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

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 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: Prof Dr Phan Thanh Sơn Nam Dr Trương Vũ Thanh 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 i TÓM TẮT LUẬN ÁN Các hợp chất chứa hay nhiều ngun tử flo phân tử có tính chất đặc biệt hình thành kích thước nhỏ độ âm điện cao flo Sự có mặt flo phân tử hợp chất làm tăng độ âm điện, tính ưa mỡ, độ ổn định sinh học hợp chất chứa đặc biệt tăng hoạt tính sinh học chúng Do vậy, hợp chất chứa flo sử dụng ngày nhiều hóa nơng, hóa dược nhiều loại vật liệu Ngoài ra, hợp chất chứa đồng vị flo 18 (18F) sử dụng rộng rãi kỹ thuật Positron Emission Tomography (PET) ứng dụng y học Chính vậy, nhiều cơng trình nghiên cứu nhà khoa học giới thực để tìm phương pháp khác tổng hợp hợp chất chứa flo Tuy nhiên, đặc điểm hoạt tính hóa học mạnh flo mà phản ứng tổng hợp có nhược điểm như: sinh nhiều sản phẩm phụ, điều kiện phản ứng khắc nghiệt, sử dụng chất phản ứng xúc tác đắt tiền phạm vi chất hẹp, v.v Hơn nữa, tất phản ứng lĩnh vực hóa học flo công bố trước sử dụng kim loại chuyển tiếp làm xúc tác đồng thể sử dụng chất phụ trợ hệ đồng thể, chưa có cơng trình nghiên cứu thực sử dụng kim loại chuyển tiếp làm chất xúc tác dị thể, góp phần vào việc tăng khả tái sử dụng tiết kiệm chi phí (dựa tìm hiểu nhóm nghiên cứu tìm kiếm SciFinder tính đến tháng năm 2018) Với phát triển mạnh mẽ từ ứng dụng hợp chất hữu kim loại MOFs hạt nano (nanoparticles), nghiên cứu tổng hợp sử dụng MOFs Cu(INA)2 hạt nano delafossite AgFeO2 làm xúc tác cho phản ứng gắn nhóm -CF3 (trifluoromethylation) gắn flo (fluorination) - phản ứng nghiên cứu phổ biến Kết khẳng định tổng hợp thành công MOFs Cu(INA)2 hạt nano AgFeO2 với đặc tính trùng khớp với nghiên cứu trước Việc sử dụng chúng vào phản ứng flo hóa mang lại kết mong đợi thể hiệu suất phản ứng cho đa số chất khác cho kết cao cao Hơn nữa, xúc tác sử dụng thu hồi sử dụng lại nhiều lần mà khơng có giảm đáng kể hiệu suất phản ứng phá vỡ cấu trúc tinh thể xúc tác Những kết khẳng định thành công đề tài nghiên cứu sử dụng xúc tác dị thể tâm kim loại chuyển tiếp lĩnh vực hóa học flo ii 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 iii 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 iv 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 Chapter : LITERATURE REVIEW 1.1 Introduction of fluorine into organic scaffolds 1.1.1 Electrophilic Fluorination 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 : EXPERIMENTAL 41 2.1 Materials and instrumentation 41 v 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 : 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 vi 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 vii LIST OF FIGURES Figure 1.1 Some popular drugs containing fluorines [9] Figure 1.2 Naturally occuring fluorinated compounds [10] Figure 1.3 Some common N-fluoro reagent classes as fluorine sources [14-17] 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-1,1diyl)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 viii Figure S 33 EI-MS spectrum of 2,4-dichloro-1-(fluoromethoxy)benzene 153 Figure S 34 1H-NMR spectrum of 2,4-dichloro-1-(fluoromethoxy)benzene 154 Figure S 35 13C-NMR spectrum of 2,4-dichloro-1-(fluoromethoxy)benzene Characterization data for 2,4-dichloro-1-(fluoromethoxy)benzene [51] Prepared as shown in the general experimental procedure in section 2.4.2 and purified on silica gel (hexane:ethylacetate = 20:1 v/v): yellow oil, 93% yield 1H NMR (500 MHz, CDCl3) δ (ppm) 7.39 (d, J = 2.5 Hz, 1H), 7.20 (m, J = 9.0, 2.5 Hz, 1H), 7.12 (d, J = Hz, 1H), 5.70 (d, J = Hz, 2H) m/z = 194 (GC-MS, EI) 155 Figure S 36 The EI-MS spectrum of 1-bromo-2-(fluoromethoxy)benzene 156 Figure S 37 1H-NMR spectrum of 1-bromo-2-(fluoromethoxy)benzene 157 Figure S 38 13C-NMR spectrum of 1-bromo-2-(fluoromethoxy)benzene Characterization data for 1-bromo-2-(fluoromethoxy)benzene Prepared as shown in the general experimental procedure in section 2.4.2 and purified on silica gel (hexane:ethylacetate = 25:1 v/v): yellow oil, 80% yield 1H NMR (500 MHz, CDCl3) δ (ppm) 7.58 (d, J = 8.0 Hz, 1H), 7.29 (t, J = 8.0 Hz, 1H), 7.18 (d, J = 8.0 Hz, 1H), 6.99 (t, J = 8.0 Hz, 1H), 5.73 (d, J = Hz, 2H) m/z = 204 (GC-MS, EI) 158 Figure S 39 The EI-MS spectrum of 1-(4-(fluoromethoxy)phenyl)ethan-1-one 159 Figure S 40 1H-NMR spectrum of 1-(4-(fluoromethoxy)phenyl)ethan-1-one 160 Figure S 41 13C-NMR spectrum of 1-(4-(fluoromethoxy)phenyl)ethan-1-one Characterization data for 1-(4-(fluoromethoxy)phenyl)ethan-1-one Prepared as shown in the general experimental procedure in section 2.4.2 and purified on silica gel (hexane:ethylacetate = 25:1 v/v): colorless oil, 82% yield 1H NMR (500 MHz, CDCl3) δ (ppm) 7.90 (d, J = 9.0 Hz, 2H), 7.01 (d, J = 9.0 Hz, 2H), 5.75 (d, J = 54.0 Hz, 2H), 2.52 (s, 3H) m/z = 168 (GC-MS, EI) 161 Figure S 42 EI-MS spectrum of 1-fluoroadamantane 162 Figure S 43 1H-NMR spectrum of 1-fluoroadamantane Characterization data for 1-fluoroadamantane [56, 213] Prepared as shown in the general experimental procedure in section 2.4.2 and purified on silica gel (hexane:dichloromethane = 25:1 v/v): white solid, 41% yield 1H NMR (500 MHz, CDCl3) δ (ppm) 2.23 (brs, 3H), 1.88 (m, 6H), 1.62 (m, 6H) 163 Figure S 44 EI-MS spectrum of 1,3-difluoroadamantane 164 Figure S 45 1H-NMR spectrum of 1,3-difluoroadamantane 165 Figure S 46 13C-NMR of 1,3-difluoroadamantane Characterization data for 1,3-difluoroadamantane [213] Prepared as shown in the general experimental procedure in section 2.4.2 and purified on silica gel (hexane:dichloromethane = 25:1 v/v): white solid, 63% yield 1H NMR (500 MHz, CDCl3) δ (ppm) 2.42 (brs, 2H), 2.08 (t, J = 5.5 Hz, 2H), 1.82 (brs, 8H), 1.49 (brs, 2H) 166 Figure S 47 The GC spectra of the optimal conditions for the fluorination of 3,3diphenylpropionic acid: (a) without TEMPO; (b) with TEMPO (the fluorinated product was the peak of 5.2 min.) 167 ... UNIVERSITY OF TECHNOLOGY &&*&& NGUYỄN VĂN TÚ INTRODUCING FLUORINE AND TRIFLUOROMETHYL GROUP INTO ORGANIC COMPOUNDS UNDER HETEROGENEOUS TRANSITION METAL CATALYSIS Major: Chemical Engineering Major... 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... to furnish fluorine containing compounds employing readily, inexpensive and effective methods under heterogeneous transition metal catalysis Moreover, the wide scope and functional group tolerance