluoromethylation of organic molecules employed numerous reagents to attach CF3group to different substrates The problems of group tolerance and the selectivity still remain in these reactions In this part, we categorize the developed methods into three major groups according to the corresponding mechanism, as following:

1.2.1 Electrophilic trifluoromethylation

The electrophilic trifluoromethylating reagents widely used in trifluoromethylation reactions are hypervalent iodonium salts (Togni’s reagents) and sunfonium salts (Umemoto’s reagents) The early development of iodonium salt was conducted by Yagupolski et al [63] and was extensively studied by Umemoto and co-workers, who showed that (perfluoroalkyl)-phenyliodonium triflates (Figure 1.5, reagent 1) were the unrivalled equivalent of Rf+ and they were applied to the syntheses of various nucleophiles such as carbanions, enolates, alkenes, silyl enol ethers, aromatics [64]

Figure 1.5 Hypervalent iodine perfluoroalkyl reagents [63-67]

However, the development had one drawback until recentlly: the failure in the preparation of trifluoromethyl aryliodonium salts, possibly due to the instability of synthetic intermediate [65]

The successful preparation of stable trifluoromethyl phenyliodonium salts were discovered by Togni and co-workers, who also successfully prepared various classes

of hypervalent iodine derivatives, and those reagents have been commonly employed since the first application, especially reagent 2 and 3 (Figure 1.5, reagents 2-8) [66, 67]

Scheme 1.26 Reactivity of alcohol Togni’s reagent 3 via various examples [65]

Reagent 3 is considered as alcohol CF3-reagent, which is much better soluble in

organic solvents than reagent 2 Its reactivity was firstly evaluated with cyclic β-keto

esters and α-nitro esters in the presence of CuCl as catalyst under mild conditions to form corresponding α-trifluoromethylated esters in moderate to high yields However, The reaction faced the complicated handling, expensive agents, hard isolation of products and limited substrate scope (Scheme 1.26, reaction 1 and 2) [68]

A variety of arenes and N-heteroarenes reacted with reagent 3 to form desired products

with the attachment of CF3 group into the position adjacent to nitrogen or activated groups on the benzene ring (Scheme 1.26, reaction 3 and 4) Additives such as zinc bis(trifluoromethylsulfonyl)imide or tris(trimethylsilyl)silyl chloride are necessary for some substrates [69] This protocol described a wide range of substrates, but the low yields and low selectivity were the main disadvantages in this reaction

Ritter-type trifluoromethylation of azoles using reagent 3 under the catalysis of HNTf2

was described (Scheme 1.26, reaction 5) [70] The reaction exhibited the suitability with a number of substituted groups on starting materials, and was the first development for the direct coupling of nitrogen and CF3, affording the desired products in moderate yields However, the generation of various byproducts lowered the selectivity of the method

In the effort of trifluoromethylating the S-hydrogen phosphorothioates, Togni and

co-workers conducted the reaction with the presence of reagent 3 in CDCl3 at room temperature [71] This method gave the desired products in moderate yields, exhibited the compatibility with alkyl groups and oppositely with alkylchloro groups on phosphorothioates Nevertheless, the reaction required extra steps, complicated handling (Scheme 1.26, reaction 6)

MacMillan and co-workers described the enantioselective trifluoromethylation of aldehydes to liberate enantioenriched α-formyl trifluoromethylated products in the productive merger of imidazolidinone and Lewis acids CuCl The approach allowed

to afford the desired products in high yield of 70 to 87% and high enantioselective excess (ee) of ca 97% (Scheme 1.26, reaction 7) [72]

Furthermore, the primary and secondary aryl and alkylphosphanes reacted with

reagent 3 to give the desired products in moderate to good yields under direct, mild

and readily conditions The limited range of substrates and the low yield are the limitations of this protocol However, the method allowed the preparation of trifluoromethylphosphanes bond to ferrocenyl cores which are the ligands for transition metals in a number of oxidation reactions (Scheme 1.26, reaction 8) [65, 68]

Scheme 1.27 The low yields in trifluoromethylation of phenols using reagent 2 [73]

Similar to reagent 3, acid CF3-reagent 2 has been widely employed in several

approaches for O-trifluoromethylation of various organic compounds The earliest study was the trifluoromethylation of phenols which formed the desired products in very low yields (Scheme 1.27) [73]

Scheme 1.28 Reactivity of acid CF3-reagent 2 via various examples [65]

Although the failure in O-trifluoromethylation of phenols, reagent 2 has shown the

efficiency in trifluoromethylation of aliphatic alcohols in the presence of the zinc (II) salt [74], sulfonic acids in the presence of strong Bronsted acid [75] (Scheme 1.28)[65]

Togni’s reagent 2 was also employed to attach CF3 synthon to unactivated terminal olefins, described by Buchwald group They successfully synthesized the organic molecules containing allylic CF3 functional group in moderate to good yield utilizing catalyst of copper (I) The mechanism was also probed, yet the details in the transformation was not elucidated despite numerous studies were conducted They generally surmised that the trifluoromethylation hurdled complex pathways and the further efforts must be done to clarify the mechanism (Scheme 1.29) [76]

Scheme 1.29 Copper (I) catalyzed-allylic trifluoromethylation of unactivated olefins [76]

Another popular electrophilic CF3 reagent used in the trifluoromethylation of organic frameworks is Yagupolski-Umemoto’s reagent, which early discovered by Yagupolski and developed by Shreeve et al and Umemoto et al They are considered as the