Transition metal free synthesis and functionalization of 5 and 6 membered heterocyclic compounds

VIETNAM NATIONAL UNIVERSITY HO CHI MINH CITY HO CHI MINH CITY UNIVERSITY OF TECHNOLOGY HUYNH VAN TIEN TRANSITION METAL-FREE SYNTHESIS AND FUNCTIONALIZATION OF 5- AND 6-MEMBERED HETEROCYCLIC COMPOUNDS Ph.D THESIS HO CHI MINH CITY - 2023 VIETNAM NATIONAL UNIVERSITY HO CHI MINH CITY HO CHI MINH CITY UNIVERSITY OF TECHNOLOGY HUYNH VAN TIEN TRANSITION METAL-FREE SYNTHESIS AND FUNCTIONALIZATION OF 5- AND 6-MEMBERED HETEROCYCLIC COMPOUNDS Major: Chemical engineering Code: 9520301 Independent examiner: Assoc Prof Dr Pham Nguyen Kim Tuyen Independent examiner: Assoc Prof Dr Tran Ngoc Quyen Examiner: Assoc Prof Dr Hoang Thi Kim Dung Examiner: Assoc Prof Dr Nguyen Phuong Tung Examiner: Assoc Prof Dr Le Thi Hong Nhan Supervisor: Prof Dr Phan Thanh Son Nam DECLARATION OF ORIGINALITY I understand the University’s policy I hereby declare that this thesis is my original research work and has not been submitted or considered for publication elsewhere I have not sought or used the services of any professional agencies to produce this work All sources used in this thesis are clearly and fully referenced in the text and references, following the referencing title indicated by the Department Dissertation author Huynh Van Tien i ABSTRACT This thesis gave new methods to synthesize 4-phenylquinazolines, 2-arylquinoxalines, N-arylindoles, and thiocromenones The formation of 4-phenylquinazolines was performed through the oxidation protocol, in which the organic peroxide was used as an oxidant that could readily generate 4-phenylquinazolines from 2-aminobenzophenones without any additional catalyst The reactions between o-phenylenediamines and phenylglyoxal derivatives in ethyl acetate to form 2-phenylquinoxalines gave excellent yields at room temperature without using the catalyst N-arylindoles were easily obtained from indoles and nitrobenzene in the absence of transition metals, at room temperature, under simple base conditions And thiocomenones were generated via a two-step one-pot protocol, in which the condensation of 2’-chloroacetophenones and aryl aldehydes formed 2’-chlorochalcone intermediates, which were then cyclized to thiocromenones by adding elemental sulfur The utilities of this thesis were (1) transition metal-free catalyst, (2) inexpensive and abundant additivities source, (3) different syntheses of heterocyclic compounds from commercially available starting materials This thesis has contributed new methods in organic synthesis and could be applied to chemical and pharmaceutical industries ii TÓM TẮT Luận án đưa phương pháp để tổng hợp dẫn xuất 4-phenylquinazoline, 2-arylquinoxaline, N-arylindole thiocromenone Các dẫn xuất 4-phenylquinazoline tổng hợp thơng qua q trình oxy hóa, peroxide hữu đóng vai trị chất oxy hóa để dễ dàng chuyển hóa dẫn xuất 2-aminobenzophenone thành sản phẩm mong muốn mà không cần sử dụng xúc tác kim loại Trong luận án này, dẫn xuất 2-phenylquinoxaline tổng hợp thông qua phản ứng ngưng tụ dẫn xuất o-phenylenediamine dẫn xuất phenylglyoxal dung mơi ethyl acetate nhiệt độ phịng thời gian ngắn đạt hiệu suất cao mà không cần thêm điều kiện khác Luận án đưa quy trình tổng hợp dẫn xuất N-arylindole từ dẫn xuất indole nitrobenzene điều kiện nhiệt độ phòng, sử dụng bazơ đơn giản NaOH không sử dụng xúc tác Đặc biệt, lần quy trình hai bước, sử dụng trực tiếp lưu huỳnh nguyên tố để tổng hợp dẫn xuất thiocromenone luận án đưa ra, bước phản ứng ngưng tụ dẫn xuất dẫn xuất 2’-chloroacetophenone với dẫn xuất benzaldehyde để hình thành sản phẩm trung gian dẫn xuất 2’-chlorochalcone, dẫn xuất sau tiếp tục thực trình oxy hóa đóng vịng thành thiocromenone thực bước hai thêm lưu huỳnh nguyên tố vào Điểm bật luận án (1) không sử dụng xúc tác kim loại chuyển tiếp, (2) sử dụng nguồn xúc tác, phụ gia phong phú, rẻ tiền, (3) tổng hợp nhiều hợp chất dị vòng khác từ nguyên liệu ban đầu phổ biến thị trường Luận án đóng góp phương pháp tổng hợp hữu có triển vọng ứng dụng lĩnh vực hóa học, dược phẩm iii ACKNOWLEDGMENT I would like to express my gratitude to the lecturers of Ho Chi Minh City University of Technology, especially Prof Dr Phan Thanh Son Nam and Dr Nguyen Thanh Tung who guided me throughout the time of studying and writing my doctoral thesis I would like to thank all members of The Materials Structure Research Laboratory of Ho Chi Minh City University of Technology, who have supported me while I the thesis Thanks to my lovely students of Department of Chemical Engineering of Ho Chi Minh City University of Technology and students from the Faculty of Chemical Technology of Ho Chi Minh City University of Food Industry for their full co-operation in my research Thanks to the Board of Directors and my partners at Ho Chi Minh City University of Food Industry who have facilitated me during I complete my graduate studies Thanks so much to my family and friends who have shared and encouraged me to overcome all the disadvantages to complete my doctoral thesis In the wealth of knowledge, I certainly will not completely satisfy all the readers I would like to receive the suggestions of readers to help me improve my knowledge Sincerely, Huynh Van Tien iv TABLE OF CONTENTS TABLE OF CONTENTS v LIST OF TABLES vii LIST OF SCHEMES viii LIST OF FIGURES xi LIST OF ABBREVIATIONS xii INTRODUCTION CHAPTER LITERATURE OVERVIEWS 1.1 Introduction of quinazoline compounds 1.1.1 Biological activity of the quinazoline compounds 1.1.2 Synthetic approaches to quinazoline derivatives 1.2 Introduction of quinoxaline compounds 1.2.1 Biological activity of quinoxaline compounds 1.2.2 Synthetic approaches to quinoxaline derivatives 1.3 Introduction of N-arylindole compounds 15 1.3.1 Biological activity of the N-arylindole compounds 15 1.3.2 Synthetic approaches to N-arylindole derivatives 16 1.4 Introduction of thiocromenone compounds 23 1.4.1 Biological activities of thiocromenone compounds 23 1.4.2 Synthetic approaches to thiocromenone derivatives 24 1.5 Aims of this work 31 CHAPTER EXPERIMENTALS 34 2.1 Materials and Instruments 34 2.1.1 Materials 34 2.1.2 Instruments 37 2.2 Experimental procedures 38 2.2.1 General procedure for the synthesis of 4-phenylquinazoline 38 2.2.2 General procedure for the synthesis of 2-phenylquinoxaline 39 v 2.2.3 General procedure for the synthesis of 1-(4-nitrophenyl)-1H-indole 39 2.2.4 General procedure for the synthesis of 2-phenyl-4H-thiochromen-4-one 40 CHAPTER RESULTS AND DISCUSSIONS 42 3.1 Synthesis of quinazoline derivatives via peroxide-mediated direct oxidative amination of C(sp3)-H bonds 42 3.2 Condensation of 1,2-phenylenediamines and dicarbonyl compounds in ethyl acetate toward quinoxalines 58 3.3 Oxidative nucleophilic functionalization of nitrobenzene with N-H bond to synthesize 1-(4-nitrophenyl)-1H-indoles 63 3.4 Elemental sulfur for the synthesis of 2-arylthiochromenones 78 CONCLUSIONS 88 LIST OF PUBLICATIONS 91 REFERENCES 92 APPENDICES 106 vi LIST OF TABLES Table 2.1 List of chemicals and their manufacturers 34 Table 3.1 Effect of oxidizing agents on the synthesis of 4-phenylquinazoline 43 Table 3.2 Effect of oxidant amount on the synthesis of 4-phenylquinazoline 44 Table 3.3 Effect of nitrogen sources on the synthesis of 4-phenylquinazoline 45 Table 3.4 Effect of nitrogen source amount on the synthesis of 4-phenylquinazoline 47 Table 3.5 Effect of temperature on the synthesis of 4-phenylquinazoline 48 Table 3.6 Synthesis of 4-phenylquinazolines via the three-component coupling reaction utilizing different sp3 carbon sourcesa 53 Table 3.7 Screening reaction conditionsa of the condensation of 1,2-phenylenediamine and phenylglyoxal toward 2-phenylquinoxaline 58 Table 3.8 Effect of temperature on the synthesis of 1-(4-nitrophenyl)-1H-indole 64 Table 3.9 Effect of reactant mole proportion on the synthesis of 1-(4-nitrophenyl)-1Hindole 65 Table 3.10 Effect of bases on the synthesis of 1-(4-nitrophenyl)-1H-indole 66 Table 3.11 Effect of base amount on the synthesis of 1-(4-nitrophenyl)-1H-indole 68 Table 3.12 Effect of solvents on the synthesis of 1-(4-nitrophenyl)-1H-indole 69 Table 3.13 Effect of concentration of starting materials on the synthesis of 1-(4nitrophenyl)-1H-indole 70 Table 3.14 Effect of reaction environments on the synthesis of 1-(4-nitrophenyl)-1Hindole 71 Table 3.15 Effect of time on the synthesis of 1-(4-nitrophenyl)-1H-indole 72 Table 3.16 Expanding the scope of reaction of indole and nitrobenzene 74 Table 3.17 Effect of solvents on the synthesis of 2-arylthiocromenone 79 Table 3.18 Effect of water on the synthesis of 2-arylthiocromenone 81 Table 3.19 Effect of amount of DMF on the synthesis of 2-arylthiocromenone 82 Table 3.20 Effect of reaction time on the synthesis of 2-arylthiocromenone 83 vii LIST OF SCHEMES Scheme 1.1 Synthesis of 2-phenylquinazolines via a tandem reaction following sp3 C-H functionalization Scheme 1.2 Synthesis of 2-arylquinazolines via benzylic sp3 C–H bond amination catalyzed by molecular iodine Scheme 1.3 Synthesis of quinazoline derivatives catalyzed by Ni-catalyst Scheme 1.4 Synthesis of quinazoline derivatives via sequential Ullmann-type coupling and aerobic oxidation Scheme 1.5 Synthesis of quinazoline derivatives via I2/KI-promoted oxidative C(sp3)C(sp2) bond formation Scheme 1.6 Synthesis of 4-phenylquinazoline via direct sp3 C-H bond functionalization Scheme 1.7 The common approaches for the synthesis of quinoxaline derivatives 10 Scheme 1.8 Synthesis of quinoxaline derivatives by using PEG solvent 11 Scheme 1.9 Synthesis of quinoxaline derivatives by using microwave 11 Scheme 1.10 Synthesis of quinoxalines from α-haloketones by using K10 clay catalyst 12 Scheme 1.11 Synthesis of quinoxaline derivatives from α-hydroxyketones 12 Scheme 1.12 Synthesis of quinoxaline derivatives from epoxides 13 Scheme 1.13 Synthesis of quinoxaline derivatives from epoxy ketones 13 Scheme 1.14 Synthesis of quinoxaline derivatives from alkenes 14 Scheme 1.15 Synthesis of quinoxaline derivatives from nitroolefins 14 Scheme 1.16 Nucleophilic substitution of p-Chloronitrobenzene 16 Scheme 1.17 A two-step synthesis of 2-nitrodiarylamines 17 Scheme 1.18 Formation of 2-nitrodiarylamines by the reaction of anilines and nitroarenes 18 Scheme 1.19 Direct methoxylation of nitroarenes 18 Scheme 1.20 Oxidative nucleophilic alkoxylation of nitrobenzenes 19 Scheme 1.21 Palladium-catalyzed coupling indoles and halogen-substituted arenes 20 Scheme 1.22 Copper-catalyzed coupling indoles and halogen-substituted arenes 20 Scheme 1.23 N-Arylation of indoles and N-(naphthalene-1-yl)picolinamide 21 viii